Coeliac disease is an inflammatory disorder of the small intestine. It has an autoimmune component and has apparent strong heritability. Coeliac disease is characterised by diarrhoea, an enlarged abdomen and poor weight gain. Coeliac disease is a lifelong condition, with the only effective treatment being complete exclusion of gluten from diet. This is effective in over 95% of cases.
Gluten is a dietary protein found in wheat, barley and rye. Gluten peptides pass through the epithelial barrier of the small intestine into the lamina propria, where they are deaminated by the enzyme transglutaminase to give negatively charged gluten peptides. In genetically predisposed individual, the deaminated gluten peptides trigger a cascade of innate and adaptive immune responses including lymphocyte infiltration into the proximal part of the small intestines leading to destruction of the intestinal epithelium and mucosa including villous atrophy and crypt hyperplasia.
The major genetic risk factors predisposing individuals to Coeliac Disease is presence of the genes for the HLA class II antigens DQ2 and DQ8. These account for over 35% of the genetic risk. Approximately 90% of patients with Coeliac Disease express the HLA-DQ2 molecules with the remaining 10% mostly expressing the HLA-DQ8 molecule. A gene dosage effect is present, with homozygous patient (for DQ2 or DQ8 genes) or patients who are heterozygous for the DQ2 and DQ8 genes having a higher disease susceptibility. Deaminated gluten peptides bind strongly to HLA-DQ2 and DQ8 presenting a HLA-gluten peptide complex that activates CD4+ T cells which produce proinflammatory cytokines, including interferon gamma, which leads directly to tissue remodelling and flattening of the intestinal mucosa. The immune response also includes the development of antibodies against gluten and auto-antibodies to endogenous tissue transglutaminase. DQA testing is now a key aspect of HLA genetic testing for Coeliac Disease. The DQ2 molecule most associated with Coeliac Disease is encoded by the HLA-DQA1*05:01 – DQB1*02:01 genes, with a small proportion encoded by the DQA1*02:01 – DQB1*02:02 genotype. The DQ8 molecule associated with Coeliac Disease is DQA1*03 – DQB1*03:02.
Genome wide association studies have indicated a large number of non HLA genes which segregate with Coeliac Disease and may potentially be associated with it.
Although diagnosis of Coeliac Disease is based mainly on histology, this is not always reliable. Genetic testing for HLA-DQ2 and DQ8 as a complement to histology has proved to be important for helping to confirm the diagnosis. DQ2 and DQ8 typing do not provide any additional diagnostic benefit in patients already known to be tissue transglutaminase antibody positive.
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