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Entry
- #607948 - MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO
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<span class="h4">#607948</span>
<br />
<strong>Table of Contents</strong>
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<li role="presentation">
<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<li role="presentation">
<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#pathogenesis">Pathogenesis</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#diagnosis">Diagnosis</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#inheritance">Inheritance</a>
</li>
<li role="presentation" style="margin-left: 1em">
<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
<a href="#animalModel">Animal Model</a>
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<li role="presentation">
<a href="#references"><strong>References</strong></a>
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<li role="presentation">
<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
<a href="#creationDate"><strong>Creation Date</strong></a>
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9660;</div>
&nbsp;
<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=(MYCOBACTERIUM TUBERCULOSIS) OR (SP110 OR CISH OR CD209 OR NRAMP1 OR IFNG OR TLR2 OR TIRAP OR IFNGR1 OR CCL2 OR IRGM)" class="mim-tip-hint" title="Clinical Trials" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=863&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607948[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=3389" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">&#9658;</div>
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<div style="display: table-cell;">Animal Models</div>
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<div><a href="https://omia.org/OMIA001856/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div>
<a id="title" class="mim-anchor"></a>
<div>
<a id="number" class="mim-anchor"></a>
<div class="text-right">
<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
<strong>ORPHA:</strong> 3389<br />
">ICD+</a>
</div>
<div>
<span class="h3">
<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
<span class="text-danger"><strong>#</strong></span>
607948
</span>
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<div>
<a id="preferredTitle" class="mim-anchor"></a>
<h3>
<span class="mim-font">
MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO
</span>
</h3>
</div>
<div>
<br />
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<div>
<a id="includedTitles" class="mim-anchor"></a>
<div>
<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
</p>
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<div>
<span class="h3 mim-font">
MYCOBACTERIUM TUBERCULOSIS, PROTECTION AGAINST, INCLUDED
</span>
</div>
</div>
<div>
<br />
</div>
</div>
<div>
<a id="phenotypeMap" class="mim-anchor"></a>
<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1006?start=-3&limit=10&highlight=1006">
2q35
</a>
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to infection by}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
NRAMP1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/600266"> 600266 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/2/1087?start=-3&limit=10&highlight=1087">
2q37.1
</a>
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
SP110
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604457"> 604457 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/3/347?start=-3&limit=10&highlight=347">
3p21.2
</a>
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
CISH
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/602441"> 602441 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/4/614?start=-3&limit=10&highlight=614">
4q31.3
</a>
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
TLR2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/603028"> 603028 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/5/677?start=-3&limit=10&highlight=677">
5q33.1
</a>
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, protection against}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
IRGM
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/608212"> 608212 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/893?start=-3&limit=10&highlight=893">
6q23.3
</a>
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
IFNGR1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/107470"> 107470 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/6/893?start=-3&limit=10&highlight=893">
6q23.3
</a>
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis infection, protection against}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
IFNGR1
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/107470"> 107470 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/11/1077?start=-3&limit=10&highlight=1077">
11q24.2
</a>
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, protection against}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
TIRAP
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/606252"> 606252 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/12/598?start=-3&limit=10&highlight=598">
12q15
</a>
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, protection against}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
IFNG
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/147570"> 147570 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/17/405?start=-3&limit=10&highlight=405">
17q12
</a>
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
CCL2
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/158105"> 158105 </a>
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
<a href="/geneMap/19/217?start=-3&limit=10&highlight=217">
19p13.2
</a>
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/607948"> 607948 </a>
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
</span>
</td>
<td>
<span class="mim-font">
CD209
</span>
</td>
<td>
<span class="mim-font">
<a href="/entry/604672"> 604672 </a>
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
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<div>
<a id="text" class="mim-anchor"></a>
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon &lt;span class='glyphicon glyphicon-plus-sign'&gt;&lt;/span&gt at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because susceptibility to Mycobacterium tuberculosis (TB) is associated with variation in many genes. Case-control studies in areas of endemic TB have pointed to variation in the HLA (see <a href="/entry/142800">142800</a>), NRAMP1 (<a href="/entry/600266">600266</a>), vitamin D receptor (VDR; <a href="/entry/601769">601769</a>), mannose-binding protein (MBL2; <a href="/entry/154545">154545</a>), and cytokine-inducible SH2-containing protein (CISH; <a href="/entry/602441">602441</a>) genes as contributing to TB susceptibility (<a href="#33" class="mim-tip-reference" title="Mitsos, L.-M., Cardon, L. R., Ryan, L., LaCourse, R., North, R. J., Gros, P. &lt;strong&gt;Susceptibility to tuberculosis: a locus on mouse chromosome 19 (Trl-4) regulates Mycobacterium tuberculosis replication in the lungs.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 6610-6615, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12740444/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12740444&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12740444[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.1031727100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12740444">Mitsos et al., 2003</a>, <a href="#29" class="mim-tip-reference" title="Khor, C. C., Vannberg, F. O., Chapman, S. J., Guo, H., Wong, S. H., Walley, A. J., Vukcevic, D., Rautanen, A., Mills, T. C., Chang, K.-C., Kam, K.-M., Crampin, A. C., and 23 others. &lt;strong&gt;CISH and susceptibility to infectious diseases.&lt;/strong&gt; New Eng. J. Med. 362: 2092-2101, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20484391/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20484391&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20484391[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa0905606&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20484391">Khor et al., 2010</a>). Variation in the CD209 (<a href="/entry/604672">604672</a>) and MCP1 (CCL2; <a href="/entry/158105">158105</a>) genes is also associated with TB susceptibility. TB susceptibility loci have been mapped to chromosome 2q35 (MTBS1; <a href="/entry/607949">607949</a>), near NRAMP1, and to chromosomes 8q12-q13 (MTBS2; <a href="/entry/611046">611046</a>) and 20q13.31-q33 (MTBS3; <a href="/entry/612929">612929</a>). X-linked susceptibility to TB has also been suggested (MTBSX; <a href="/entry/300259">300259</a>). Protection against TB has been associated with SNPs in the TIRAP (<a href="/entry/606252">606252</a>), IFNG (<a href="/entry/147570">147570</a>), and IFNGR1 (<a href="/entry/107470">107470</a>) genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12740444+20484391" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">&#9660;</span>
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<strong>Description</strong>
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<p>Mycobacterium tuberculosis latently infects approximately one-third of humanity and is comparable only to human immunodeficiency virus (HIV; see <a href="/entry/609423">609423</a>) as a leading infectious cause of mortality worldwide. Obstacles for controlling TB infection include lengthy treatment regimens of 6 to 9 months, drug resistance, lack of a highly efficacious vaccine, and incomplete understanding of the factors that control infectivity and disease progression. Although only 10% of individuals infected with M. tuberculosis develop active disease, the immune responses associated with TB susceptibility or resistance are not known. In addition, it is not known why some individuals have disseminated TB that spreads to the meninges and central nervous system, while most people have localized disease in the lungs. A number of studies suggest that host genetic factors influence susceptibility and resistance to TB (review by <a href="#9" class="mim-tip-reference" title="Berrington, W. R., Hawn, T. R. &lt;strong&gt;Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?&lt;/strong&gt; Immun. Rev. 219: 167-186, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17850489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17850489&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17850489[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-065X.2007.00545.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17850489">Berrington and Hawn, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17850489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Pathogenesis</strong>
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<p><a href="#36" class="mim-tip-reference" title="Price, N. M., Farrar, J., Chau, T. T. H., Mai, N. T. H., Hien, T. T., Friedland, J. S. &lt;strong&gt;Identification of a matrix-degrading phenotype in human tuberculosis in vitro and in vivo.&lt;/strong&gt; J. Immun. 166: 4223-4230, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11238675/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11238675&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.166.6.4223&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11238675">Price et al. (2001)</a> detected a significantly higher concentration of MMP9 (<a href="/entry/120361">120361</a>) per leukocyte in cerebrospinal fluid from adult tuberculous meningitis patients than in patients with bacterial or viral meningitis. In vitro studies indicated that viable bacilli were not required to stimulate MMP9 production. In contrast to the changes in MMP9 expression, MMP2 (<a href="/entry/120360">120360</a>) and tissue inhibitor of metalloproteinase-1 (TIMP1; <a href="/entry/305370">305370</a>) were constitutively expressed, and the latter did not oppose the MMP9 activity. Elevated MMP9 activity was related to unconsciousness, confusion, focal neurologic damage, and death in the tuberculous meningitis patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11238675" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Geijtenbeek, T. B. H., van Vliet, S. J., Koppel, E. A., Sanchez-Hernandez, M., Vandenbroucke-Grauls, C. M. J. E., Appelmelk, B., van Kooyk, Y. &lt;strong&gt;Mycobacteria target DC-SIGN to suppress dendritic cell function.&lt;/strong&gt; J. Exp. Med. 197: 7-17, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12515809/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12515809&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12515809[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1084/jem.20021229&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12515809">Geijtenbeek et al. (2003)</a> found that DCSIGN (CD209; <a href="/entry/604672">604672</a>) captured and internalized intact Mycobacterium bovis BCG or avirulent M. tuberculosis through the glycolipid mycobacterial cell wall component ManLAM. Both bacilli and ManLAM were targeted to lysosomes and colocalized with LAMP1 (<a href="/entry/153330">153330</a>) in immature DCs. Antibodies against DCSIGN blocked BCG infection of DCs. Binding of secreted ManLAM to DCSIGN prevented mycobacteria- or LPS-induced DC maturation and induced IL10 (<a href="/entry/124092">124092</a>) production, suggesting that DCSIGN-ManLAM interaction may interfere with TLR-mediated signaling and development of an antiinflammatory response. <a href="#21" class="mim-tip-reference" title="Geijtenbeek, T. B. H., van Vliet, S. J., Koppel, E. A., Sanchez-Hernandez, M., Vandenbroucke-Grauls, C. M. J. E., Appelmelk, B., van Kooyk, Y. &lt;strong&gt;Mycobacteria target DC-SIGN to suppress dendritic cell function.&lt;/strong&gt; J. Exp. Med. 197: 7-17, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12515809/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12515809&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12515809[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1084/jem.20021229&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12515809">Geijtenbeek et al. (2003)</a> proposed that M. tuberculosis may target DCSIGN both to infect DCs and to downregulate DC-mediated immune responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12515809" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Tailleux, L., Schwartz, O., Herrmann, J.-L., Pivert, E., Jackson, M., Amara, A., Legres, L., Dreher, D., Nicod, L. P., Gluckman, J. C., Lagrange, P. H., Gicquel, B., Neyrolles, O. &lt;strong&gt;DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells.&lt;/strong&gt; J. Exp. Med. 197: 121-127, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12515819/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12515819&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12515819[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1084/jem.20021468&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12515819">Tailleux et al. (2003)</a> showed that M. tuberculosis entered DCs after binding to DCSIGN, whereas the major macrophage receptors for M. tuberculosis, CR3 (see ITGAM; <a href="/entry/120980">120980</a>) and MRC1 (<a href="/entry/153618">153618</a>), played only a minor role in DC infection. Flow cytometric and histopathologic analyses showed expression of DCSIGN on lung DCs from uninfected patients and on lymph node granuloma cells infected with M. tuberculosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12515819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using flow cytometric analysis of bronchoalveolar lavage cells from tuberculosis (TB), asthma, and sarcoidosis patients and control individuals, <a href="#48" class="mim-tip-reference" title="Tailleux, L., Pham-Thi, N., Bergeron-Lafaurie, A., Herrmann, J.-L., Charles, P., Schwartz, O., Scheinmann, P., Lagrange, P. H., de Blic, J., Tazi, A., Gicquel, B., Neyrolles, O. &lt;strong&gt;DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis.&lt;/strong&gt; PLoS Med. 2: e381, 2005. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16279841/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16279841&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16279841[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pmed.0020381&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16279841">Tailleux et al. (2005)</a> found that most alveolar macrophages from TB patients expressed DCSIGN, whereas the lectin was barely detected in cells from the other subjects. FACS, RT-PCR, and ELISA analyses indicated that M. tuberculosis infection induced DCSIGN expression by a mechanism independent of TLR4 (<a href="/entry/603030">603030</a>), IL4 (<a href="/entry/147780">147780</a>), and IL13 (<a href="/entry/147683">147683</a>). Immunohistochemical analysis showed bacillary concentration in lung regions enriched in DCSIGN-expressing alveolar macrophages. Binding experiments revealed that DCSIGN-expressing alveolar macrophages were preferential targets for M. tuberculosis compared with DCSIGN-negative cells. <a href="#48" class="mim-tip-reference" title="Tailleux, L., Pham-Thi, N., Bergeron-Lafaurie, A., Herrmann, J.-L., Charles, P., Schwartz, O., Scheinmann, P., Lagrange, P. H., de Blic, J., Tazi, A., Gicquel, B., Neyrolles, O. &lt;strong&gt;DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis.&lt;/strong&gt; PLoS Med. 2: e381, 2005. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16279841/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16279841&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16279841[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pmed.0020381&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16279841">Tailleux et al. (2005)</a> did not detect IL10 in bronchoalveolar lavage or induction of IL10 in infected cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16279841" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Mycobacterium tuberculosis (Mtb) can persist in unidentified niches in the host long before the onset of disease symptoms and even after effective treatment. Latent tuberculosis is a major risk factor for active disease. <a href="#16" class="mim-tip-reference" title="Das, B., Kashino, S. S., Pulu, I., Kalita, D., Swami, V., Yeger, H., Felsher, D. W., Campos-Neto, A. &lt;strong&gt;CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis.&lt;/strong&gt; Sci. Transl. Med. 5: 170ra13, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23363977/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23363977&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23363977[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/scitranslmed.3004912&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23363977">Das et al. (2013)</a> hypothesized that bone marrow stem cells (BMSCs), comprising both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), may provide an ideal protective niche since they are found in tuberculosis lung granulomas of infected humans and mice; renew themselves; possess drug efflux pumps, such as ABCG2 (<a href="/entry/603756">603756</a>); produce only low levels of reactive oxygen species; are quiescent; and are found in the immune-privileged niche in bone marrow. By screening BMSCs expressing the CD133 (<a href="/entry/604365">604365</a>) marker and several BMSC subpopulations, <a href="#16" class="mim-tip-reference" title="Das, B., Kashino, S. S., Pulu, I., Kalita, D., Swami, V., Yeger, H., Felsher, D. W., Campos-Neto, A. &lt;strong&gt;CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis.&lt;/strong&gt; Sci. Transl. Med. 5: 170ra13, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23363977/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23363977&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23363977[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/scitranslmed.3004912&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23363977">Das et al. (2013)</a> found that undifferentiated CD271 (NGFR; <a href="/entry/162010">162010</a>)-positive/CD45 (<a href="/entry/151460">151460</a>)-negative MSCs, but not CD34 (<a href="/entry/142230">142230</a>)-positive/CD45-positive HSCs, were permissive for and tolerated Mtb. Experiments in mice showed that Mtb, even if in a nonreplicating state, resided in MSCs in both bone marrow and lungs, particularly in the ABCG2-positive side population of lung MSCs. Studies in patients who had successfully completed monitored tuberculosis treatment demonstrated that Mtb DNA and, in some patients, viable Mtb could be isolated from CD271-positive/CD45-negative bone marrow MSCs. <a href="#16" class="mim-tip-reference" title="Das, B., Kashino, S. S., Pulu, I., Kalita, D., Swami, V., Yeger, H., Felsher, D. W., Campos-Neto, A. &lt;strong&gt;CD271+ bone marrow mesenchymal stem cells may provide a niche for dormant Mycobacterium tuberculosis.&lt;/strong&gt; Sci. Transl. Med. 5: 170ra13, 2013. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23363977/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23363977&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=23363977[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1126/scitranslmed.3004912&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23363977">Das et al. (2013)</a> proposed that CD271-positive bone marrow MSCs can provide a long-term protective niche in which dormant Mtb resides. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23363977" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using transcriptomic analysis, <a href="#30" class="mim-tip-reference" title="Kubler, A., Larsson, C., Luna, B., Andrade, B. B., Amaral, E. P., Urbanowski, M., Orandle, M., Bock, K., Ammerman, N. C., Cheung, L. S., Winglee, K., Halushka, M., Park, J. K., Sher, A., Friedland, J. S., Elkington, P. T., Bishai, W. R. &lt;strong&gt;Cathepsin K contributes to cavitation and collagen turnover in pulmonary tuberculosis.&lt;/strong&gt; J. Infect. Dis. 213: 618-626, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26416658/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26416658&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26416658[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/infdis/jiv458&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26416658">Kubler et al. (2016)</a> showed that several collagen-degrading proteases, including Mmp1 (<a href="/entry/120353">120353</a>), Mmp13 (<a href="/entry/600108">600108</a>), Mmp14 (<a href="/entry/600754">600754</a>), Cma1 (<a href="/entry/118938">118938</a>), and Ctsk (<a href="/entry/601105">601105</a>), were highly upregulated in a rabbit cavitary TB model. Ctsk was the most upregulated type I collagenase in both cavitary and granulomatous tissue, as assessed by RT-PCR and immunohistochemical analysis, and the authors noted that it is unique in its ability to cleave type I collagen (see COL1A1, <a href="/entry/120150">120150</a>) inside and outside the helical region. Serum levels of CICP and free urinary deoxypyridinoline, turnover products of type I collagen, were increased, whereas urinary helical peptide was decreased, in rabbits with terminal cavities. Expression of Col1a1, Col1a2 (<a href="/entry/120160">120160</a>), and Col3a1 (<a href="/entry/120180">120180</a>) was increased in cavity wall tissue. Immunohistochemical analysis demonstrated CTSK expression in mononuclear and multinucleated giant cells at the periphery of pulmonary lesions and cavity surfaces in patients with TB. Plasma CTSK was significantly higher in patients with active TB compared with healthy controls. <a href="#30" class="mim-tip-reference" title="Kubler, A., Larsson, C., Luna, B., Andrade, B. B., Amaral, E. P., Urbanowski, M., Orandle, M., Bock, K., Ammerman, N. C., Cheung, L. S., Winglee, K., Halushka, M., Park, J. K., Sher, A., Friedland, J. S., Elkington, P. T., Bishai, W. R. &lt;strong&gt;Cathepsin K contributes to cavitation and collagen turnover in pulmonary tuberculosis.&lt;/strong&gt; J. Infect. Dis. 213: 618-626, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/26416658/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;26416658&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=26416658[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/infdis/jiv458&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="26416658">Kubler et al. (2016)</a> proposed that CTSK-mediated collagen degradation plays an important role in cavity formation in TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26416658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a zebrafish genetic screen, <a href="#8" class="mim-tip-reference" title="Berg, R. D., Levitte, S., O&#x27;Sullivan, M. P., O&#x27;Leary, S. M., Cambier, C. J., Cameron, J., Takaki, K. K., Moens, C. B., Tobin, D. M., Keane, J., Ramakrishnan, L. &lt;strong&gt;Lysosomal disorders drive susceptibility to tuberculosis by compromising macrophage migration.&lt;/strong&gt; Cell 165: 139-152, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/27015311/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;27015311&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=27015311[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2016.02.034&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="27015311">Berg et al. (2016)</a> identified a mutation in the transcriptional coregulator Snapc1b (<a href="/entry/600591">600591</a>) that resulted in hypersusceptibility to Mycobacterium marinum. RNA sequencing analysis of Snapc1b mutants showed reduced expression of cathepsins B (CTSB; <a href="/entry/116810">116810</a>) and L (CTSL; <a href="/entry/116880">116880</a>). Mutant macrophages accumulated undigested lysosomal material, disrupting endocytic recycling and impairing macrophage migration to and engulfment of dying cells and cell debris. Macrophages with lysosomal storage could not migrate toward mycobacteria-infected macrophages undergoing apoptosis in a tuberculous granuloma. Unengulfed apoptotic macrophages underwent secondary necrosis, resulting in granuloma breakdown and increased mycobacterial growth. Bronchoalveolar lavage analysis showed that the phenotype could be recapitulated in human smokers, who are at increased risk for TB. Alveolar macrophages of smokers accumulated tobacco smoke particulates and did not migrate to M. tuberculosis. Smoking cessation ameliorated the condition, and ex-smoker alveolar macrophages migrated nearly as well to M. tuberculosis as cells of nonsmokers. Likewise, macrophages from patients with Gaucher disease (see <a href="/entry/230800">230800</a>) had migration defects, and these patients had greater susceptibility to infections, including mycobacteria. <a href="#8" class="mim-tip-reference" title="Berg, R. D., Levitte, S., O&#x27;Sullivan, M. P., O&#x27;Leary, S. M., Cambier, C. J., Cameron, J., Takaki, K. K., Moens, C. B., Tobin, D. M., Keane, J., Ramakrishnan, L. &lt;strong&gt;Lysosomal disorders drive susceptibility to tuberculosis by compromising macrophage migration.&lt;/strong&gt; Cell 165: 139-152, 2016.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/27015311/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;27015311&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=27015311[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2016.02.034&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="27015311">Berg et al. (2016)</a> concluded that incapacitation of microbicidal first-responding macrophages may contribute to smokers' susceptibility to TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27015311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#53" class="mim-tip-reference" title="Wu, Q., Hossfeld, A., Gerberick, A., Saljoughian, N., Tiwari, C., Mehra, S., Ganesan, L. P., Wozniak, D. J., Rajaram, M. V. S. &lt;strong&gt;Effect of Mycobacterium tuberculosis enhancement of macrophage P-glycoprotein expression and activity on intracellular survival during antituberculosis drug treatment.&lt;/strong&gt; J. Infect. Dis. 220: 1989-1998, 2019.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/31412123/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;31412123&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/infdis/jiz405&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="31412123">Wu et al. (2019)</a> found that M. tuberculosis infection enhanced MDR1 (ABCB1; <a href="/entry/171050">171050</a>) expression in monocyte-derived macrophages (MDMs) and in lungs of infected mice. This MDR1 upregulation in human macrophages required virulence factors released by M. tuberculosis and the Esx1 secretion system. M. tuberculosis infection enhanced expression of MIR431 (<a href="/entry/611708">611708</a>), which resulted in MIR431-mediated suppression of HSF1 (<a href="/entry/140580">140580</a>) and increased MDR1 expression in MDMs. Enhanced MDR1 expression increased extrusion of antituberculosis drugs from the macrophage, lowered the effective intracellular minimum inhibitory concentration, and promoted survival of M. tuberculosis during antibiotic treatment. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31412123" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Reviews</em></strong></p><p>
<a href="#4" class="mim-tip-reference" title="Behr, M., Schurr, E., Gros, P. &lt;strong&gt;TB: screening for responses to a vile visitor.&lt;/strong&gt; Cell 140: 615-618, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20211131/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20211131&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2010.02.030&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20211131">Behr et al. (2010)</a> reviewed several studies implicating stimulation of antiinflammatory molecules and inhibition of autophagy by virulent mycobacteria as a means to evade the host immune system. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20211131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="diagnosis" class="mim-anchor"></a>
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<strong>Diagnosis</strong>
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<p>By RT-PCR and immunohistochemical analysis, <a href="#23" class="mim-tip-reference" title="Gopal, R., Monin, L., Torres, D., Slight, S., Mehra, S., McKenna, K. C., Fallert Junecko, B. A., Reinhart, T. A., Kolls, J., Baez-Saldana, R., Cruz-Lagunas, A., Rodriguez-Reyna, T. S., and 15 others. &lt;strong&gt;S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis.&lt;/strong&gt; Am. J. Respir. Crit. Care Med. 188: 1137-1146, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24047412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24047412&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24047412[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.201304-0803OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24047412">Gopal et al. (2013)</a> demonstrated that rhesus macaques and humans with active TB compared with latent TB infection had increased levels of S100A8 (<a href="/entry/123885">123885</a>) and neutrophils expressing S100A8. Additionally, serum levels of S100A8/S100A9 (<a href="/entry/123885">123885</a>/<a href="/entry/123886">123886</a>), IP10 (CXCL10; <a href="/entry/147310">147310</a>), and the neutrophil and keratinocyte chemoattractant KC (CXCL1; <a href="/entry/155730">155730</a>) were increased in active TB compared with latent TB infection. <a href="#23" class="mim-tip-reference" title="Gopal, R., Monin, L., Torres, D., Slight, S., Mehra, S., McKenna, K. C., Fallert Junecko, B. A., Reinhart, T. A., Kolls, J., Baez-Saldana, R., Cruz-Lagunas, A., Rodriguez-Reyna, T. S., and 15 others. &lt;strong&gt;S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis.&lt;/strong&gt; Am. J. Respir. Crit. Care Med. 188: 1137-1146, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24047412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24047412&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24047412[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.201304-0803OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24047412">Gopal et al. (2013)</a> proposed that serum levels of S100A8/S100A9, along with chemokines such as KC, can be used as surrogate markers of lung inflammation during TB and can predict the development of active TB in patients with latent TB infection in TB-endemic, high-risk populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24047412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="inheritance" class="mim-anchor"></a>
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<p><a href="#1" class="mim-tip-reference" title="Abel, L., Casanova, J.-L. &lt;strong&gt;Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance. (Editorial)&lt;/strong&gt; Am. J. Hum. Genet. 67: 274-277, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10882573/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10882573&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/303033&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10882573">Abel and Casanova (2000)</a> reviewed the evidence for genetic predisposition to clinical tuberculosis. From published reports, they recognized a gap between causal susceptibility in rare individuals and uncertain predisposition in general populations. They expressed the opinion that these 2 aspects of genetic predisposition to tuberculosis do not conflict but, rather, are likely to represent the 2 ends of a continuous spectrum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="mapping" class="mim-anchor"></a>
<h4 href="#mimMappingFold" id="mimMappingToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<p><a href="#5" class="mim-tip-reference" title="Bellamy, R., Beyers, N., McAdam, K. P. W. J., Ruwende, C., Gie, R., Samaai, P., Bester, D., Meyer, M., Corrah, T., Collin, M., Camidge, D. R., Wilkinson, D., Hoal-van Helden, E., Whittle, H. C., Amos, W., van Helden, P., Hill, A. V. S. &lt;strong&gt;Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.&lt;/strong&gt; Proc. Nat. Acad. Sci. 97: 8005-8009, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/10859364/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;10859364&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.140201897&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="10859364">Bellamy et al. (2000)</a> conducted a 2-stage genomewide linkage study of 136 African families to search for regions of the human genome containing tuberculosis susceptibility genes. They used sib-pair families that contained 2 full sibs who had both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis susceptibility gene, affected sib-pairs inherit the same parental alleles much more than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sib-pairs from The Gambia and South Africa. In this process, they identified 7 chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis. From these regions, 22 markers were genotyped in a second set of 81 sib-pairs from the same countries. Markers on 15q11-q13 and Xq (<a href="/entry/300259">300259</a>) showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. An X chromosome susceptibility gene might contribute to the excess of males with tuberculosis observed in many different populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10859364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Cervino, A. C. L., Lakis, S., Sow, O., Bellamy, R., Beyers, N., Hoal-van Helden, E., van Helden, P., McAdam, K. P. W. J., Hill, A. V. S. &lt;strong&gt;Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11-13 in African families.&lt;/strong&gt; Hum. Molec. Genet. 11: 1599-1603, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12075004/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12075004&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/11.14.1599&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12075004">Cervino et al. (2002)</a> tested 10 microsatellite markers and 5 positional candidate genes in the 15q11-q13 chromosomal region for deviation from random transmission from parents to affected offspring. A borderline significant association with a 7-bp deletion in the UBE3A gene (<a href="/entry/601623">601623</a>) (P = 0.01) was found. This polymorphism was then evaluated further in a larger series of families with tuberculosis, including 44 Guinean families and 57 families from South Africa. Testing for association between the deletion and tuberculosis across all the families using the exact symmetry test further supported the association (overall P = 0.002). The authors suggested that UBE3A or a closely flanking gene may be a tuberculosis susceptibility locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12075004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A region of mouse chromosome 11 that is syntenic with human chromosome 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. To examine this region in humans, <a href="#25" class="mim-tip-reference" title="Jamieson, S. E., Miller, E. N., Black, G. F., Peacock, C. S., Cordell, H. J. &lt;strong&gt;Howson, J. M. M.; Shaw, M.-A.; Burgner, D.; Xu, W.; Lins-Lainson, Z.; Shaw, J. J.; Ramos, F.; Silveira, F.; Blackwell, J. M.: Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians.&lt;/strong&gt; Genes Immun. 5: 46-57, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14735149/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14735149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.gene.6364029&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14735149">Jamieson et al. (2004)</a> studied 92 multicase tuberculosis families (627 individuals) and 72 multicase leprosy (<a href="/entry/246300">246300</a>) families (372 individuals) from Brazil. Multipoint nonparametric analysis using 16 microsatellites showed 2 peaks of linkage for leprosy at D17S250 and D17S1795 and a single peak for tuberculosis at D17S250. Combined analysis showed significant linkage at D17S250, equivalent to an allele sharing lod score of 2.48 (p of 0.0004). <a href="#25" class="mim-tip-reference" title="Jamieson, S. E., Miller, E. N., Black, G. F., Peacock, C. S., Cordell, H. J. &lt;strong&gt;Howson, J. M. M.; Shaw, M.-A.; Burgner, D.; Xu, W.; Lins-Lainson, Z.; Shaw, J. J.; Ramos, F.; Silveira, F.; Blackwell, J. M.: Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians.&lt;/strong&gt; Genes Immun. 5: 46-57, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14735149/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14735149&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.gene.6364029&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14735149">Jamieson et al. (2004)</a> typed 49 informative SNPs in candidate genes, and family-based allelic testing that was robust to family clustering showed significant associations with tuberculosis susceptibility at 4 genes, NOS2A (<a href="/entry/163730">163730</a>), CCL18 (<a href="/entry/603757">603757</a>), CCL4 (<a href="/entry/182284">182284</a>), and STAT5B (<a href="/entry/604260">604260</a>), separated by intervals up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control dataset showed that the 4 genes contributed separate main effects, consistent with a cluster of susceptibility genes across chromosome 17q11.2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14735149" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 2-stage genomewide scan of 38 multicase tuberculosis families (349 individuals) in Brazil, <a href="#32" class="mim-tip-reference" title="Miller, E. N., Jamieson, S. E., Joberty, C., Fakiola, M., Hudson, D., Peacock, C. S., Cordell, H. J., Shaw, M.-A., Lins-Lainson, Z., Shaw, J. J., Ramos, F., Silveira, F., Blackwell, J. M. &lt;strong&gt;Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians.&lt;/strong&gt; Genes Immun. 5: 63-67, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14735151/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14735151&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/sj.gene.6364031&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14735151">Miller et al. (2004)</a> found suggestive evidence for linkage to chromosomes 10q26.13, 11q12.3, and 20p12.1. Peak lod scores for these regions were 1.31 (p of 0.007), 1.85 (p of 0.0018), and 1.78 (p of 0.0021), respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14735151" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using genomewide linkage and positional mapping of TB-affected sib pairs in South Africans of mixed racial origin and in Africans from northern Malawi, <a href="#14" class="mim-tip-reference" title="Cooke, G. S., Campbell, S. J., Bennett, S., Lienhardt, C., McAdam, K. P. W. J., Sirugo, G., Sow, O., Gustafson, P., Mwangulu, F., van Helden, P., Fine, P., Hoal, E. G., Hill, A. V. S. &lt;strong&gt;Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis.&lt;/strong&gt; Am. J. Resp. Crit. Care Med. 178: 203-207, 2008. Note: Erratum: Am. J. Resp. Crit. Care Med. 179: 624 only, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18420963/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18420963&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.200710-1554OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18420963">Cooke et al. (2008)</a> identified 2 novel putative TB susceptibility loci on chromosomes 6p21-q23 and 20q13.31-q33 (MTBS3; <a href="/entry/612929">612929</a>). The latter locus had a highly significant single-point lod score of 3.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18420963" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>See <a href="/entry/613636">613636</a> for information on TST1, a locus on chromosome 11p14 associated with absence of tuberculin skin test (TST) reactivity.</p><p>See <a href="/entry/613637">613637</a> for information on TST2, a quantitative trait locus of chromosome 5p15 for TST reactivity measured in millimeters.</p>
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<p>There is substantial evidence from studies on racial variation in susceptibility to tuberculosis (<a href="#44" class="mim-tip-reference" title="Stead, W. W., Senner, J. W., Reddick, W. T., Lofgren, J. P. &lt;strong&gt;Racial differences in susceptibility to infection by Mycobacterium tuberculosis.&lt;/strong&gt; New Eng. J. Med. 322: 422-427, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2300105/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2300105&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199002153220702&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="2300105">Stead et al., 1990</a>; <a href="#45" class="mim-tip-reference" title="Stead, W. W. &lt;strong&gt;Genetics and resistance to tuberculosis: could resistance be enhanced by genetic engineering?&lt;/strong&gt; Ann. Intern. Med. 116: 937-941, 1992.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/1580452/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;1580452&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.7326/0003-4819-116-11-937&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="1580452">Stead, 1992</a>) and twin studies (<a href="#13" class="mim-tip-reference" title="Comstock, G. W. &lt;strong&gt;Tuberculosis in twins: a re-analysis of the Prophit survey.&lt;/strong&gt; Am. Rev. Resp. Dis. 117: 621-624, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/565607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;565607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/arrd.1978.117.4.621&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="565607">Comstock, 1978</a>; <a href="#7" class="mim-tip-reference" title="Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Whittle, H. C., Hill, A. V. S. &lt;strong&gt;Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.&lt;/strong&gt; New Eng. J. Med. 338: 640-644, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9486992/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9486992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199803053381002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9486992">Bellamy et al., 1998</a>) that host genetic factors are important in determining susceptibility to infection with Mycobacterium tuberculosis and the subsequent development of clinical disease. In a large case-control study in Gambians, including more than 800 subjects, Bellamy et al. (<a href="#7" class="mim-tip-reference" title="Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Whittle, H. C., Hill, A. V. S. &lt;strong&gt;Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.&lt;/strong&gt; New Eng. J. Med. 338: 640-644, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9486992/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9486992&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJM199803053381002&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9486992">1998</a>, <a href="#6" class="mim-tip-reference" title="Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Thursz, M., Whittle, H. C., Hill, A. V. S. &lt;strong&gt;Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.&lt;/strong&gt; J. Infect. Dis. 179: 721-724, 1999.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9952386/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9952386&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/314614&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9952386">1999</a>) showed that genetic variants of NRAMP1 and VDR are associated with smear-positive pulmonary tuberculosis. However, together, these can only account for a small proportion of the overall genetic component suggested by twin studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9952386+9486992+565607+1580452+2300105" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Selvaraj, P., Kurian, S. M., Chandra, G., Reetha, A. M., Charles, N., Narayanan, P. R. &lt;strong&gt;Vitamin D receptor gene variants of BsmI, ApaI, TaqI, and FokI polymorphisms in spinal tuberculosis. (Letter)&lt;/strong&gt; Clin. Genet. 65: 73-76, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15032981/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15032981&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j..2004.00183.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15032981">Selvaraj et al. (2004)</a> presented evidence suggesting that polymorphisms in the VDR gene may predispose to spinal TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15032981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Bornman, L., Campbell, S. J., Fielding K., Bah, B., Sillah, J., Gustafson, P., Manneh, K., Lisse, I., Allen, A., Sirugo, G., Sylla, A., Aaby, P., McAdam, K. P. W. J., Bah-Sow, O., Bennett, S., Lienhardt, C., Hill, A. V. S. &lt;strong&gt;Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study.&lt;/strong&gt; J. Infect. Dis. 190: 1631-1641, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15478069/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15478069&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/424462&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15478069">Bornman et al. (2004)</a> genotyped the VDR SNPs FokI, BsmI, ApaI, and TaqI in TB patients, controls, and families in the Gambia, Guinea, and Guinea-Bissau. By transmission-disequilibrium analysis of family data, they found a significant global association of TB with the SNP combinations FokI-BsmI-ApaI- TaqI and FokI-ApaI driven by increased transmission of the FokI F and ApaI A alleles in combination to affected offspring. Case-control analysis showed no significant association between TB and VDR variants. <a href="#10" class="mim-tip-reference" title="Bornman, L., Campbell, S. J., Fielding K., Bah, B., Sillah, J., Gustafson, P., Manneh, K., Lisse, I., Allen, A., Sirugo, G., Sylla, A., Aaby, P., McAdam, K. P. W. J., Bah-Sow, O., Bennett, S., Lienhardt, C., Hill, A. V. S. &lt;strong&gt;Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study.&lt;/strong&gt; J. Infect. Dis. 190: 1631-1641, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15478069/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15478069&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/424462&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15478069">Bornman et al. (2004)</a> concluded that there is a haplotype, rather than a genotype, association between VDR variants and susceptibility to TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15478069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Mitsos, L.-M., Cardon, L. R., Ryan, L., LaCourse, R., North, R. J., Gros, P. &lt;strong&gt;Susceptibility to tuberculosis: a locus on mouse chromosome 19 (Trl-4) regulates Mycobacterium tuberculosis replication in the lungs.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 6610-6615, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12740444/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12740444&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12740444[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.1031727100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12740444">Mitsos et al. (2003)</a> noted that only a small proportion of individuals who come in contact with M. tuberculosis develop active TB, and a wide clinical spectrum of disease severity is observed in such individuals. Appearance of full-blown disease is determined in part by microbial virulence determinants and by environmental and host factors, such as social conditions and immune status, most critically by the presence of concomitant HIV infection. An important genetic component of vulnerability to TB in humans affecting susceptibility per se, disease progression, and ultimate outcome had been well documented <a href="#11" class="mim-tip-reference" title="Casanova, J.-L., Abel, L. &lt;strong&gt;Genetic dissection of immunity to mycobacteria: the human model.&lt;/strong&gt; Annu. Rev. Immun. 20: 581-620, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11861613/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11861613&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1146/annurev.immunol.20.081501.125851&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11861613">Casanova and Abel (2002)</a>. This genetic component is supported by epidemiologic data pointing to racial differences in susceptibility, as well as familial aggregation. Studies of first-contact epidemics in isolated populations with no ancestral experience of this infection, survival data from accidental injection of virulent M. tuberculosis during a BCG vaccination trial (the Lubeck disaster), and studies in twins showing higher concordance rates of TB in monozygotic versus dizygotic twins provided compelling evidence that host genes affect the outcome of M. tuberculosis infection (<a href="#26" class="mim-tip-reference" title="Kallmann, F. J., Reisner, D. &lt;strong&gt;Twin studies on the significance of genetic factors in tuberculosis.&lt;/strong&gt; Am. Rev. Tuberc. 47: 549-574, 1943."None>Kallmann and Reisner, 1943</a>; <a href="#42" class="mim-tip-reference" title="Simonds, B. &lt;strong&gt;Tuberculosis in Twins.&lt;/strong&gt; London: Pitman Medical Publishing Company 1963. Pp. 1-81."None>Simonds, 1963</a>; <a href="#13" class="mim-tip-reference" title="Comstock, G. W. &lt;strong&gt;Tuberculosis in twins: a re-analysis of the Prophit survey.&lt;/strong&gt; Am. Rev. Resp. Dis. 117: 621-624, 1978.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/565607/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;565607&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/arrd.1978.117.4.621&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="565607">Comstock, 1978</a>). Rare mutations in the IFN-gamma receptor-1 gene (IFNGR1; <a href="/entry/107470">107470</a>) had been demonstrated in familial generalized BCG infection and in familial disseminated infection with an atypical mycobacterium (see <a href="/entry/209950">209950</a>). Similarly, susceptibility to mycobacterial infections had been demonstrated in rare mutations in the interleukin-12 receptor (IL12RB1; <a href="/entry/601604">601604</a>) and in interleukin-12B (IL12B; <a href="/entry/161561">161561</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12740444+565607+11861613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Ozbek, N., Fieschi, C., Yilmaz, B. T., de Beaucoudrey, L., Demirhan, B., Feinberg, J., Bikmaz, Y. E., Casanova, J.-L. &lt;strong&gt;Interleukin-12 receptor beta-1 chain deficiency in a child with disseminated tuberculosis.&lt;/strong&gt; Clin. Infect. Dis. 40: e55-e58, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15736007/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15736007&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/427879&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15736007">Ozbek et al. (2005)</a> reported an 11-year-old Turkish girl with IL12RB1 deficiency and severe abdominal tuberculosis. She was the fourth child of healthy, consanguineous parents. Like her parents and sibs, she had had no adverse effect from BCG vaccination, and there was no family history of mycobacterial disease or other intracellular infectious diseases. The patient did not show augmented production of IFNG (<a href="/entry/147570">147570</a>) in response to antigen plus IL12. <a href="#35" class="mim-tip-reference" title="Ozbek, N., Fieschi, C., Yilmaz, B. T., de Beaucoudrey, L., Demirhan, B., Feinberg, J., Bikmaz, Y. E., Casanova, J.-L. &lt;strong&gt;Interleukin-12 receptor beta-1 chain deficiency in a child with disseminated tuberculosis.&lt;/strong&gt; Clin. Infect. Dis. 40: e55-e58, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/15736007/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;15736007&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/427879&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="15736007">Ozbek et al. (2005)</a> identified a homozygous splice site mutation in the IL12RB1 gene that led to skipping of exon 9 (<a href="/entry/601604#0006">601604.0006</a>). They concluded that a diagnosis of IL12RB1 deficiency should be considered for children with unusually severe tuberculosis, even if they have no personal or family history of infection with weakly virulent Mycobacterium or Salmonella species. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15736007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Soborg, C., Madsen, H. O., Andersen, A. B., Lillebaek, T., Kok-Jensen, A., Garred, P. &lt;strong&gt;Mannose-binding lectin polymorphisms in clinical tuberculosis.&lt;/strong&gt; J. Infect. Dis. 188: 777-782, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12934195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12934195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/377183&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12934195">Soborg et al. (2003)</a> examined MBL genotypes and serum MBL levels in 109 patients with clinical tuberculosis and 250 controls. Heterozygotes with a variant MBL structural allele associated with low functional serum MBL on one chromosome and a normal MBL structural allele with a low-expression promoter polymorphism on the other chromosome appeared to be relatively protected against clinical tuberculosis, whereas genotypes associated with high MBL expression and genotypes conferring MBL deficiency were not. <a href="#43" class="mim-tip-reference" title="Soborg, C., Madsen, H. O., Andersen, A. B., Lillebaek, T., Kok-Jensen, A., Garred, P. &lt;strong&gt;Mannose-binding lectin polymorphisms in clinical tuberculosis.&lt;/strong&gt; J. Infect. Dis. 188: 777-782, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12934195/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12934195&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/377183&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12934195">Soborg et al. (2003)</a> proposed that low serum MBL may be protective against tuberculosis by limiting complement activation and uptake of bacilli by complement receptors. In the absence of MBL, bacilli may be taken up directly by mannose receptors (e.g., MRC1; <a href="/entry/153618">153618</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12934195" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Barreiro, L. B., Neyrolles, O., Babb, C. L., Tailleux, L., Quach, H., McElreavey, K., van Helden, P. D., Hoal, E. G., Gicquel, B., Quintana-Murci, L. &lt;strong&gt;Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis.&lt;/strong&gt; PLoS Med. 3: e20, 2006. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16379498/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16379498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pmed.0030020&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16379498">Barreiro et al. (2006)</a> examined CD209 polymorphisms in 351 TB patients and 360 healthy controls from a South African Coloured population (historically derived from Khoisan, Malaysian, Bantu, and European descent populations) living in communities with some of the highest reported incidence rates of TB in the world. They identified 2 CD209 promoter variants, -871A (<a href="/entry/604672#0002">604672.0002</a>) and -336G (<a href="/entry/604672#0001">604672.0001</a>), that were associated with increased risk of TB. One haplotype of 8 SNPs, including -871G and -336A, showed a highly significant association with the control group. Further analysis of sub-Saharan African, European, and Asian populations showed that the protective -336A and -871G alleles were present at higher frequencies in Eurasians than in Africans. <a href="#3" class="mim-tip-reference" title="Barreiro, L. B., Neyrolles, O., Babb, C. L., Tailleux, L., Quach, H., McElreavey, K., van Helden, P. D., Hoal, E. G., Gicquel, B., Quintana-Murci, L. &lt;strong&gt;Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis.&lt;/strong&gt; PLoS Med. 3: e20, 2006. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16379498/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16379498&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.pmed.0030020&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16379498">Barreiro et al. (2006)</a> suggested that the longer and more intense duration of TB exposure in Europe may have exerted stronger selective pressures in this population and may have had an impact on susceptibility to infection by other pathogens, such as HIV and dengue (see <a href="/entry/614371">614371</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16379498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Malik, S., Greenwood, C. M. T., Eguale, T., Kifle, A., Beyene, J., Habte, A., Tadesse, A., Gebrexabher, H., Britton, S., Schurr, E. &lt;strong&gt;Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia.&lt;/strong&gt; Hum. Genet. 118: 752-759, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16292672/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16292672&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-005-0092-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16292672">Malik et al. (2006)</a> reported a significant association (p = 0.007 after Bonferroni correction) between a synonymous 307G-A SNP in the gene encoding surfactant pulmonary-associated protein A1 (SFTPA1; <a href="/entry/178630">178630</a>) and susceptibility to tuberculosis in an Ethiopian population. The authors suggested that the polymorphism may affect splicing and/or mRNA maturation. <a href="#31" class="mim-tip-reference" title="Malik, S., Greenwood, C. M. T., Eguale, T., Kifle, A., Beyene, J., Habte, A., Tadesse, A., Gebrexabher, H., Britton, S., Schurr, E. &lt;strong&gt;Variants of the SFTPA1 and SFTPA2 genes and susceptibility to tuberculosis in Ethiopia.&lt;/strong&gt; Hum. Genet. 118: 752-759, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16292672/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16292672&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-005-0092-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16292672">Malik et al. (2006)</a> noted that <a href="#19" class="mim-tip-reference" title="Floros, J., Lin, H.-M., Garcia, A., Salazar, M. A., Guo, X., DiAngelo, S., Montano, M., Luo, J., Pardo, A., Selman, M. &lt;strong&gt;Surfactant protein genetic marker alleles identify a subgroup of tuberculosis in a Mexican population.&lt;/strong&gt; J. Infect. Dis. 182: 1473-1478, 2000.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11023470/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11023470&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1086/315866&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11023470">Floros et al. (2000)</a> had previously reported an association between SFTPA1 polymorphisms and tuberculosis in a Mexican population. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11023470+16292672" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Goldfeld, A. E., Delgado, J. C., Thim, S., Bozon, M. V., Uglialoro, A. M., Turbay, D., Cohen, C., Yunis, E. J. &lt;strong&gt;Association of an HLA-DQ allele with clinical tuberculosis.&lt;/strong&gt; JAMA 279: 226-228, 1998.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/9438744/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;9438744&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1001/jama.279.3.226&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="9438744">Goldfeld et al. (1998)</a> demonstrated a significant association between the *0503 allele of HLA-DQB1 (<a href="/entry/604305">604305</a>) and susceptibility to tuberculosis in Cambodian patients. This appeared to be the first identified gene associated with the development of clinical tuberculosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9438744" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 436 Cambodian patients with tuberculosis, <a href="#17" class="mim-tip-reference" title="Delgado, J. C., Baena, A., Thim, S., Goldfeld, A. E. &lt;strong&gt;Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia.&lt;/strong&gt; J. Immun. 176: 1090-1097, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16393997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16393997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.176.2.1090&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16393997">Delgado et al. (2006)</a> found that susceptibility to tuberculosis was significantly associated with homozygosity for the asp57 allele of HLA-DQB1. Two immunogenic proteins of Mycobacterium tuberculosis, Esat6 and Cfp10, bound less well to asp57 than to ala57. Presentation of these tuberculosis proteins to T cells resulted in significantly decreased production of IFNG when the antigen-presenting cells expressed asp57 rather than ala57. <a href="#17" class="mim-tip-reference" title="Delgado, J. C., Baena, A., Thim, S., Goldfeld, A. E. &lt;strong&gt;Aspartic acid homozygosity at codon 57 of HLA-DQ beta is associated with susceptibility to pulmonary tuberculosis in Cambodia.&lt;/strong&gt; J. Immun. 176: 1090-1097, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16393997/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16393997&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.176.2.1090&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16393997">Delgado et al. (2006)</a> concluded that HLA-DQB1 has a role in the host immune response to tuberculosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16393997" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Flores-Villanueva, P. O., Ruiz-Morales, J. A., Song, C.-H., Flores, L. M., Jo, E.-K., Montano, M., Barnes, P. F., Selman, M., Granados, J. &lt;strong&gt;A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis.&lt;/strong&gt; J. Exp. Med. 202: 1649-1658, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16352737/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16352737&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16352737[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1084/jem.20050126&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16352737">Flores-Villanueva et al. (2005)</a> found that Mexicans heterozygous or homozygous for the -2518G allele of the -2518A-G SNP (<a href="/entry/158105#0003">158105.0003</a>) had a 2.3- and 5.4-fold increased risk of developing active pulmonary tuberculosis, respectively. Among Korean patients, the increased risk was 2.8- and 6.9-fold higher, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16352737" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#50" class="mim-tip-reference" title="Thye, T., Nejentsev, S., Intemann, C. D., Browne, E. N., Chinbuah, M. A., Gyapong, J., Osei, I., Owusu-Dabo, E., Zeitels, L. R., Herb, F., Horstmann, R. D., Meyer, C. G. &lt;strong&gt;MCP-1 promoter variant -362C associated with protection from pulmonary tuberculosis in Ghana, West Africa.&lt;/strong&gt; Hum. Molec. Genet. 18: 381-388, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/18940815/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;18940815&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=18940815[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/hmg/ddn352&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="18940815">Thye et al. (2009)</a> determined the -2518 genotype and additional MCP1 variants in over 2,000 cases with pulmonary TB and more than 2,300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and over 1,400 TB patients and more than 1,500 controls from Russia. In contrast to the report of <a href="#18" class="mim-tip-reference" title="Flores-Villanueva, P. O., Ruiz-Morales, J. A., Song, C.-H., Flores, L. M., Jo, E.-K., Montano, M., Barnes, P. F., Selman, M., Granados, J. &lt;strong&gt;A functional promoter polymorphism in monocyte chemoattractant protein-1 is associated with increased susceptibility to pulmonary tuberculosis.&lt;/strong&gt; J. Exp. Med. 202: 1649-1658, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16352737/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16352737&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=16352737[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1084/jem.20050126&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16352737">Flores-Villanueva et al. (2005)</a>, MCP1 -2518 (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1024611;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1024611</a>) was significantly associated with resistance to TB in cases versus controls (odds ratio (OR) 0.81, corrected P value (Pcorr) = 0.0012) and nuclear families (OR 0.72, Pcorr = 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P = 0.86). These and other results did not support an association of MCP1 -2518 with TB. In the Ghanaian population, 8 additional MCP1 polymorphisms were genotyped. MCP1 -362C was associated with resistance to TB in the case-control collection (OR 0.83, Pcorr = 0.00017) and in the affected families (OR 0.7, Pcorr = 0.004). Linkage disequilibrium (LD) and logistic regression analyses indicated that, in Ghanaians, the effect was due exclusively to the MCP1 -362 variant, whereas the effect of -2518 may in part be explained by its LD with -362. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16352737+18940815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Studies in mice (<a href="#20" class="mim-tip-reference" title="Flynn, J. L., Goldstein, M. M., Chan, J., Triebold, K. J., Pfeffer, K., Lowenstein, C. J., Schreiber, R., Mak, T. W., Bloom, B. R. &lt;strong&gt;Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.&lt;/strong&gt; Immunity 2: 561-572, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7540941/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7540941&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/1074-7613(95)90001-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7540941">Flynn et al., 1995</a>) and observations in patients receiving infliximab (remicade) for treatment of rheumatoid arthritis (<a href="/entry/180300">180300</a>) or Crohn disease (see IBD1, <a href="/entry/266600">266600</a>) (<a href="#27" class="mim-tip-reference" title="Keane, J, Gershon, S, Wise, R. P., Mirabile-Levens, E., Kasznica, J., Schwieterman, W. D., Siegel, J. N, Braun, M. M. &lt;strong&gt;Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.&lt;/strong&gt; New Eng. J. Med. 345: 1098-1104, 2001.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11596589/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11596589&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1056/NEJMoa011110&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11596589">Keane et al., 2001</a>) have shown that antibody-mediated neutralization of TNF (<a href="/entry/191160">191160</a>) increases susceptibility to TB. However, excess TNF may be associated with severe TB pathology (<a href="#2" class="mim-tip-reference" title="Barnes, P. F., Fong, S. J., Brennan, P. J., Twomey, P. E., Mazumder, A., Modlin, R. L. &lt;strong&gt;Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis.&lt;/strong&gt; J. Immun. 145: 149-154, 1990.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/2113553/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;2113553&lt;/a&gt;]" pmid="2113553">Barnes et al., 1990</a>). Using path and segregation analysis and controlling for environmental differences, <a href="#46" class="mim-tip-reference" title="Stein, C. M., Nshuti, L., Chiunda, A. B., Boom, W. H., Elston, R. C., Mugerwa, R. D., Iyengar, S. K., Whalen, C. C. &lt;strong&gt;Evidence for a major gene influence on tumor necrosis factor-alpha expression in tuberculosis: path and segregation analysis.&lt;/strong&gt; Hum. Hered. 60: 109-118, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16224188/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16224188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088913&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16224188">Stein et al. (2005)</a> evaluated TNF secretion levels in Ugandan TB patients. The results suggested that there is a strong genetic influence, due to a major gene, on TNF expression in TB, and that there may be heterozygote advantage. The effect of shared environment on TNF expression in TB was minimal. <a href="#46" class="mim-tip-reference" title="Stein, C. M., Nshuti, L., Chiunda, A. B., Boom, W. H., Elston, R. C., Mugerwa, R. D., Iyengar, S. K., Whalen, C. C. &lt;strong&gt;Evidence for a major gene influence on tumor necrosis factor-alpha expression in tuberculosis: path and segregation analysis.&lt;/strong&gt; Hum. Hered. 60: 109-118, 2005.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16224188/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16224188&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1159/000088913&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16224188">Stein et al. (2005)</a> concluded that TNF expression is an endophenotype for TB that may increase power to detect disease-predisposing loci. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=16224188+11596589+2113553+7540941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>As a follow-up to their studies examining TNF levels in response to M. tuberculosis culture filtrate antigen as an intermediate phenotype model for TB susceptibility in a Ugandan population, <a href="#47" class="mim-tip-reference" title="Stein, C. M., Zalwango, S., Chiunda, A. B., Millard, C., Leontiev, D. V., Horvath, A. L., Cartier, K. C., Chervenak, K., Boom, W. H., Elston, R. C., Mugerwa, R. D., Whalen, C. C., Iyengar, S. K. &lt;strong&gt;Linkage and association analysis of candidate genes for TB and TNF-alpha cytokine expression: evidence for association with IFNGR1, IL-10, and TNF receptor 1 genes.&lt;/strong&gt; Hum. Genet. 121: 663-673, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17431682/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17431682&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-007-0357-8&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17431682">Stein et al. (2007)</a> studied genes related to TNF regulation by positional candidate linkage followed by family-based SNP association analysis. They found that the IL10, IFNGR1, and TNFR1 (TNFRSF1A; <a href="/entry/191190">191190</a>) genes were linked and associated to both TB and TNF. These associations were with active TB rather than susceptibility to latent infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17431682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To test the hypothesis that a polymorphism in IFNG (<a href="/entry/147570">147570</a>) is associated with susceptibility to tuberculosis, <a href="#38" class="mim-tip-reference" title="Rossouw, M., Nel, H. J., Cooke, G. S., van Helden, P. D., Hoal, E. G. &lt;strong&gt;Association between tuberculosis and a polymorphic NF-kappa-B binding site in the interferon gamma gene.&lt;/strong&gt; Lancet 361: 1871-1872, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12788577/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12788577&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/S0140-6736(03)13491-5&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12788577">Rossouw et al. (2003)</a> conducted 2 independent studies. In a case-control study of 313 tuberculosis cases, they noted a significant association between a polymorphism (+874A-T; <a href="/entry/147570#0002">147570.0002</a>) in IFNG and protection against tuberculosis in a South African population (p = 0.0055). This finding was replicated in a family-based study, in which the transmission disequilibrium test was used in 131 families (p = 0.005). The transcription factor NF-kappa-B (NFKB1; <a href="/entry/164011">164011</a>) binds preferentially to the +874T allele, which was overrepresented in controls, suggesting that genetically-determined variability in IFNG and expression might be important for the development of tuberculosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12788577" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a case-control study of 682 TB patients and 619 controls from 3 West African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), <a href="#15" class="mim-tip-reference" title="Cooke, G. S., Campbell, S. J., Sillah, J., Gustafson, P., Bah, B., Sirugo, G., Bennett, S., McAdam, K. P. W. J., Sow, O., Lienhardt, C., Hill, A. V. S. &lt;strong&gt;Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis.&lt;/strong&gt; Am. J. Resp. Crit. Care Med. 174: 339-343, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16690980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16690980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.200601-088OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16690980">Cooke et al. (2006)</a> observed the IFNG +874AA genotype more frequently in TB patients than controls, but the trend was not statistically significant. However, the +874A-T SNP was in strong linkage disequilibrium with 2 other SNPs, -1616G-A and +3234T-C, and both the -1616GG and +3234TT genotypes were significantly associated with TB. Haplotype analysis in a smaller Gambian population sample showed that the 3 alleles putatively associated with TB were all found on the most common West African haplotype, which, although overtransmitted, was not significantly associated with disease in this smaller population. <a href="#15" class="mim-tip-reference" title="Cooke, G. S., Campbell, S. J., Sillah, J., Gustafson, P., Bah, B., Sirugo, G., Bennett, S., McAdam, K. P. W. J., Sow, O., Lienhardt, C., Hill, A. V. S. &lt;strong&gt;Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis.&lt;/strong&gt; Am. J. Resp. Crit. Care Med. 174: 339-343, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16690980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16690980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.200601-088OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16690980">Cooke et al. (2006)</a> also found that the -56CC genotype of the IFNGR1 (<a href="/entry/107470">107470</a>) promoter -56C-T SNP (<a href="/entry/107470#0012">107470.0012</a>) was associated with protection from TB. No associations with TB were observed with SNPs in the IFNGR2 gene (<a href="/entry/147569">147569</a>). <a href="#15" class="mim-tip-reference" title="Cooke, G. S., Campbell, S. J., Sillah, J., Gustafson, P., Bah, B., Sirugo, G., Bennett, S., McAdam, K. P. W. J., Sow, O., Lienhardt, C., Hill, A. V. S. &lt;strong&gt;Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis.&lt;/strong&gt; Am. J. Resp. Crit. Care Med. 174: 339-343, 2006.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/16690980/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;16690980&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.200601-088OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="16690980">Cooke et al. (2006)</a> concluded that there is a significant role for genetic variation in IFNG and IFNGR1 in susceptibility to TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16690980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Khor, C. C., Chapman, S. J., Vannberg, F. O., Dunne, A., Murphy, C., Ling, E. Y., Frodsham, A. J., Walley, A. J., Kyrieleis, O., Khan, A., Aucan, C., Segal, S., and 22 others. &lt;strong&gt;A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.&lt;/strong&gt; Nature Genet. 39: 523-528, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17322885/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17322885&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17322885[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1038/ng1976&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17322885">Khor et al. (2007)</a> found that heterozygous carriage of a leucine substitution at ser180 of the TIRAP gene (<a href="/entry/606252#0001">606252.0001</a>) associated independently with protection against 4 infectious diseases, including tuberculosis, in several different study populations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17322885" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The immunity-related GTPase IRGM (<a href="/entry/608212">608212</a>) is a mediator of innate immune responses and induces autophagy. <a href="#24" class="mim-tip-reference" title="Intemann, C. D., Thye, T., Niemann, S., Browne, E. N. L., Amanua Chinbuah, M., Enimil, A., Gyapong, J., Osei, I., Owusu-Dabo, E., Helm, S., Rusch-Gerdes, S., Horstmann, R. D., Meyer, C. G. &lt;strong&gt;Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains.&lt;/strong&gt; PLoS Pathog. 5: e1000577, 2009. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19750224/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19750224&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19750224[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.ppat.1000577&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19750224">Intemann et al. (2009)</a> examined variants in the IRGM gene using a case-control study of 2,010 HIV-seronegative TB patients and 2,346 healthy controls in Ghana. They found a trend for association of homozygosity for -261C-T (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs9637876;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs9637876</a>), which is located within an Alu sequence in the promoter region of IRGM, with protection from TB. IRGM -261TT was significantly associated with protection from TB caused by M. tuberculosis (OR = 0.79; P = 0.017), but not by M. africanum, a strain restricted to West Africa, or M. bovis. Further stratification of mycobacterial genotypes revealed that protection associated with -261TT applied exclusively to carriers of M. tuberculosis from the Euro-American (EUAM) lineage (OR = 0.63; nominal P = 0.0004; corrected P = 0.0019), but not to carriers of M. tuberculosis from the East African-Indian, Beijing, or Dehli lineages. The EUAM lineage of the M. tuberculosis clade, but not other strains, has a damaged gene encoding a phenolic glycolipid. No association was found for carriers of the heterozygous -261CT genotype. The -261T IRGM variant was predicted to disrupt several transcription factor-binding sites, and luciferase analysis showed significantly increased expression of the -261T IRGM variant compared with the -261C IRGM variant, suggesting enhanced expression of the mature IRGM protein. <a href="#24" class="mim-tip-reference" title="Intemann, C. D., Thye, T., Niemann, S., Browne, E. N. L., Amanua Chinbuah, M., Enimil, A., Gyapong, J., Osei, I., Owusu-Dabo, E., Helm, S., Rusch-Gerdes, S., Horstmann, R. D., Meyer, C. G. &lt;strong&gt;Autophagy gene variant IRGM -261T contributes to protection from tuberculosis caused by Mycobacterium tuberculosis but not by M. africanum strains.&lt;/strong&gt; PLoS Pathog. 5: e1000577, 2009. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19750224/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19750224&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=19750224[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.ppat.1000577&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19750224">Intemann et al. (2009)</a> proposed that IRGM and autophagy have a role in protection against natural infection with EUAM strains, and that M. tuberculosis lineages expressing mycobacterial phenolic glycolipid inhibit innate immune responses involving autophagy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19750224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Given the altered balance of pro- and antiinflammatory eicosanoids in zebrafish with mutations in leukotriene A4 hydrolase (LTA4H; <a href="/entry/151570">151570</a>), <a href="#51" class="mim-tip-reference" title="Tobin, D. M., Vary, J. C., Jr., Ray, J. P., Walsh, G. S., Dunstan, S. J., Bang, N. D., Hagge, D. A., Khadge, S., King, M.-C., Hawn, T. R., Moens, C. B., Ramakrishnan, L. &lt;strong&gt;The Ita4h locus modulates susceptibility to Mycobacterial infection in zebrafish and humans.&lt;/strong&gt; Cell 140: 717-730, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20211140/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20211140&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20211140[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2010.02.013&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20211140">Tobin et al. (2010)</a> hypothesized that LTA4H polymorphisms may alter the response to human mycobacterial infections that cause TB and leprosy (see <a href="/entry/609888">609888</a>). Comparison of 692 Vietnamese HIV-seronegative pulmonary and meningeal TB patients with 759 healthy controls revealed fewer heterozygotes at each of 6 LTA4H SNPs (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1978331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1978331</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs17677715;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs17677715</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2247570;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2247570</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2660898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2660898</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2660845;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2660845</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2540475;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2540475</a>) in TB patients. Comparison of frequencies of heterozygotes versus homozygotes among TB patients and controls yielded odds ratios (ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons, association of heterozygosity with lower incidence of TB was significant at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1978331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1978331</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2660898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2660898</a> (P = 0.011 and 0.0003, respectively, after Bonferroni correction), the 2 SNPs intragenic in LTA4H with common minor allele frequencies. Among 53 meningeal TB patients heterozygous at both <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1978331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1978331</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2660898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2660898</a>, only 4% died within 300 days after diagnosis. In contrast, mortality was 16% among 156 meningeal TB patients homozygous at these SNPs. Evaluation of 335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy patients with erythema nodosum leprosum (ENL), and 443 MB leprosy patients without ENL from Nepal showed that LTA4H heterozygosity at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1978331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1978331</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2660898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2660898</a> was significantly associated with a lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1978331;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1978331</a>, and OR = 0.70 and P = 0.021 for <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2660898;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2660898</a>). <a href="#51" class="mim-tip-reference" title="Tobin, D. M., Vary, J. C., Jr., Ray, J. P., Walsh, G. S., Dunstan, S. J., Bang, N. D., Hagge, D. A., Khadge, S., King, M.-C., Hawn, T. R., Moens, C. B., Ramakrishnan, L. &lt;strong&gt;The Ita4h locus modulates susceptibility to Mycobacterial infection in zebrafish and humans.&lt;/strong&gt; Cell 140: 717-730, 2010.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/20211140/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;20211140&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=20211140[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/j.cell.2010.02.013&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="20211140">Tobin et al. (2010)</a> concluded that LTA4H heterozygosity is associated with protection from TB infection, lower mortality among patients with severe TB infection, and protection from development of severe leprosy disease among exposed individuals. They proposed that LTA4H heterozygosity may reflect an optimal balance, or rheostat mechanism, of pro- and antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and that modulation of lipoxins, informed by LTA4H genotypes, may result in better outcomes for patients with TB meningitis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20211140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a retrospective case-control study of 151 TB patients and 116 controls in Turkey, <a href="#34" class="mim-tip-reference" title="Ogus, A. C., Yoldas, B., Ozdemir, T., Uguz, A., Olcen, S., Keser, I., Coskun, M., Cilli, A., Yegin, O. &lt;strong&gt;The arg753-to-gln polymorphism of the human Toll-like receptor 2 gene in tuberculosis disease.&lt;/strong&gt; Europ. Resp. J. 23: 219-223, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14979495/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14979495&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1183/09031936.03.00061703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14979495">Ogus et al. (2004)</a> found an increased risk of TB in carriers of a nonsynonymous 2258G-A SNP in the TLR2 gene that results in an arg753-to-gln (R753Q; <a href="/entry/603028#0003">603028.0003</a>) substitution. The risk of developing TB was 6.0-fold and 1.6-fold higher in AA homozygotes and GA heterozygotes, respectively. <a href="#34" class="mim-tip-reference" title="Ogus, A. C., Yoldas, B., Ozdemir, T., Uguz, A., Olcen, S., Keser, I., Coskun, M., Cilli, A., Yegin, O. &lt;strong&gt;The arg753-to-gln polymorphism of the human Toll-like receptor 2 gene in tuberculosis disease.&lt;/strong&gt; Europ. Resp. J. 23: 219-223, 2004.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/14979495/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;14979495&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1183/09031936.03.00061703&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="14979495">Ogus et al. (2004)</a> concluded that the R753Q substitution in TLR2 may influence susceptibility to and severity of TB disease and suggested that larger studies are needed to clarify the issue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14979495" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a mixed case-control association analysis of 279 African American and 198 Caucasian TB patients and 166 African American and 123 Caucasian controls, <a href="#52" class="mim-tip-reference" title="Velez, D. R., Hulme, W. F., Myers, J. L., Weinberg, J. B., Levesque, M. C., Stryjewski, M. E., Abbate, E., Estevan, R., Patillo, S. G., Gilbert, J. R., Hamilton, C. D., Scott, W. K. &lt;strong&gt;NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans.&lt;/strong&gt; Hum. Genet. 126: 643-653, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19575238/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19575238&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-009-0713-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19575238">Velez et al. (2009)</a> identified 10 SNPs in NOS2A that were associated with TB in African Americans but not Caucasians. Additionally, they identified gene-gene interactions between SNPs in NOS2A and IFNGR1 and TLR4. <a href="#52" class="mim-tip-reference" title="Velez, D. R., Hulme, W. F., Myers, J. L., Weinberg, J. B., Levesque, M. C., Stryjewski, M. E., Abbate, E., Estevan, R., Patillo, S. G., Gilbert, J. R., Hamilton, C. D., Scott, W. K. &lt;strong&gt;NOS2A, TLR4, and IFNGR1 interactions influence pulmonary tuberculosis susceptibility in African-Americans.&lt;/strong&gt; Hum. Genet. 126: 643-653, 2009.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/19575238/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;19575238&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1007/s00439-009-0713-y&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="19575238">Velez et al. (2009)</a> proposed that NOS2A variants may contribute to TB susceptibility in individuals of African descent and that these variants may act synergistically with SNPs in IFNGR1 and TLR4. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19575238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a candidate gene case-population study of 671 Vietnamese TB patients and 760 cord blood controls, <a href="#41" class="mim-tip-reference" title="Shah, J. A., Vary, J. C., Chau, T. T. H., Bang, N. D., Yen, N. T. B., Farrar, J. J., Dunstan, S. J., Hawn, T. R. &lt;strong&gt;Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis.&lt;/strong&gt; J. Immun. 189: 1737-1746, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22778396/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22778396&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22778396[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.1103541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22778396">Shah et al. (2012)</a> found that the minor alleles of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3750920;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3750920</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs5743899;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs5743899</a> in the TOLLIP gene (<a href="/entry/606277">606277</a>) were associated with protection from and susceptibility to TB, respectively (p = 7.03 x 10(-16) and p = 6.97 x 10(-7), respectively). <a href="#41" class="mim-tip-reference" title="Shah, J. A., Vary, J. C., Chau, T. T. H., Bang, N. D., Yen, N. T. B., Farrar, J. J., Dunstan, S. J., Hawn, T. R. &lt;strong&gt;Human TOLLIP regulates TLR2 and TLR4 signaling and its polymorphisms are associated with susceptibility to tuberculosis.&lt;/strong&gt; J. Immun. 189: 1737-1746, 2012.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/22778396/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;22778396&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=22778396[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.1103541&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="22778396">Shah et al. (2012)</a> concluded that regulation of the TLR pathway by TOLLIP is critical in susceptibility to TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22778396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#54" class="mim-tip-reference" title="Zhang, G., Zhou, B., Li, S., Yue, J., Yang, H., Wen, Y., Zhan, S., Wang, W., Liao, M., Zhang, M., Zeng, G., Feng, C. G., Sassetti, C. M., Chen, X. &lt;strong&gt;Allele-specific induction of IL-1-beta expression by C/EBP-beta and PU.1 contributes to increased tuberculosis susceptibility.&lt;/strong&gt; PLoS Pathog. 10: e1004426, 2014. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25329476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25329476&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25329476[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.ppat.1004426&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25329476">Zhang et al. (2014)</a> examined the genotype distribution of 4 IL1B (<a href="/entry/147720">147720</a>) SNPs with potential regulatory effects in 2 independent Chinese populations with TB and 2 independent sets of healthy controls (1,799 total TB cases and 1,707 total controls). They found that only the frequency of the T allele of the -31C-T SNP (<a href="/entry/147720#0001">147720.0001</a>; <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1143627;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1143627</a>) in the IL1B promoter was significantly higher in patients with active TB, both pulmonary and extrapulmonary. High-resolution computer-assisted tomography analysis indicated that the -31T allele was associated with more severe pulmonary TB than the -31C allele. Stimulation of monocytes with Mtb antigens resulted in higher amounts of IL1B protein and mRNA, but not of IL1R antagonist (IL1RN; <a href="/entry/147679">147679</a>), in healthy controls carrying -31TT or -31TC compared with those carrying -31CC. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mtb antigens resulted in no significant differences in IFNG or IL17 (<a href="/entry/603149">603149</a>) production in controls; however, stimulation was associated with higher IFNG production in TB patients carrying -31TT. Analysis of bronchoalveolar lavage fluid from patients with active TB showed that higher IL1B production was associated with higher neutrophil recruitment. EMSA supershift analysis detected higher binding of CEBPA (<a href="/entry/116897">116897</a>) and PU.1 (SPI1; <a href="/entry/165170">165170</a>) to the -31T oligonucleotide compared with the -31C oligonucleotide. <a href="#54" class="mim-tip-reference" title="Zhang, G., Zhou, B., Li, S., Yue, J., Yang, H., Wen, Y., Zhan, S., Wang, W., Liao, M., Zhang, M., Zeng, G., Feng, C. G., Sassetti, C. M., Chen, X. &lt;strong&gt;Allele-specific induction of IL-1-beta expression by C/EBP-beta and PU.1 contributes to increased tuberculosis susceptibility.&lt;/strong&gt; PLoS Pathog. 10: e1004426, 2014. Note: Electronic Article.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/25329476/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;25329476&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=25329476[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1371/journal.ppat.1004426&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="25329476">Zhang et al. (2014)</a> concluded that the higher IL1B production and neutrophil recruitment associated with -31T lead to increased tuberculosis susceptibility, tissue-damaging inflammatory responses, and accelerated disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25329476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using direct sequencing, <a href="#39" class="mim-tip-reference" title="Salie, M., van der Merwe, L., Moller, M., Daya, M., van der Spuy, G., van Helden, P. D., Martin, M. P., Gao, X., Warren, R. M., Carrington, M., Hoal, E. G. &lt;strong&gt;Associations between human leukocyte antigen class I variants and the Mycobacterium tuberculosis subtypes causing disease.&lt;/strong&gt; J. Infect. Dis. 209: 216-223, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23945374/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23945374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/infdis/jit443&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23945374">Salie et al. (2014)</a> typed the HLA class I (see HLA-B, <a href="/entry/142830">142830</a>) alleles from 300 South African patients with TB. The patients were recruited from suburban Cape Town, where TB prevalence is high, HIV infection is low, and the population is highly admixed. <a href="#39" class="mim-tip-reference" title="Salie, M., van der Merwe, L., Moller, M., Daya, M., van der Spuy, G., van Helden, P. D., Martin, M. P., Gao, X., Warren, R. M., Carrington, M., Hoal, E. G. &lt;strong&gt;Associations between human leukocyte antigen class I variants and the Mycobacterium tuberculosis subtypes causing disease.&lt;/strong&gt; J. Infect. Dis. 209: 216-223, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23945374/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23945374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/infdis/jit443&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23945374">Salie et al. (2014)</a> also genotyped the Mtb strains in each patient. They found that the Beijing Mtb strain occurred more frequently in individuals with multiple disease episodes and that the HLA-B27 allele lowered the odds of having an additional episode and of developing an infection with another Mtb strain. <a href="#39" class="mim-tip-reference" title="Salie, M., van der Merwe, L., Moller, M., Daya, M., van der Spuy, G., van Helden, P. D., Martin, M. P., Gao, X., Warren, R. M., Carrington, M., Hoal, E. G. &lt;strong&gt;Associations between human leukocyte antigen class I variants and the Mycobacterium tuberculosis subtypes causing disease.&lt;/strong&gt; J. Infect. Dis. 209: 216-223, 2014.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/23945374/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;23945374&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1093/infdis/jit443&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="23945374">Salie et al. (2014)</a> showed that various HLA types were associated with strains originating from both the European American and East Asian lineages, suggesting coevolutionary events between host and pathogen. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23945374" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
See <a href="/entry/604457#0003">604457.0003</a> and <a href="/entry/604457#0004">604457.0004</a> for discussion of a possible association between susceptibility to Mycobacterium tuberculosis and variation in the SP110 gene.</p><p>For discussion of a possible association between protection against latent Mycobacterium tuberculosis infection (LTBI) and variation in the ULK1 gene, see <a href="/entry/603168">603168</a>.</p><p><strong><em>Reviews</em></strong></p><p>
<a href="#9" class="mim-tip-reference" title="Berrington, W. R., Hawn, T. R. &lt;strong&gt;Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?&lt;/strong&gt; Immun. Rev. 219: 167-186, 2007.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/17850489/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;17850489&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=17850489[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1111/j.1600-065X.2007.00545.x&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="17850489">Berrington and Hawn (2007)</a> reviewed common genetic variation in the innate immune response and its influence on TB susceptibility. They emphasized variants identified through human genetic studies as associated with TB susceptibility and the functional effects of these polymorphisms on the cellular immune response. Their Table 1 summarized the candidate genes and variants examined to date, the status of replication studies, associations of the variants with other diseases, and the functional effects of the variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17850489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#20" class="mim-tip-reference" title="Flynn, J. L., Goldstein, M. M., Chan, J., Triebold, K. J., Pfeffer, K., Lowenstein, C. J., Schreiber, R., Mak, T. W., Bloom, B. R. &lt;strong&gt;Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.&lt;/strong&gt; Immunity 2: 561-572, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7540941/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7540941&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/1074-7613(95)90001-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7540941">Flynn et al. (1995)</a> found that mice lacking the Tnf receptor p55 gene (TNFRSF1A; <a href="/entry/191190">191190</a>) and infected intravenously with Mycobacterium tuberculosis showed significantly decreased survival, higher bacterial loads, increased necrosis, delayed reactive nitrogen intermediate production and Inos (NOS2A; <a href="/entry/163730">163730</a>) expression, and reduced protection after BCG vaccination than wildtype mice. Based on these results and studies using a monoclonal antibody to neutralize Tnf in mice, <a href="#20" class="mim-tip-reference" title="Flynn, J. L., Goldstein, M. M., Chan, J., Triebold, K. J., Pfeffer, K., Lowenstein, C. J., Schreiber, R., Mak, T. W., Bloom, B. R. &lt;strong&gt;Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice.&lt;/strong&gt; Immunity 2: 561-572, 1995.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/7540941/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;7540941&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1016/1074-7613(95)90001-2&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="7540941">Flynn et al. (1995)</a> concluded that Tnf and Tnf receptor p55 are necessary, if not solely responsible, for protection against murine TB infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7540941" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Roach, D. R., Bean, A. G., Demangel, C., France, M. P., Briscoe, H., Britton, W.J. &lt;strong&gt;TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection.&lt;/strong&gt; J. Immun. 168: 4620-4627, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11971010/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11971010&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.168.9.4620&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11971010">Roach et al. (2002)</a> noted that TNF is essential for the formation and maintenance of granulomas and for resistance against infection with Mycobacterium tuberculosis. Mice lacking Tnf mount a delayed chemokine response associated with a delayed cellular infiltrate. Subsequent excessive chemokine production and an intense but loose and undifferentiated cluster of T cells and macrophages, capable of producing high levels of Ifng in vitro, were unable to protect Tnf -/- mice from fatal tuberculosis after approximately 28 days, whereas all wildtype mice survived for at least 16 weeks. <a href="#37" class="mim-tip-reference" title="Roach, D. R., Bean, A. G., Demangel, C., France, M. P., Briscoe, H., Britton, W.J. &lt;strong&gt;TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection.&lt;/strong&gt; J. Immun. 168: 4620-4627, 2002.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/11971010/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;11971010&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.4049/jimmunol.168.9.4620&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="11971010">Roach et al. (2002)</a> concluded that TNF is required for the early induction of chemokine production and the recruitment of cells forming a protective granuloma. The TNF-independent production of chemokines results in a dysregulated inflammatory response unable to contain M. tuberculosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11971010" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The mouse DBA/2 (D2) strain is very susceptible to infection with virulent Mycobacterium tuberculosis, whereas C57BL/6 (B6) is much more resistant. Infection of D2 and B6 mice with M. tuberculosis by the respiratory route is biphasic: during the first 3 weeks, there is rapid bacterial growth in the lung of both strains, whereas beyond this point replication stops in B6 but continues in D2, causing rapidly fatal pulmonary disease. By QTL mapping, <a href="#33" class="mim-tip-reference" title="Mitsos, L.-M., Cardon, L. R., Ryan, L., LaCourse, R., North, R. J., Gros, P. &lt;strong&gt;Susceptibility to tuberculosis: a locus on mouse chromosome 19 (Trl-4) regulates Mycobacterium tuberculosis replication in the lungs.&lt;/strong&gt; Proc. Nat. Acad. Sci. 100: 6610-6615, 2003.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/12740444/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;12740444&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=12740444[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1073/pnas.1031727100&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="12740444">Mitsos et al. (2003)</a> identified a major locus on chromosome 19 (lod = 5.6), designated tuberculosis resistance locus-4 (Trl4), which regulated pulmonary replication of M. tuberculosis and accounted for 25% of the phenotypic variance. B6 alleles at Trl4 were inherited in an incompletely dominant fashion and associated with reduced bacterial replication. An additional effect of a QTL on mouse chromosome 7 previously shown to affect survival to intravenous infection with M. tuberculosis, Trl3, was also noted. F2 mice homozygous for B6 alleles at both Trl3 and Trl4 were as resistant as B6 parents, whereas mice homozygous for D2 alleles were as susceptible as D2 parents. The evidence suggested a strong genetic interaction between the Trl3 locus on chromosome 7 and the Trl4 locus on chromosome 19, which are syntenic with human chromosomes 19q13 and 10q, respectively. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12740444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using 'diversity outbred' (DO) mice, <a href="#23" class="mim-tip-reference" title="Gopal, R., Monin, L., Torres, D., Slight, S., Mehra, S., McKenna, K. C., Fallert Junecko, B. A., Reinhart, T. A., Kolls, J., Baez-Saldana, R., Cruz-Lagunas, A., Rodriguez-Reyna, T. S., and 15 others. &lt;strong&gt;S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis.&lt;/strong&gt; Am. J. Respir. Crit. Care Med. 188: 1137-1146, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24047412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24047412&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24047412[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.201304-0803OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24047412">Gopal et al. (2013)</a> observed different lung inflammatory responses and susceptibility to infection with Mtb. Lower Mtb burdens were associated with well-organized B-lymphoid follicles and elevated Ifng (<a href="/entry/147570">147570</a>). Mice with increased pulmonary inflammation harbored more S100a8-expressing neutrophils and showed increased Cxcl1, Il17 (<a href="/entry/603149">603149</a>), and lung S100a8/S100a9 expression. Treatment of Mtb-infected wildtype mice with anti-Ifng resulted in increased accumulation of S100a8-expressing neutrophils and exacerbation of inflammation. In contrast, treatment of Mtb-infected S100a9 -/- mice, which also do not express S100a8, with anti-Ifng resulted in loss of lung inflammation and neutrophil accumulation. <a href="#23" class="mim-tip-reference" title="Gopal, R., Monin, L., Torres, D., Slight, S., Mehra, S., McKenna, K. C., Fallert Junecko, B. A., Reinhart, T. A., Kolls, J., Baez-Saldana, R., Cruz-Lagunas, A., Rodriguez-Reyna, T. S., and 15 others. &lt;strong&gt;S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis.&lt;/strong&gt; Am. J. Respir. Crit. Care Med. 188: 1137-1146, 2013.[PubMed: &lt;a href=&quot;https://pubmed.ncbi.nlm.nih.gov/24047412/&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed&#x27;, &#x27;domain&#x27;: &#x27;pubmed.ncbi.nlm.nih.gov&#x27;})&quot;&gt;24047412&lt;/a&gt;, &lt;a href=&quot;https://www.ncbi.nlm.nih.gov/pmc/?term=24047412[PMID]&amp;report=imagesdocsum&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;name&#x27;: &#x27;PubMed Image&#x27;, &#x27;domain&#x27;: &#x27;ncbi.nlm.nih.gov&#x27;})&quot;&gt;images&lt;/a&gt;] [&lt;a href=&quot;https://doi.org/10.1164/rccm.201304-0803OC&quot; target=&quot;_blank&quot; onclick=&quot;gtag(&#x27;event&#x27;, &#x27;mim_outbound&#x27;, {&#x27;destination&#x27;: &#x27;Publisher&#x27;})&quot;&gt;Full Text&lt;/a&gt;]" pmid="24047412">Gopal et al. (2013)</a> concluded that IL17 overexpression, through an S100A8/S100A9-dependent pathway, mediates exacerbated neutrophil recruitment and lung inflammation during TB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24047412" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Abel2000" class="mim-anchor"></a>
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<p class="mim-text-font">
Abel, L., Casanova, J.-L.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882573/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882573</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882573" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/303033" target="_blank">Full Text</a>]
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<a id="Barnes1990" class="mim-anchor"></a>
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Barnes, P. F., Fong, S. J., Brennan, P. J., Twomey, P. E., Mazumder, A., Modlin, R. L.
<strong>Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis.</strong>
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<a id="Barreiro2006" class="mim-anchor"></a>
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Barreiro, L. B., Neyrolles, O., Babb, C. L., Tailleux, L., Quach, H., McElreavey, K., van Helden, P. D., Hoal, E. G., Gicquel, B., Quintana-Murci, L.
<strong>Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis.</strong>
PLoS Med. 3: e20, 2006. Note: Electronic Article.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16379498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16379498</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16379498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1371/journal.pmed.0030020" target="_blank">Full Text</a>]
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<a id="Behr2010" class="mim-anchor"></a>
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Behr, M., Schurr, E., Gros, P.
<strong>TB: screening for responses to a vile visitor.</strong>
Cell 140: 615-618, 2010.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20211131/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20211131</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20211131" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.cell.2010.02.030" target="_blank">Full Text</a>]
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<a id="Bellamy2000" class="mim-anchor"></a>
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Bellamy, R., Beyers, N., McAdam, K. P. W. J., Ruwende, C., Gie, R., Samaai, P., Bester, D., Meyer, M., Corrah, T., Collin, M., Camidge, D. R., Wilkinson, D., Hoal-van Helden, E., Whittle, H. C., Amos, W., van Helden, P., Hill, A. V. S.
<strong>Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.</strong>
Proc. Nat. Acad. Sci. 97: 8005-8009, 2000.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10859364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10859364</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10859364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1073/pnas.140201897" target="_blank">Full Text</a>]
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<a id="Bellamy1999" class="mim-anchor"></a>
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Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Thursz, M., Whittle, H. C., Hill, A. V. S.
<strong>Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.</strong>
J. Infect. Dis. 179: 721-724, 1999.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9952386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9952386</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9952386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/314614" target="_blank">Full Text</a>]
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<a id="Bellamy1998" class="mim-anchor"></a>
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Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Whittle, H. C., Hill, A. V. S.
<strong>Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.</strong>
New Eng. J. Med. 338: 640-644, 1998.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9486992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9486992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9486992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1056/NEJM199803053381002" target="_blank">Full Text</a>]
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<a id="Berg2016" class="mim-anchor"></a>
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Berg, R. D., Levitte, S., O'Sullivan, M. P., O'Leary, S. M., Cambier, C. J., Cameron, J., Takaki, K. K., Moens, C. B., Tobin, D. M., Keane, J., Ramakrishnan, L.
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Cell 165: 139-152, 2016.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27015311/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27015311</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27015311[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27015311" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1016/j.cell.2016.02.034" target="_blank">Full Text</a>]
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<a id="Berrington2007" class="mim-anchor"></a>
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Berrington, W. R., Hawn, T. R.
<strong>Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?</strong>
Immun. Rev. 219: 167-186, 2007.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17850489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17850489</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17850489[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17850489" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1111/j.1600-065X.2007.00545.x" target="_blank">Full Text</a>]
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<a id="Bornman2004" class="mim-anchor"></a>
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Bornman, L., Campbell, S. J., Fielding K., Bah, B., Sillah, J., Gustafson, P., Manneh, K., Lisse, I., Allen, A., Sirugo, G., Sylla, A., Aaby, P., McAdam, K. P. W. J., Bah-Sow, O., Bennett, S., Lienhardt, C., Hill, A. V. S.
<strong>Vitamin D receptor polymorphisms and susceptibility to tuberculosis in West Africa: a case-control and family study.</strong>
J. Infect. Dis. 190: 1631-1641, 2004.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15478069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15478069</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15478069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1086/424462" target="_blank">Full Text</a>]
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<a id="Casanova2002" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Casanova, J.-L., Abel, L.
<strong>Genetic dissection of immunity to mycobacteria: the human model.</strong>
Annu. Rev. Immun. 20: 581-620, 2002.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11861613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11861613</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11861613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1146/annurev.immunol.20.081501.125851" target="_blank">Full Text</a>]
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<a id="Cervino2002" class="mim-anchor"></a>
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Cervino, A. C. L., Lakis, S., Sow, O., Bellamy, R., Beyers, N., Hoal-van Helden, E., van Helden, P., McAdam, K. P. W. J., Hill, A. V. S.
<strong>Fine mapping of a putative tuberculosis-susceptibility locus on chromosome 15q11-13 in African families.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12075004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12075004</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12075004" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1093/hmg/11.14.1599" target="_blank">Full Text</a>]
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<a id="13" class="mim-anchor"></a>
<a id="Comstock1978" class="mim-anchor"></a>
<div class="">
<p class="mim-text-font">
Comstock, G. W.
<strong>Tuberculosis in twins: a re-analysis of the Prophit survey.</strong>
Am. Rev. Resp. Dis. 117: 621-624, 1978.
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/565607/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">565607</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=565607" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
[<a href="https://doi.org/10.1164/arrd.1978.117.4.621" target="_blank">Full Text</a>]
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<a id="Cooke2008" class="mim-anchor"></a>
<div class="">
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Cooke, G. S., Campbell, S. J., Bennett, S., Lienhardt, C., McAdam, K. P. W. J., Sirugo, G., Sow, O., Gustafson, P., Mwangulu, F., van Helden, P., Fine, P., Hoal, E. G., Hill, A. V. S.
<strong>Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis.</strong>
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[<a href="https://doi.org/10.1164/rccm.200710-1554OC" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1164/rccm.200601-088OC" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/scitranslmed.3004912" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.4049/jimmunol.176.2.1090" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1084/jem.20050126" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/315866" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/1074-7613(95)90001-2" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1084/jem.20021229" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1001/jama.279.3.226" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1183/09031936.03.00061703" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/427879" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.4049/jimmunol.166.6.4223" target="_blank">Full Text</a>]
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Bao Lige - updated : 11/22/2019
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<div class="row collapse" id="mimCollapseContributors">
<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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Paul J. Converse - updated : 03/06/2017<br>Paul J. Converse - updated : 2/12/2016<br>Paul J. Converse - updated : 11/12/2014<br>Paul J. Converse - updated : 11/10/2014<br>Paul J. Converse - updated : 10/7/2014<br>Paul J. Converse - updated : 7/1/2013<br>Paul J. Converse - updated : 3/18/2013<br>Paul J. Converse - updated : 8/6/2010<br>Paul J. Converse - updated : 7/1/2010<br>Paul J. Converse - updated : 3/25/2010<br>Paul J. Converse - updated : 3/11/2010<br>Matthew B. Gross - updated : 8/20/2009<br>Matthew B. Gross - updated : 7/27/2009<br>Paul J. Converse - updated : 7/7/2009<br>Paul J. Converse - updated : 5/15/2009<br>George E. Tiller - updated : 4/21/2009<br>Paul J. Converse - updated : 12/12/2008<br>Paul J. Converse - updated : 8/21/2007<br>Paul J. Converse - updated : 10/2/2006<br>Paul J. Converse - updated : 9/5/2006<br>Paul J. Converse - updated : 8/29/2006<br>Paul J. Converse - updated : 8/23/2006<br>Paul J. Converse - updated : 6/22/2006<br>Cassandra L. Kniffin - updated : 3/31/2006<br>Paul J. Converse - updated : 1/25/2006<br>Paul J. Converse - updated : 1/10/2006<br>Paul J. Converse - updated : 8/15/2005
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<a id="creationDate" class="mim-anchor"></a>
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Creation Date:
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<span class="mim-text-font">
Victor A. McKusick : 7/15/2003
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<span class="mim-text-font">
mgross : 11/22/2019
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mgross : 03/06/2017<br>mgross : 03/06/2017<br>carol : 02/20/2017<br>ckniffin : 02/20/2017<br>carol : 06/24/2016<br>mgross : 2/12/2016<br>carol : 1/5/2015<br>mgross : 12/9/2014<br>mgross : 11/12/2014<br>mgross : 11/10/2014<br>mgross : 11/10/2014<br>mgross : 10/7/2014<br>mgross : 7/1/2013<br>mgross : 3/18/2013<br>mgross : 3/18/2013<br>mgross : 12/1/2011<br>carol : 3/21/2011<br>terry : 12/8/2010<br>alopez : 11/10/2010<br>mgross : 11/10/2010<br>mgross : 8/6/2010<br>terry : 7/1/2010<br>alopez : 6/10/2010<br>mgross : 3/25/2010<br>mgross : 3/11/2010<br>mgross : 3/11/2010<br>mgross : 8/20/2009<br>mgross : 7/27/2009<br>mgross : 7/27/2009<br>mgross : 7/27/2009<br>mgross : 7/9/2009<br>mgross : 7/9/2009<br>mgross : 7/9/2009<br>terry : 7/7/2009<br>terry : 6/3/2009<br>wwang : 5/27/2009<br>mgross : 5/18/2009<br>terry : 5/15/2009<br>alopez : 4/21/2009<br>alopez : 4/21/2009<br>mgross : 12/12/2008<br>carol : 10/24/2008<br>alopez : 9/23/2008<br>mgross : 8/22/2007<br>terry : 8/21/2007<br>alopez : 6/28/2007<br>alopez : 6/13/2007<br>mgross : 5/21/2007<br>carol : 4/24/2007<br>terry : 11/3/2006<br>wwang : 10/27/2006<br>mgross : 10/2/2006<br>mgross : 9/5/2006<br>mgross : 8/29/2006<br>mgross : 8/23/2006<br>mgross : 6/22/2006<br>wwang : 4/6/2006<br>ckniffin : 3/31/2006<br>carol : 3/10/2006<br>mgross : 1/25/2006<br>mgross : 1/10/2006<br>terry : 12/21/2005<br>mgross : 8/15/2005<br>terry : 5/21/2004<br>carol : 1/30/2004<br>tkritzer : 1/30/2004<br>tkritzer : 7/16/2003
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<h3>
<span class="mim-font">
<strong>#</strong> 607948
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<h3>
<span class="mim-font">
MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO
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<p>
<span class="mim-font">
Other entities represented in this entry:
</span>
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<span class="h3 mim-font">
MYCOBACTERIUM TUBERCULOSIS, PROTECTION AGAINST, INCLUDED
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<p>
<span class="mim-text-font">
<strong>ORPHA:</strong> 3389; &nbsp;
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<h4>
<span class="mim-font">
<strong>Phenotype-Gene Relationships</strong>
</span>
</h4>
<div>
<table class="table table-bordered table-condensed small mim-table-padding">
<thead>
<tr class="active">
<th>
Location
</th>
<th>
Phenotype
</th>
<th>
Phenotype <br /> MIM number
</th>
<th>
Inheritance
</th>
<th>
Phenotype <br /> mapping key
</th>
<th>
Gene/Locus
</th>
<th>
Gene/Locus <br /> MIM number
</th>
</tr>
</thead>
<tbody>
<tr>
<td>
<span class="mim-font">
2q35
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to infection by}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
NRAMP1
</span>
</td>
<td>
<span class="mim-font">
600266
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
2q37.1
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
SP110
</span>
</td>
<td>
<span class="mim-font">
604457
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
3p21.2
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
CISH
</span>
</td>
<td>
<span class="mim-font">
602441
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
4q31.3
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
TLR2
</span>
</td>
<td>
<span class="mim-font">
603028
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
5q33.1
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, protection against}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
IRGM
</span>
</td>
<td>
<span class="mim-font">
608212
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
6q23.3
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
IFNGR1
</span>
</td>
<td>
<span class="mim-font">
107470
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
6q23.3
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis infection, protection against}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
IFNGR1
</span>
</td>
<td>
<span class="mim-font">
107470
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
11q24.2
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, protection against}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
TIRAP
</span>
</td>
<td>
<span class="mim-font">
606252
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
12q15
</span>
</td>
<td>
<span class="mim-font">
{Tuberculosis, protection against}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
IFNG
</span>
</td>
<td>
<span class="mim-font">
147570
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
17q12
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
CCL2
</span>
</td>
<td>
<span class="mim-font">
158105
</span>
</td>
</tr>
<tr>
<td>
<span class="mim-font">
19p13.2
</span>
</td>
<td>
<span class="mim-font">
{Mycobacterium tuberculosis, susceptibility to}
</span>
</td>
<td>
<span class="mim-font">
607948
</span>
</td>
<td>
<span class="mim-font">
</span>
</td>
<td>
<span class="mim-font">
3
</span>
</td>
<td>
<span class="mim-font">
CD209
</span>
</td>
<td>
<span class="mim-font">
604672
</span>
</td>
</tr>
</tbody>
</table>
</div>
</div>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>TEXT</strong>
</span>
</h4>
<span class="mim-text-font">
<p>A number sign (#) is used with this entry because susceptibility to Mycobacterium tuberculosis (TB) is associated with variation in many genes. Case-control studies in areas of endemic TB have pointed to variation in the HLA (see 142800), NRAMP1 (600266), vitamin D receptor (VDR; 601769), mannose-binding protein (MBL2; 154545), and cytokine-inducible SH2-containing protein (CISH; 602441) genes as contributing to TB susceptibility (Mitsos et al., 2003, Khor et al., 2010). Variation in the CD209 (604672) and MCP1 (CCL2; 158105) genes is also associated with TB susceptibility. TB susceptibility loci have been mapped to chromosome 2q35 (MTBS1; 607949), near NRAMP1, and to chromosomes 8q12-q13 (MTBS2; 611046) and 20q13.31-q33 (MTBS3; 612929). X-linked susceptibility to TB has also been suggested (MTBSX; 300259). Protection against TB has been associated with SNPs in the TIRAP (606252), IFNG (147570), and IFNGR1 (107470) genes. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Description</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Mycobacterium tuberculosis latently infects approximately one-third of humanity and is comparable only to human immunodeficiency virus (HIV; see 609423) as a leading infectious cause of mortality worldwide. Obstacles for controlling TB infection include lengthy treatment regimens of 6 to 9 months, drug resistance, lack of a highly efficacious vaccine, and incomplete understanding of the factors that control infectivity and disease progression. Although only 10% of individuals infected with M. tuberculosis develop active disease, the immune responses associated with TB susceptibility or resistance are not known. In addition, it is not known why some individuals have disseminated TB that spreads to the meninges and central nervous system, while most people have localized disease in the lungs. A number of studies suggest that host genetic factors influence susceptibility and resistance to TB (review by Berrington and Hawn, 2007). </p>
</span>
<div>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Pathogenesis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Price et al. (2001) detected a significantly higher concentration of MMP9 (120361) per leukocyte in cerebrospinal fluid from adult tuberculous meningitis patients than in patients with bacterial or viral meningitis. In vitro studies indicated that viable bacilli were not required to stimulate MMP9 production. In contrast to the changes in MMP9 expression, MMP2 (120360) and tissue inhibitor of metalloproteinase-1 (TIMP1; 305370) were constitutively expressed, and the latter did not oppose the MMP9 activity. Elevated MMP9 activity was related to unconsciousness, confusion, focal neurologic damage, and death in the tuberculous meningitis patients. </p><p>Geijtenbeek et al. (2003) found that DCSIGN (CD209; 604672) captured and internalized intact Mycobacterium bovis BCG or avirulent M. tuberculosis through the glycolipid mycobacterial cell wall component ManLAM. Both bacilli and ManLAM were targeted to lysosomes and colocalized with LAMP1 (153330) in immature DCs. Antibodies against DCSIGN blocked BCG infection of DCs. Binding of secreted ManLAM to DCSIGN prevented mycobacteria- or LPS-induced DC maturation and induced IL10 (124092) production, suggesting that DCSIGN-ManLAM interaction may interfere with TLR-mediated signaling and development of an antiinflammatory response. Geijtenbeek et al. (2003) proposed that M. tuberculosis may target DCSIGN both to infect DCs and to downregulate DC-mediated immune responses. </p><p>Tailleux et al. (2003) showed that M. tuberculosis entered DCs after binding to DCSIGN, whereas the major macrophage receptors for M. tuberculosis, CR3 (see ITGAM; 120980) and MRC1 (153618), played only a minor role in DC infection. Flow cytometric and histopathologic analyses showed expression of DCSIGN on lung DCs from uninfected patients and on lymph node granuloma cells infected with M. tuberculosis. </p><p>Using flow cytometric analysis of bronchoalveolar lavage cells from tuberculosis (TB), asthma, and sarcoidosis patients and control individuals, Tailleux et al. (2005) found that most alveolar macrophages from TB patients expressed DCSIGN, whereas the lectin was barely detected in cells from the other subjects. FACS, RT-PCR, and ELISA analyses indicated that M. tuberculosis infection induced DCSIGN expression by a mechanism independent of TLR4 (603030), IL4 (147780), and IL13 (147683). Immunohistochemical analysis showed bacillary concentration in lung regions enriched in DCSIGN-expressing alveolar macrophages. Binding experiments revealed that DCSIGN-expressing alveolar macrophages were preferential targets for M. tuberculosis compared with DCSIGN-negative cells. Tailleux et al. (2005) did not detect IL10 in bronchoalveolar lavage or induction of IL10 in infected cells. </p><p>Mycobacterium tuberculosis (Mtb) can persist in unidentified niches in the host long before the onset of disease symptoms and even after effective treatment. Latent tuberculosis is a major risk factor for active disease. Das et al. (2013) hypothesized that bone marrow stem cells (BMSCs), comprising both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), may provide an ideal protective niche since they are found in tuberculosis lung granulomas of infected humans and mice; renew themselves; possess drug efflux pumps, such as ABCG2 (603756); produce only low levels of reactive oxygen species; are quiescent; and are found in the immune-privileged niche in bone marrow. By screening BMSCs expressing the CD133 (604365) marker and several BMSC subpopulations, Das et al. (2013) found that undifferentiated CD271 (NGFR; 162010)-positive/CD45 (151460)-negative MSCs, but not CD34 (142230)-positive/CD45-positive HSCs, were permissive for and tolerated Mtb. Experiments in mice showed that Mtb, even if in a nonreplicating state, resided in MSCs in both bone marrow and lungs, particularly in the ABCG2-positive side population of lung MSCs. Studies in patients who had successfully completed monitored tuberculosis treatment demonstrated that Mtb DNA and, in some patients, viable Mtb could be isolated from CD271-positive/CD45-negative bone marrow MSCs. Das et al. (2013) proposed that CD271-positive bone marrow MSCs can provide a long-term protective niche in which dormant Mtb resides. </p><p>Using transcriptomic analysis, Kubler et al. (2016) showed that several collagen-degrading proteases, including Mmp1 (120353), Mmp13 (600108), Mmp14 (600754), Cma1 (118938), and Ctsk (601105), were highly upregulated in a rabbit cavitary TB model. Ctsk was the most upregulated type I collagenase in both cavitary and granulomatous tissue, as assessed by RT-PCR and immunohistochemical analysis, and the authors noted that it is unique in its ability to cleave type I collagen (see COL1A1, 120150) inside and outside the helical region. Serum levels of CICP and free urinary deoxypyridinoline, turnover products of type I collagen, were increased, whereas urinary helical peptide was decreased, in rabbits with terminal cavities. Expression of Col1a1, Col1a2 (120160), and Col3a1 (120180) was increased in cavity wall tissue. Immunohistochemical analysis demonstrated CTSK expression in mononuclear and multinucleated giant cells at the periphery of pulmonary lesions and cavity surfaces in patients with TB. Plasma CTSK was significantly higher in patients with active TB compared with healthy controls. Kubler et al. (2016) proposed that CTSK-mediated collagen degradation plays an important role in cavity formation in TB. </p><p>Using a zebrafish genetic screen, Berg et al. (2016) identified a mutation in the transcriptional coregulator Snapc1b (600591) that resulted in hypersusceptibility to Mycobacterium marinum. RNA sequencing analysis of Snapc1b mutants showed reduced expression of cathepsins B (CTSB; 116810) and L (CTSL; 116880). Mutant macrophages accumulated undigested lysosomal material, disrupting endocytic recycling and impairing macrophage migration to and engulfment of dying cells and cell debris. Macrophages with lysosomal storage could not migrate toward mycobacteria-infected macrophages undergoing apoptosis in a tuberculous granuloma. Unengulfed apoptotic macrophages underwent secondary necrosis, resulting in granuloma breakdown and increased mycobacterial growth. Bronchoalveolar lavage analysis showed that the phenotype could be recapitulated in human smokers, who are at increased risk for TB. Alveolar macrophages of smokers accumulated tobacco smoke particulates and did not migrate to M. tuberculosis. Smoking cessation ameliorated the condition, and ex-smoker alveolar macrophages migrated nearly as well to M. tuberculosis as cells of nonsmokers. Likewise, macrophages from patients with Gaucher disease (see 230800) had migration defects, and these patients had greater susceptibility to infections, including mycobacteria. Berg et al. (2016) concluded that incapacitation of microbicidal first-responding macrophages may contribute to smokers' susceptibility to TB. </p><p>Wu et al. (2019) found that M. tuberculosis infection enhanced MDR1 (ABCB1; 171050) expression in monocyte-derived macrophages (MDMs) and in lungs of infected mice. This MDR1 upregulation in human macrophages required virulence factors released by M. tuberculosis and the Esx1 secretion system. M. tuberculosis infection enhanced expression of MIR431 (611708), which resulted in MIR431-mediated suppression of HSF1 (140580) and increased MDR1 expression in MDMs. Enhanced MDR1 expression increased extrusion of antituberculosis drugs from the macrophage, lowered the effective intracellular minimum inhibitory concentration, and promoted survival of M. tuberculosis during antibiotic treatment. </p><p><strong><em>Reviews</em></strong></p><p>
Behr et al. (2010) reviewed several studies implicating stimulation of antiinflammatory molecules and inhibition of autophagy by virulent mycobacteria as a means to evade the host immune system. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Diagnosis</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>By RT-PCR and immunohistochemical analysis, Gopal et al. (2013) demonstrated that rhesus macaques and humans with active TB compared with latent TB infection had increased levels of S100A8 (123885) and neutrophils expressing S100A8. Additionally, serum levels of S100A8/S100A9 (123885/123886), IP10 (CXCL10; 147310), and the neutrophil and keratinocyte chemoattractant KC (CXCL1; 155730) were increased in active TB compared with latent TB infection. Gopal et al. (2013) proposed that serum levels of S100A8/S100A9, along with chemokines such as KC, can be used as surrogate markers of lung inflammation during TB and can predict the development of active TB in patients with latent TB infection in TB-endemic, high-risk populations. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Inheritance</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Abel and Casanova (2000) reviewed the evidence for genetic predisposition to clinical tuberculosis. From published reports, they recognized a gap between causal susceptibility in rare individuals and uncertain predisposition in general populations. They expressed the opinion that these 2 aspects of genetic predisposition to tuberculosis do not conflict but, rather, are likely to represent the 2 ends of a continuous spectrum. </p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Mapping</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Bellamy et al. (2000) conducted a 2-stage genomewide linkage study of 136 African families to search for regions of the human genome containing tuberculosis susceptibility genes. They used sib-pair families that contained 2 full sibs who had both been affected by clinical tuberculosis. For any chromosomal region containing a major tuberculosis susceptibility gene, affected sib-pairs inherit the same parental alleles much more than expected by chance. In the first round of the screen, 299 highly informative genetic markers, spanning the entire human genome, were typed in 92 sib-pairs from The Gambia and South Africa. In this process, they identified 7 chromosomal regions that showed provisional evidence of coinheritance with clinical tuberculosis. From these regions, 22 markers were genotyped in a second set of 81 sib-pairs from the same countries. Markers on 15q11-q13 and Xq (300259) showed suggestive evidence of linkage (lod = 2.00 and 1.77, respectively) to tuberculosis. An X chromosome susceptibility gene might contribute to the excess of males with tuberculosis observed in many different populations. </p><p>Cervino et al. (2002) tested 10 microsatellite markers and 5 positional candidate genes in the 15q11-q13 chromosomal region for deviation from random transmission from parents to affected offspring. A borderline significant association with a 7-bp deletion in the UBE3A gene (601623) (P = 0.01) was found. This polymorphism was then evaluated further in a larger series of families with tuberculosis, including 44 Guinean families and 57 families from South Africa. Testing for association between the deletion and tuberculosis across all the families using the exact symmetry test further supported the association (overall P = 0.002). The authors suggested that UBE3A or a closely flanking gene may be a tuberculosis susceptibility locus. </p><p>A region of mouse chromosome 11 that is syntenic with human chromosome 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. To examine this region in humans, Jamieson et al. (2004) studied 92 multicase tuberculosis families (627 individuals) and 72 multicase leprosy (246300) families (372 individuals) from Brazil. Multipoint nonparametric analysis using 16 microsatellites showed 2 peaks of linkage for leprosy at D17S250 and D17S1795 and a single peak for tuberculosis at D17S250. Combined analysis showed significant linkage at D17S250, equivalent to an allele sharing lod score of 2.48 (p of 0.0004). Jamieson et al. (2004) typed 49 informative SNPs in candidate genes, and family-based allelic testing that was robust to family clustering showed significant associations with tuberculosis susceptibility at 4 genes, NOS2A (163730), CCL18 (603757), CCL4 (182284), and STAT5B (604260), separated by intervals up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control dataset showed that the 4 genes contributed separate main effects, consistent with a cluster of susceptibility genes across chromosome 17q11.2. </p><p>In a 2-stage genomewide scan of 38 multicase tuberculosis families (349 individuals) in Brazil, Miller et al. (2004) found suggestive evidence for linkage to chromosomes 10q26.13, 11q12.3, and 20p12.1. Peak lod scores for these regions were 1.31 (p of 0.007), 1.85 (p of 0.0018), and 1.78 (p of 0.0021), respectively. </p><p>Using genomewide linkage and positional mapping of TB-affected sib pairs in South Africans of mixed racial origin and in Africans from northern Malawi, Cooke et al. (2008) identified 2 novel putative TB susceptibility loci on chromosomes 6p21-q23 and 20q13.31-q33 (MTBS3; 612929). The latter locus had a highly significant single-point lod score of 3.1. </p><p>See 613636 for information on TST1, a locus on chromosome 11p14 associated with absence of tuberculin skin test (TST) reactivity.</p><p>See 613637 for information on TST2, a quantitative trait locus of chromosome 5p15 for TST reactivity measured in millimeters.</p>
</span>
<div>
<br />
</div>
<div>
<h4>
<span class="mim-font">
<strong>Molecular Genetics</strong>
</span>
</h4>
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<span class="mim-text-font">
<p>There is substantial evidence from studies on racial variation in susceptibility to tuberculosis (Stead et al., 1990; Stead, 1992) and twin studies (Comstock, 1978; Bellamy et al., 1998) that host genetic factors are important in determining susceptibility to infection with Mycobacterium tuberculosis and the subsequent development of clinical disease. In a large case-control study in Gambians, including more than 800 subjects, Bellamy et al. (1998, 1999) showed that genetic variants of NRAMP1 and VDR are associated with smear-positive pulmonary tuberculosis. However, together, these can only account for a small proportion of the overall genetic component suggested by twin studies. </p><p>Selvaraj et al. (2004) presented evidence suggesting that polymorphisms in the VDR gene may predispose to spinal TB. </p><p>Bornman et al. (2004) genotyped the VDR SNPs FokI, BsmI, ApaI, and TaqI in TB patients, controls, and families in the Gambia, Guinea, and Guinea-Bissau. By transmission-disequilibrium analysis of family data, they found a significant global association of TB with the SNP combinations FokI-BsmI-ApaI- TaqI and FokI-ApaI driven by increased transmission of the FokI F and ApaI A alleles in combination to affected offspring. Case-control analysis showed no significant association between TB and VDR variants. Bornman et al. (2004) concluded that there is a haplotype, rather than a genotype, association between VDR variants and susceptibility to TB. </p><p>Mitsos et al. (2003) noted that only a small proportion of individuals who come in contact with M. tuberculosis develop active TB, and a wide clinical spectrum of disease severity is observed in such individuals. Appearance of full-blown disease is determined in part by microbial virulence determinants and by environmental and host factors, such as social conditions and immune status, most critically by the presence of concomitant HIV infection. An important genetic component of vulnerability to TB in humans affecting susceptibility per se, disease progression, and ultimate outcome had been well documented Casanova and Abel (2002). This genetic component is supported by epidemiologic data pointing to racial differences in susceptibility, as well as familial aggregation. Studies of first-contact epidemics in isolated populations with no ancestral experience of this infection, survival data from accidental injection of virulent M. tuberculosis during a BCG vaccination trial (the Lubeck disaster), and studies in twins showing higher concordance rates of TB in monozygotic versus dizygotic twins provided compelling evidence that host genes affect the outcome of M. tuberculosis infection (Kallmann and Reisner, 1943; Simonds, 1963; Comstock, 1978). Rare mutations in the IFN-gamma receptor-1 gene (IFNGR1; 107470) had been demonstrated in familial generalized BCG infection and in familial disseminated infection with an atypical mycobacterium (see 209950). Similarly, susceptibility to mycobacterial infections had been demonstrated in rare mutations in the interleukin-12 receptor (IL12RB1; 601604) and in interleukin-12B (IL12B; 161561). </p><p>Ozbek et al. (2005) reported an 11-year-old Turkish girl with IL12RB1 deficiency and severe abdominal tuberculosis. She was the fourth child of healthy, consanguineous parents. Like her parents and sibs, she had had no adverse effect from BCG vaccination, and there was no family history of mycobacterial disease or other intracellular infectious diseases. The patient did not show augmented production of IFNG (147570) in response to antigen plus IL12. Ozbek et al. (2005) identified a homozygous splice site mutation in the IL12RB1 gene that led to skipping of exon 9 (601604.0006). They concluded that a diagnosis of IL12RB1 deficiency should be considered for children with unusually severe tuberculosis, even if they have no personal or family history of infection with weakly virulent Mycobacterium or Salmonella species. </p><p>Soborg et al. (2003) examined MBL genotypes and serum MBL levels in 109 patients with clinical tuberculosis and 250 controls. Heterozygotes with a variant MBL structural allele associated with low functional serum MBL on one chromosome and a normal MBL structural allele with a low-expression promoter polymorphism on the other chromosome appeared to be relatively protected against clinical tuberculosis, whereas genotypes associated with high MBL expression and genotypes conferring MBL deficiency were not. Soborg et al. (2003) proposed that low serum MBL may be protective against tuberculosis by limiting complement activation and uptake of bacilli by complement receptors. In the absence of MBL, bacilli may be taken up directly by mannose receptors (e.g., MRC1; 153618). </p><p>Barreiro et al. (2006) examined CD209 polymorphisms in 351 TB patients and 360 healthy controls from a South African Coloured population (historically derived from Khoisan, Malaysian, Bantu, and European descent populations) living in communities with some of the highest reported incidence rates of TB in the world. They identified 2 CD209 promoter variants, -871A (604672.0002) and -336G (604672.0001), that were associated with increased risk of TB. One haplotype of 8 SNPs, including -871G and -336A, showed a highly significant association with the control group. Further analysis of sub-Saharan African, European, and Asian populations showed that the protective -336A and -871G alleles were present at higher frequencies in Eurasians than in Africans. Barreiro et al. (2006) suggested that the longer and more intense duration of TB exposure in Europe may have exerted stronger selective pressures in this population and may have had an impact on susceptibility to infection by other pathogens, such as HIV and dengue (see 614371). </p><p>Malik et al. (2006) reported a significant association (p = 0.007 after Bonferroni correction) between a synonymous 307G-A SNP in the gene encoding surfactant pulmonary-associated protein A1 (SFTPA1; 178630) and susceptibility to tuberculosis in an Ethiopian population. The authors suggested that the polymorphism may affect splicing and/or mRNA maturation. Malik et al. (2006) noted that Floros et al. (2000) had previously reported an association between SFTPA1 polymorphisms and tuberculosis in a Mexican population. </p><p>Goldfeld et al. (1998) demonstrated a significant association between the *0503 allele of HLA-DQB1 (604305) and susceptibility to tuberculosis in Cambodian patients. This appeared to be the first identified gene associated with the development of clinical tuberculosis. </p><p>In a study of 436 Cambodian patients with tuberculosis, Delgado et al. (2006) found that susceptibility to tuberculosis was significantly associated with homozygosity for the asp57 allele of HLA-DQB1. Two immunogenic proteins of Mycobacterium tuberculosis, Esat6 and Cfp10, bound less well to asp57 than to ala57. Presentation of these tuberculosis proteins to T cells resulted in significantly decreased production of IFNG when the antigen-presenting cells expressed asp57 rather than ala57. Delgado et al. (2006) concluded that HLA-DQB1 has a role in the host immune response to tuberculosis. </p><p>Flores-Villanueva et al. (2005) found that Mexicans heterozygous or homozygous for the -2518G allele of the -2518A-G SNP (158105.0003) had a 2.3- and 5.4-fold increased risk of developing active pulmonary tuberculosis, respectively. Among Korean patients, the increased risk was 2.8- and 6.9-fold higher, respectively. </p><p>Thye et al. (2009) determined the -2518 genotype and additional MCP1 variants in over 2,000 cases with pulmonary TB and more than 2,300 healthy controls and 332 affected nuclear families from Ghana, West Africa, and over 1,400 TB patients and more than 1,500 controls from Russia. In contrast to the report of Flores-Villanueva et al. (2005), MCP1 -2518 (rs1024611) was significantly associated with resistance to TB in cases versus controls (odds ratio (OR) 0.81, corrected P value (Pcorr) = 0.0012) and nuclear families (OR 0.72, Pcorr = 0.04) and not with disease susceptibility, whereas in the Russian sample no evidence of association was found (P = 0.86). These and other results did not support an association of MCP1 -2518 with TB. In the Ghanaian population, 8 additional MCP1 polymorphisms were genotyped. MCP1 -362C was associated with resistance to TB in the case-control collection (OR 0.83, Pcorr = 0.00017) and in the affected families (OR 0.7, Pcorr = 0.004). Linkage disequilibrium (LD) and logistic regression analyses indicated that, in Ghanaians, the effect was due exclusively to the MCP1 -362 variant, whereas the effect of -2518 may in part be explained by its LD with -362. </p><p>Studies in mice (Flynn et al., 1995) and observations in patients receiving infliximab (remicade) for treatment of rheumatoid arthritis (180300) or Crohn disease (see IBD1, 266600) (Keane et al., 2001) have shown that antibody-mediated neutralization of TNF (191160) increases susceptibility to TB. However, excess TNF may be associated with severe TB pathology (Barnes et al., 1990). Using path and segregation analysis and controlling for environmental differences, Stein et al. (2005) evaluated TNF secretion levels in Ugandan TB patients. The results suggested that there is a strong genetic influence, due to a major gene, on TNF expression in TB, and that there may be heterozygote advantage. The effect of shared environment on TNF expression in TB was minimal. Stein et al. (2005) concluded that TNF expression is an endophenotype for TB that may increase power to detect disease-predisposing loci. </p><p>As a follow-up to their studies examining TNF levels in response to M. tuberculosis culture filtrate antigen as an intermediate phenotype model for TB susceptibility in a Ugandan population, Stein et al. (2007) studied genes related to TNF regulation by positional candidate linkage followed by family-based SNP association analysis. They found that the IL10, IFNGR1, and TNFR1 (TNFRSF1A; 191190) genes were linked and associated to both TB and TNF. These associations were with active TB rather than susceptibility to latent infection. </p><p>To test the hypothesis that a polymorphism in IFNG (147570) is associated with susceptibility to tuberculosis, Rossouw et al. (2003) conducted 2 independent studies. In a case-control study of 313 tuberculosis cases, they noted a significant association between a polymorphism (+874A-T; 147570.0002) in IFNG and protection against tuberculosis in a South African population (p = 0.0055). This finding was replicated in a family-based study, in which the transmission disequilibrium test was used in 131 families (p = 0.005). The transcription factor NF-kappa-B (NFKB1; 164011) binds preferentially to the +874T allele, which was overrepresented in controls, suggesting that genetically-determined variability in IFNG and expression might be important for the development of tuberculosis. </p><p>In a case-control study of 682 TB patients and 619 controls from 3 West African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), Cooke et al. (2006) observed the IFNG +874AA genotype more frequently in TB patients than controls, but the trend was not statistically significant. However, the +874A-T SNP was in strong linkage disequilibrium with 2 other SNPs, -1616G-A and +3234T-C, and both the -1616GG and +3234TT genotypes were significantly associated with TB. Haplotype analysis in a smaller Gambian population sample showed that the 3 alleles putatively associated with TB were all found on the most common West African haplotype, which, although overtransmitted, was not significantly associated with disease in this smaller population. Cooke et al. (2006) also found that the -56CC genotype of the IFNGR1 (107470) promoter -56C-T SNP (107470.0012) was associated with protection from TB. No associations with TB were observed with SNPs in the IFNGR2 gene (147569). Cooke et al. (2006) concluded that there is a significant role for genetic variation in IFNG and IFNGR1 in susceptibility to TB. </p><p>Khor et al. (2007) found that heterozygous carriage of a leucine substitution at ser180 of the TIRAP gene (606252.0001) associated independently with protection against 4 infectious diseases, including tuberculosis, in several different study populations. </p><p>The immunity-related GTPase IRGM (608212) is a mediator of innate immune responses and induces autophagy. Intemann et al. (2009) examined variants in the IRGM gene using a case-control study of 2,010 HIV-seronegative TB patients and 2,346 healthy controls in Ghana. They found a trend for association of homozygosity for -261C-T (rs9637876), which is located within an Alu sequence in the promoter region of IRGM, with protection from TB. IRGM -261TT was significantly associated with protection from TB caused by M. tuberculosis (OR = 0.79; P = 0.017), but not by M. africanum, a strain restricted to West Africa, or M. bovis. Further stratification of mycobacterial genotypes revealed that protection associated with -261TT applied exclusively to carriers of M. tuberculosis from the Euro-American (EUAM) lineage (OR = 0.63; nominal P = 0.0004; corrected P = 0.0019), but not to carriers of M. tuberculosis from the East African-Indian, Beijing, or Dehli lineages. The EUAM lineage of the M. tuberculosis clade, but not other strains, has a damaged gene encoding a phenolic glycolipid. No association was found for carriers of the heterozygous -261CT genotype. The -261T IRGM variant was predicted to disrupt several transcription factor-binding sites, and luciferase analysis showed significantly increased expression of the -261T IRGM variant compared with the -261C IRGM variant, suggesting enhanced expression of the mature IRGM protein. Intemann et al. (2009) proposed that IRGM and autophagy have a role in protection against natural infection with EUAM strains, and that M. tuberculosis lineages expressing mycobacterial phenolic glycolipid inhibit innate immune responses involving autophagy. </p><p>Given the altered balance of pro- and antiinflammatory eicosanoids in zebrafish with mutations in leukotriene A4 hydrolase (LTA4H; 151570), Tobin et al. (2010) hypothesized that LTA4H polymorphisms may alter the response to human mycobacterial infections that cause TB and leprosy (see 609888). Comparison of 692 Vietnamese HIV-seronegative pulmonary and meningeal TB patients with 759 healthy controls revealed fewer heterozygotes at each of 6 LTA4H SNPs (rs1978331, rs17677715, rs2247570, rs2660898, rs2660845, and rs2540475) in TB patients. Comparison of frequencies of heterozygotes versus homozygotes among TB patients and controls yielded odds ratios (ORs) less than 1 at all 6 SNPs. Adjusting for multiple comparisons, association of heterozygosity with lower incidence of TB was significant at rs1978331 and rs2660898 (P = 0.011 and 0.0003, respectively, after Bonferroni correction), the 2 SNPs intragenic in LTA4H with common minor allele frequencies. Among 53 meningeal TB patients heterozygous at both rs1978331 and rs2660898, only 4% died within 300 days after diagnosis. In contrast, mortality was 16% among 156 meningeal TB patients homozygous at these SNPs. Evaluation of 335 paucibacillary leprosy patients, 121 multibacillary (MB) leprosy patients with erythema nodosum leprosum (ENL), and 443 MB leprosy patients without ENL from Nepal showed that LTA4H heterozygosity at rs1978331 and rs2660898 was significantly associated with a lower incidence of MB leprosy without ENL (OR = 0.62 and P = 0.001 for rs1978331, and OR = 0.70 and P = 0.021 for rs2660898). Tobin et al. (2010) concluded that LTA4H heterozygosity is associated with protection from TB infection, lower mortality among patients with severe TB infection, and protection from development of severe leprosy disease among exposed individuals. They proposed that LTA4H heterozygosity may reflect an optimal balance, or rheostat mechanism, of pro- and antiinflammatory eicosanoids (i.e., LTB4 and LXA4, respectively), and that modulation of lipoxins, informed by LTA4H genotypes, may result in better outcomes for patients with TB meningitis. </p><p>Using a retrospective case-control study of 151 TB patients and 116 controls in Turkey, Ogus et al. (2004) found an increased risk of TB in carriers of a nonsynonymous 2258G-A SNP in the TLR2 gene that results in an arg753-to-gln (R753Q; 603028.0003) substitution. The risk of developing TB was 6.0-fold and 1.6-fold higher in AA homozygotes and GA heterozygotes, respectively. Ogus et al. (2004) concluded that the R753Q substitution in TLR2 may influence susceptibility to and severity of TB disease and suggested that larger studies are needed to clarify the issue. </p><p>Using a mixed case-control association analysis of 279 African American and 198 Caucasian TB patients and 166 African American and 123 Caucasian controls, Velez et al. (2009) identified 10 SNPs in NOS2A that were associated with TB in African Americans but not Caucasians. Additionally, they identified gene-gene interactions between SNPs in NOS2A and IFNGR1 and TLR4. Velez et al. (2009) proposed that NOS2A variants may contribute to TB susceptibility in individuals of African descent and that these variants may act synergistically with SNPs in IFNGR1 and TLR4. </p><p>Using a candidate gene case-population study of 671 Vietnamese TB patients and 760 cord blood controls, Shah et al. (2012) found that the minor alleles of rs3750920 and rs5743899 in the TOLLIP gene (606277) were associated with protection from and susceptibility to TB, respectively (p = 7.03 x 10(-16) and p = 6.97 x 10(-7), respectively). Shah et al. (2012) concluded that regulation of the TLR pathway by TOLLIP is critical in susceptibility to TB. </p><p>Zhang et al. (2014) examined the genotype distribution of 4 IL1B (147720) SNPs with potential regulatory effects in 2 independent Chinese populations with TB and 2 independent sets of healthy controls (1,799 total TB cases and 1,707 total controls). They found that only the frequency of the T allele of the -31C-T SNP (147720.0001; rs1143627) in the IL1B promoter was significantly higher in patients with active TB, both pulmonary and extrapulmonary. High-resolution computer-assisted tomography analysis indicated that the -31T allele was associated with more severe pulmonary TB than the -31C allele. Stimulation of monocytes with Mtb antigens resulted in higher amounts of IL1B protein and mRNA, but not of IL1R antagonist (IL1RN; 147679), in healthy controls carrying -31TT or -31TC compared with those carrying -31CC. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mtb antigens resulted in no significant differences in IFNG or IL17 (603149) production in controls; however, stimulation was associated with higher IFNG production in TB patients carrying -31TT. Analysis of bronchoalveolar lavage fluid from patients with active TB showed that higher IL1B production was associated with higher neutrophil recruitment. EMSA supershift analysis detected higher binding of CEBPA (116897) and PU.1 (SPI1; 165170) to the -31T oligonucleotide compared with the -31C oligonucleotide. Zhang et al. (2014) concluded that the higher IL1B production and neutrophil recruitment associated with -31T lead to increased tuberculosis susceptibility, tissue-damaging inflammatory responses, and accelerated disease progression. </p><p>Using direct sequencing, Salie et al. (2014) typed the HLA class I (see HLA-B, 142830) alleles from 300 South African patients with TB. The patients were recruited from suburban Cape Town, where TB prevalence is high, HIV infection is low, and the population is highly admixed. Salie et al. (2014) also genotyped the Mtb strains in each patient. They found that the Beijing Mtb strain occurred more frequently in individuals with multiple disease episodes and that the HLA-B27 allele lowered the odds of having an additional episode and of developing an infection with another Mtb strain. Salie et al. (2014) showed that various HLA types were associated with strains originating from both the European American and East Asian lineages, suggesting coevolutionary events between host and pathogen. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
See 604457.0003 and 604457.0004 for discussion of a possible association between susceptibility to Mycobacterium tuberculosis and variation in the SP110 gene.</p><p>For discussion of a possible association between protection against latent Mycobacterium tuberculosis infection (LTBI) and variation in the ULK1 gene, see 603168.</p><p><strong><em>Reviews</em></strong></p><p>
Berrington and Hawn (2007) reviewed common genetic variation in the innate immune response and its influence on TB susceptibility. They emphasized variants identified through human genetic studies as associated with TB susceptibility and the functional effects of these polymorphisms on the cellular immune response. Their Table 1 summarized the candidate genes and variants examined to date, the status of replication studies, associations of the variants with other diseases, and the functional effects of the variants. </p>
</span>
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</div>
<div>
<h4>
<span class="mim-font">
<strong>Animal Model</strong>
</span>
</h4>
</div>
<span class="mim-text-font">
<p>Flynn et al. (1995) found that mice lacking the Tnf receptor p55 gene (TNFRSF1A; 191190) and infected intravenously with Mycobacterium tuberculosis showed significantly decreased survival, higher bacterial loads, increased necrosis, delayed reactive nitrogen intermediate production and Inos (NOS2A; 163730) expression, and reduced protection after BCG vaccination than wildtype mice. Based on these results and studies using a monoclonal antibody to neutralize Tnf in mice, Flynn et al. (1995) concluded that Tnf and Tnf receptor p55 are necessary, if not solely responsible, for protection against murine TB infection. </p><p>Roach et al. (2002) noted that TNF is essential for the formation and maintenance of granulomas and for resistance against infection with Mycobacterium tuberculosis. Mice lacking Tnf mount a delayed chemokine response associated with a delayed cellular infiltrate. Subsequent excessive chemokine production and an intense but loose and undifferentiated cluster of T cells and macrophages, capable of producing high levels of Ifng in vitro, were unable to protect Tnf -/- mice from fatal tuberculosis after approximately 28 days, whereas all wildtype mice survived for at least 16 weeks. Roach et al. (2002) concluded that TNF is required for the early induction of chemokine production and the recruitment of cells forming a protective granuloma. The TNF-independent production of chemokines results in a dysregulated inflammatory response unable to contain M. tuberculosis. </p><p>The mouse DBA/2 (D2) strain is very susceptible to infection with virulent Mycobacterium tuberculosis, whereas C57BL/6 (B6) is much more resistant. Infection of D2 and B6 mice with M. tuberculosis by the respiratory route is biphasic: during the first 3 weeks, there is rapid bacterial growth in the lung of both strains, whereas beyond this point replication stops in B6 but continues in D2, causing rapidly fatal pulmonary disease. By QTL mapping, Mitsos et al. (2003) identified a major locus on chromosome 19 (lod = 5.6), designated tuberculosis resistance locus-4 (Trl4), which regulated pulmonary replication of M. tuberculosis and accounted for 25% of the phenotypic variance. B6 alleles at Trl4 were inherited in an incompletely dominant fashion and associated with reduced bacterial replication. An additional effect of a QTL on mouse chromosome 7 previously shown to affect survival to intravenous infection with M. tuberculosis, Trl3, was also noted. F2 mice homozygous for B6 alleles at both Trl3 and Trl4 were as resistant as B6 parents, whereas mice homozygous for D2 alleles were as susceptible as D2 parents. The evidence suggested a strong genetic interaction between the Trl3 locus on chromosome 7 and the Trl4 locus on chromosome 19, which are syntenic with human chromosomes 19q13 and 10q, respectively. </p><p>Using 'diversity outbred' (DO) mice, Gopal et al. (2013) observed different lung inflammatory responses and susceptibility to infection with Mtb. Lower Mtb burdens were associated with well-organized B-lymphoid follicles and elevated Ifng (147570). Mice with increased pulmonary inflammation harbored more S100a8-expressing neutrophils and showed increased Cxcl1, Il17 (603149), and lung S100a8/S100a9 expression. Treatment of Mtb-infected wildtype mice with anti-Ifng resulted in increased accumulation of S100a8-expressing neutrophils and exacerbation of inflammation. In contrast, treatment of Mtb-infected S100a9 -/- mice, which also do not express S100a8, with anti-Ifng resulted in loss of lung inflammation and neutrophil accumulation. Gopal et al. (2013) concluded that IL17 overexpression, through an S100A8/S100A9-dependent pathway, mediates exacerbated neutrophil recruitment and lung inflammation during TB. </p>
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</div>
</div>
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<h4>
<span class="mim-font">
<strong>REFERENCES</strong>
</span>
</h4>
<div>
<p />
</div>
<div>
<ol>
<li>
<p class="mim-text-font">
Abel, L., Casanova, J.-L.
<strong>Genetic predisposition to clinical tuberculosis: bridging the gap between simple and complex inheritance. (Editorial)</strong>
Am. J. Hum. Genet. 67: 274-277, 2000.
[PubMed: 10882573]
[Full Text: https://doi.org/10.1086/303033]
</p>
</li>
<li>
<p class="mim-text-font">
Barnes, P. F., Fong, S. J., Brennan, P. J., Twomey, P. E., Mazumder, A., Modlin, R. L.
<strong>Local production of tumor necrosis factor and IFN-gamma in tuberculous pleuritis.</strong>
J. Immun. 145: 149-154, 1990.
[PubMed: 2113553]
</p>
</li>
<li>
<p class="mim-text-font">
Barreiro, L. B., Neyrolles, O., Babb, C. L., Tailleux, L., Quach, H., McElreavey, K., van Helden, P. D., Hoal, E. G., Gicquel, B., Quintana-Murci, L.
<strong>Promoter variation in the DC-SIGN-encoding gene CD209 is associated with tuberculosis.</strong>
PLoS Med. 3: e20, 2006. Note: Electronic Article.
[PubMed: 16379498]
[Full Text: https://doi.org/10.1371/journal.pmed.0030020]
</p>
</li>
<li>
<p class="mim-text-font">
Behr, M., Schurr, E., Gros, P.
<strong>TB: screening for responses to a vile visitor.</strong>
Cell 140: 615-618, 2010.
[PubMed: 20211131]
[Full Text: https://doi.org/10.1016/j.cell.2010.02.030]
</p>
</li>
<li>
<p class="mim-text-font">
Bellamy, R., Beyers, N., McAdam, K. P. W. J., Ruwende, C., Gie, R., Samaai, P., Bester, D., Meyer, M., Corrah, T., Collin, M., Camidge, D. R., Wilkinson, D., Hoal-van Helden, E., Whittle, H. C., Amos, W., van Helden, P., Hill, A. V. S.
<strong>Genetic susceptibility to tuberculosis in Africans: a genome-wide scan.</strong>
Proc. Nat. Acad. Sci. 97: 8005-8009, 2000.
[PubMed: 10859364]
[Full Text: https://doi.org/10.1073/pnas.140201897]
</p>
</li>
<li>
<p class="mim-text-font">
Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Thursz, M., Whittle, H. C., Hill, A. V. S.
<strong>Tuberculosis and chronic hepatitis B virus infection in Africans and variation in the vitamin D receptor gene.</strong>
J. Infect. Dis. 179: 721-724, 1999.
[PubMed: 9952386]
[Full Text: https://doi.org/10.1086/314614]
</p>
</li>
<li>
<p class="mim-text-font">
Bellamy, R., Ruwende, C., Corrah, T., McAdam, K. P. W. J., Whittle, H. C., Hill, A. V. S.
<strong>Variations in the NRAMP1 gene and susceptibility to tuberculosis in West Africans.</strong>
New Eng. J. Med. 338: 640-644, 1998.
[PubMed: 9486992]
[Full Text: https://doi.org/10.1056/NEJM199803053381002]
</p>
</li>
<li>
<p class="mim-text-font">
Berg, R. D., Levitte, S., O'Sullivan, M. P., O'Leary, S. M., Cambier, C. J., Cameron, J., Takaki, K. K., Moens, C. B., Tobin, D. M., Keane, J., Ramakrishnan, L.
<strong>Lysosomal disorders drive susceptibility to tuberculosis by compromising macrophage migration.</strong>
Cell 165: 139-152, 2016.
[PubMed: 27015311]
[Full Text: https://doi.org/10.1016/j.cell.2016.02.034]
</p>
</li>
<li>
<p class="mim-text-font">
Berrington, W. R., Hawn, T. R.
<strong>Mycobacterium tuberculosis, macrophages, and the innate immune response: does common variation matter?</strong>
Immun. Rev. 219: 167-186, 2007.
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Contributors:
</span>
</div>
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
<span class="mim-text-font">
Bao Lige - updated : 11/22/2019<br>Paul J. Converse - updated : 03/06/2017<br>Paul J. Converse - updated : 2/12/2016<br>Paul J. Converse - updated : 11/12/2014<br>Paul J. Converse - updated : 11/10/2014<br>Paul J. Converse - updated : 10/7/2014<br>Paul J. Converse - updated : 7/1/2013<br>Paul J. Converse - updated : 3/18/2013<br>Paul J. Converse - updated : 8/6/2010<br>Paul J. Converse - updated : 7/1/2010<br>Paul J. Converse - updated : 3/25/2010<br>Paul J. Converse - updated : 3/11/2010<br>Matthew B. Gross - updated : 8/20/2009<br>Matthew B. Gross - updated : 7/27/2009<br>Paul J. Converse - updated : 7/7/2009<br>Paul J. Converse - updated : 5/15/2009<br>George E. Tiller - updated : 4/21/2009<br>Paul J. Converse - updated : 12/12/2008<br>Paul J. Converse - updated : 8/21/2007<br>Paul J. Converse - updated : 10/2/2006<br>Paul J. Converse - updated : 9/5/2006<br>Paul J. Converse - updated : 8/29/2006<br>Paul J. Converse - updated : 8/23/2006<br>Paul J. Converse - updated : 6/22/2006<br>Cassandra L. Kniffin - updated : 3/31/2006<br>Paul J. Converse - updated : 1/25/2006<br>Paul J. Converse - updated : 1/10/2006<br>Paul J. Converse - updated : 8/15/2005
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Victor A. McKusick : 7/15/2003
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mgross : 11/22/2019<br>mgross : 03/06/2017<br>mgross : 03/06/2017<br>carol : 02/20/2017<br>ckniffin : 02/20/2017<br>carol : 06/24/2016<br>mgross : 2/12/2016<br>carol : 1/5/2015<br>mgross : 12/9/2014<br>mgross : 11/12/2014<br>mgross : 11/10/2014<br>mgross : 11/10/2014<br>mgross : 10/7/2014<br>mgross : 7/1/2013<br>mgross : 3/18/2013<br>mgross : 3/18/2013<br>mgross : 12/1/2011<br>carol : 3/21/2011<br>terry : 12/8/2010<br>alopez : 11/10/2010<br>mgross : 11/10/2010<br>mgross : 8/6/2010<br>terry : 7/1/2010<br>alopez : 6/10/2010<br>mgross : 3/25/2010<br>mgross : 3/11/2010<br>mgross : 3/11/2010<br>mgross : 8/20/2009<br>mgross : 7/27/2009<br>mgross : 7/27/2009<br>mgross : 7/27/2009<br>mgross : 7/9/2009<br>mgross : 7/9/2009<br>mgross : 7/9/2009<br>terry : 7/7/2009<br>terry : 6/3/2009<br>wwang : 5/27/2009<br>mgross : 5/18/2009<br>terry : 5/15/2009<br>alopez : 4/21/2009<br>alopez : 4/21/2009<br>mgross : 12/12/2008<br>carol : 10/24/2008<br>alopez : 9/23/2008<br>mgross : 8/22/2007<br>terry : 8/21/2007<br>alopez : 6/28/2007<br>alopez : 6/13/2007<br>mgross : 5/21/2007<br>carol : 4/24/2007<br>terry : 11/3/2006<br>wwang : 10/27/2006<br>mgross : 10/2/2006<br>mgross : 9/5/2006<br>mgross : 8/29/2006<br>mgross : 8/23/2006<br>mgross : 6/22/2006<br>wwang : 4/6/2006<br>ckniffin : 3/31/2006<br>carol : 3/10/2006<br>mgross : 1/25/2006<br>mgross : 1/10/2006<br>terry : 12/21/2005<br>mgross : 8/15/2005<br>terry : 5/21/2004<br>carol : 1/30/2004<br>tkritzer : 1/30/2004<br>tkritzer : 7/16/2003
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