Molecular Genetics of Coeliac Disease


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.

Keywords: coeliac; autoimmune; genetics; genome‐wide association; resequencing

Figure 1.

Flow diagram highlighting clinical manifestations of disease upon gluten ingestion.

Figure 2.

Model of deamidated gluten peptide presentation by APC to T cells for subsequent loading onto HLA‐DQ2 or HLA‐DQ8 heterodimers. Gluten peptides (or gliadin peptides, which is a gluten protein) pass through a fairly permeable epithelial layer of the small intestine in untreated coeliac disease. Intestinal permeability is compromised by IELs producing more interferon thereby intensifying the immune reaction. Gliadin peptides react with transglutaminase 2 (TG2) serum autoantobodies in the lamina propria. TG2 is the autoantigen of coeliac disease and plays a primary role of crosslinking and deamidation of gliadin. Ingested gliadin is crosslinked by TG2 causing specific deamidation of glutamine into glutamic acid. After deamidation the gliadin peptides can be presented more efficiently to gliadin reactive CD4 T cells by APCs via HLA‐DQ2 or HLA‐DQ8.

Figure 3.

HLA haplotype combinations in coeliac disease. White boxes denote ‘other’ haplotype. DQ2.5 cis is shown as a heterozygote; a DQ2.5 cis homozygote will carry same alleles on both chromosomes. Majority of CD patients express HLA‐DQ2.5 encoded either in cis on the DR3‐DQ2 haplotype, or in trans on the DR5‐DQ7/DR7‐DQ2 haplotype for heterozygous individuals. HLA‐DQ2.2 confers low risk for CD if expressed solely. HLA‐DQ8 is expressed in DQ2‐negative patients (Abadie et al., ). Adapted from Dubois and van Heel ().



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Van Heel DA and Hunt KA (2005) Genetics in coeliac disease. Best Practice & Research: Clinical Gastroenterology 19(3): 323–339.

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Mistry, Vanisha, and van Heel, David(Dec 2011) Molecular Genetics of Coeliac Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0022476]