Alternative titles; symbols
DO: 10608;
Cytogenetic location: 3q25-q26 Genomic coordinates (GRCh38) : 3:149,200,001-183,000,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q25-q26 | {Celiac disease, susceptibility to, 10} | 612008 | 2 |
Celiac disease, also known as celiac sprue and gluten-sensitive enteropathy, is a multifactorial disorder of the small intestine that is influenced by both environmental and genetic factors. It is characterized by malabsorption resulting from inflammatory injury to the mucosa of the small intestine after the ingestion of wheat gluten or related rye and barley proteins (summary by Farrell and Kelly, 2002).
For additional information and a discussion of genetic heterogeneity of celiac disease, see 212750.
The form of susceptibility to celiac disease here designated CELIAC10 is influenced by genetic variation in the 3q25-q26 region, within a 70-kD linkage disequilibrium (LD) block near the IL12A gene (161560).
To identify risk variants contributing to celiac disease susceptibility other than those in the HLA-DQ region (see CELIAC1, 212750), Hunt et al. (2008) genotyped 1,020 of the most strongly associated non-HLA markers identified by van Heel et al. (2007) in an additional 1,643 cases of celiac disease and 3,406 controls. Two single-nucleotide polymorphisms (SNPs), rs17810546 and rs9811792, in a 70-kb LD block showed strong association with celiac disease (rs17810546 P overall = 1.07 x 10(-9)). This region is immediately 5-prime of IL12A (161560). The 2 associated SNPs may represent independent association signals. SNP rs17810546 also showed modest correlation with SNPs in both IL12A and the schwannomin (607379)-interacting protein gene SCHIP1 (619206). IL12A encodes the IL12 p35 subunit, which together with IL12 p40 (IL12B; 161561) forms IL12 p70, the heterodimeric IL12 cytokine that has a broad range of biologic activities on T and natural killer cells. IL12 induces interferon-gamma (IFNG; 147570)-secreting Th1 cells, one of the immunologic hallmarks of celiac disease.
In an Italian cohort involving 538 patients with celiac disease and 593 healthy controls, Romanos et al. (2009) confirmed association at rs17810546 (p = 0.0004) and rs9811792 (p = 0.0313).
Zhernakova et al. (2010) assessed signatures of natural selection for 10 confirmed celiac disease loci in several genomewide data sets comprising 8,154 controls from 4 European populations and 195 individuals from a North African population and found consistent signs of positive selection for disease-associated alleles at 3 loci, with the strongest signatures of selection observed for rs17810546 from the IL12A locus.
Farrell, R. J., Kelly, C. P. Celiac sprue. New Eng. J. Med. 346: 180-188, 2002. [PubMed: 11796853] [Full Text: https://doi.org/10.1056/NEJMra010852]
Hunt, K. A., Zhernakova, A., Turner, G., Heap, G. A. R., Franke, L., Bruinenberg, M., Romanos, J., Dinesen, L. C., Ryan, A. W., Panesar, D., Gwilliam, R., Takeuchi, F., and 25 others. Newly identified genetic risk variants for celiac disease related to the immune response. Nature Genet. 40: 395-402, 2008. [PubMed: 18311140] [Full Text: https://doi.org/10.1038/ng.102]
Romanos, J., Barisani, D., Trynka, G., Zhernakova, A., Bardella, M. T., Wijmenga, C. Six new coeliac disease loci replicated in an Italian population confirm association with coeliac disease. J. Med. Genet. 46: 60-63, 2009. [PubMed: 18805825] [Full Text: https://doi.org/10.1136/jmg.2008.061457]
van Heel, D. A., Franke, L., Hunt, K. A., Gwilliam, R., Zhernakova, A., Inouye, M., Wapenaar, M. C., Barnardo, M. C. N. M., Bethel, G., Holmes, G. K. T., Feighery, C., Jewell, D., and 16 others. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nature Genet. 39: 827-829, 2007. [PubMed: 17558408] [Full Text: https://doi.org/10.1038/ng2058]
Zhernakova, A., Elbers, C. C., Ferwerda, B., Romanos, J., Tryunka, G., Dubois, P. C., de Kovel, C. G. F., Francke, L., Oosting, M., Barisani, D., Bardella, M. T., Finnish Celiac Disease Study Group, Joosten, L. A. B., Saavalainen, P., van Heel, D. A., Catassi, C., Netea,, M. G., Wijmenga, C. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am. J. Hum. Genet. 86: 970-977, 2010. [PubMed: 20560212] [Full Text: https://doi.org/10.1016/j.ajhg.2010.05.004]