Molecular Genetics of Coeliac Disease

Abstract

Coeliac disease (CD) is a common inflammatory disease of the small intestine. It has a prevalence of 1% in the population and is strongly heritable. Current germline disease risk variants explain ∼50% of known heritability, the majority contributed by a strong human leukocyte antigen (HLA)‐DQ association. The role of HLA‐DQ in the immunology of CD is well understood, for example the role of tissue transglutaminase and HLA‐DQ in modifying and binding immuno‐dominant dietary cereal (gluten) peptides. Genome‐wide association studies have found 39 loci with risk variants of more modest effect. The use of high‐throughput sequencing technologies to locate rare variants of larger effect may aid in the complete resolution of this complex trait, as well as in other autoimmune diseases, which show considerable overlap in immunological pathways. Key Concepts: Coeliac disease has a strong genetic component with an environmental trigger, gluten. Coeliac disease shows strong HLA association, which is necessary but not sufficient for disease development. Genome‐wide association studies have located common variants of modest effect size. Rare variants with larger effect are hypothesised to contribute to common complex disease. Exome sequencing a large number of individuals from multigenerational families might isolate precise causal variants.