Unlocking the genetics of coeliac disease

PhD ceremony: Ms. M.B. Trynka, 12.45 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Unlocking the genetics of coeliac disease

Promotor(s): prof. C. Wijmenga

Faculty: Medical Sciences

Coeliac disease is the most common food intolerance disorder, affecting approx. 1% of Western populations. In genetically susceptible individuals, the presence of gluten peptides, which are abundant in dietary products such as bread and pasta, triggers an immune response that leads to inflammation and damage of the small intestine. The major genetic risk factor is HLA (human leukocyte antigen). Until 2007 only 8 other, non-HLA loci were reported to be associated with coeliac disease. The aim of this research was to identify more regions conferring genetic susceptibility to the disease.

The thesis describes an association study of two loci harbouring genes involved in NF-κB signalling. Furthermore, the genetic factors shared by two autoimmune diseases, coeliac disease and rheumatoid arthritis, are described. A large, genome-wide association study of multiple European cohorts identified 13 additional risk loci. The genetic progress made in coeliac disease and its shared background with other immune-related diseases is reviewed. Sequencing-based, dense genotyping allowed fine-mapping of coeliac disease risk regions and identified 13 more regions conferring risk for the disease. We replicated coeliac loci in a Northern Indian population, and thus demonstrated how the use of ethnically distinct populations can aid in fine-mapping causal variants. A total number of 40 risk loci is currently associated with coeliac disease, which cumulatively explain 53% of the disease heritability. This research has improved our understanding of the disease biology and pointed to many immune pathways that are altered in coeliac disease patients.