Genetics of celiac disease and its diagnostic value

PhD ceremony: Ms. J. Romanos, 14.30 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: Genetics of celiac disease and its diagnostic value

Promotor(s): prof. C. Wijmenga

Faculty: Medical Sciences

Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides. Because the disease has variable and sometimes vague symptoms, it often remains undiagnosed. CD is a multi-factorial disorder with the major genetic risk factor being HLA-DQ2/DQ8 molecules. The aim of this thesis was to discuss the identification and replication of genetic risk variants for CD and to develop a risk model to improve diagnosis. We validated a novel HLA-tagSNP approach for high-throughput genotyping in three European populations. We replicated the first genome-wide association findings in an Italian population and showed that CD risk loci are differently associated in different populations. Since CD is a major socio-economic burden, improved diagnosis and early prevention is sorely needed. Genetic risk profiling could be used as a diagnostic or screening tool for CD. We studied the risk profile based on HLA and 10 non-HLA risk alleles, and improved and validated this model using 26 and 57 variants and replicated the results in two other cohorts. Both studies showed that adding non-HLA risk alleles improves identification of high-risk individuals. Finally, we discuss who can benefit from this genetic profiling and how to improve the accuracy of risk prediction.