Alternative titles; symbols
DO: 10608;
Cytogenetic location: 12q24 Genomic coordinates (GRCh38) : 12:108,600,001-133,275,309
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24 | {Celiac disease, susceptibility to, 13} | 612011 | 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.
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. Hunt et al. (2008) identified 2 correlated SNPs, rs653178 (P overall = 8 x 10(-8)) and rs3184504 that mapped in the vicinity of the SH2B3 gene (605093). Modest LD was seen over a broader region of approximately 1 Mb containing multiple other genes. Strong association with type 1 diabetes was reported in this region with rs3184504 entirely accounting for the association signal (Todd et al., 2007). SH2B3 is strongly expressed in monocytes and dendritic cells, as well as to a lesser extent in resting B, T, and natural killer cells. Hunt et al. (2008) found SH2B3 to be strongly expressed in small intestine; higher expression in inflamed celiac biopsies may reflect leukocyte recruitment and activation. The nonsynonymous SNP rs3184504 is located in exon 3 of SH2B3, leading to an R262W amino acid change in the pleckstrin homology domain. This domain may be important in plasma membrane targeting. SH2B3 regulates T-cell receptor, growth factor, and cytokine receptor-mediated signaling implicated in leukocyte and myeloid cell homeostasis. Hunt et al. (2008) also noted strong correlation between rs3184504 and another SNP, rs653178 (r(2) = 0.99).
Smyth et al. (2008) evaluated the association between type 1 diabetes (222100) and 8 loci related to the risk of celiac disease in 8,064 patients with type 1 diabetes, 2,828 families providing 3,064 parent-child trios, and 9,339 controls. The authors confirmed association between IDDM20 (612520) and rs3184504 in the SH2B3 gene, which is associated with CELIAC13.
In an Italian cohort involving 538 patients with celiac disease and 593 healthy controls, Romanos et al. (2009) confirmed association at rs3184504 (p = 0.0050).
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, including rs3184504 at SH2B3 in the European populations. Functional investigation of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide showed that carriers of the SH2B3 rs3184504 'A' risk allele showed stronger activation of the NOD2 recognition pathway than did carriers of the nonrisk 'G' allele, suggesting that SH2B3 plays a role in protection against bacterial infection and providing a possible explanation for the selective sweep, which occurred sometime between 1,200 and 1,700 years ago.
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]
Smyth, D. J., Plagnol, V., Walker, N. M., Cooper, J. D., Downes, K., Yang, J. H. M., Howson, J. M. M., Stevens, H., McManus, R., Wijmenga, C., Heap, G. A., Dubois, P. C., Clayton, D. G., Hunt, K. A., van Heel, D. A., Todd, J. A. Shared and distinct genetic variants in type 1 diabetes and celiac disease. New Eng. J. Med. 359: 2767-2777, 2008. [PubMed: 19073967] [Full Text: https://doi.org/10.1056/NEJMoa0807917]
Todd, J. A., Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., Bailey, R., Nejentsev, S., Field, S. F., Payne, F., Lowe, C. E., Szeszko, J. S., and 30 others. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nature Genet. 39: 857-864, 2007. [PubMed: 17554260] [Full Text: https://doi.org/10.1038/ng2068]
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]