Celiac Disease, Susceptibility To, 4

A number sign (#) is used with this entry because susceptibility to celiac disease mapping to the chromosome 19p13.1 region can be accounted for by an intronic SNP in the MYO9B gene (602129.0001).

Description

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.

Mapping

Van Belzen et al. (2003) performed a genomewide screen in an effort to identify non-HLA genes involved in celiac disease. They obtained strong evidence for linkage (multiple maximum lod score 4.43) to 19p13.1 in celiac disease in a cohort of affected sib pairs of European descent from the Netherlands. This chromosomal location was also suggested by meta and pooled analyses of European celiac disease data that did not include the Dutch cohort (Babron et al., 2003).

Molecular Genetics

Monsuur et al. (2005) revealed a significant and replicable association, p = 2.1 x 10(-6), to a common variant, rs2305764, located in intron 28 of the MYO9B gene (602129). Individuals heterozygous with respect to the at-risk allele (602129.0001) had a modest but significantly higher risk of developing celiac disease (odds ratio = 1.66), whereas individuals homozygous with respect to that allele had a risk of developing celiac disease increased to 2.27, with population-attributable risks of 25% and 23%, respectively. Thus, a defect in MYO9B may be a factor involved in the early mucosal events preceding the well-understood inflammatory response. A genetic variant in the 3-prime part of MYO9B may perturb tight junction gate and fence function. As a consequence, immunogenic gluten peptides can enter the deeper mucosal layer more easily. This is the site at which the HLA-DQ2 (146880)-mediated antigen presentation to the CD4+ cells initiates the inflammatory response. MYO9B was the first non-HLA gene identified for celiac disease by positional cloning.