Contribution of Relatedness and Genetic Factors to the Clinical Picture of Coeliac Disease

Coeliac disease, a systemic autoimmune disorder induced by dietary gluten, is widespread globally, but in Finland even particularly prevalent although still heavily underdiagnosed. One reason contributing to this is the remarkably multifaceted clinical picture of coeliac disease. The originally typical gastrointestinal symptoms are currently being increasingly replaced by a milder presentation with extraintestinal symptoms and even totally asymptomatic presentation is no longer abnormal. Nevertheless, coeliac disease patients do not differ from each other only in terms of symptoms. There is a wide individual variation concerning the onset, severity and progression of symptoms as well as response to dietary treatment i.e., gluten-free diet (GFD). The reasons and contributary factors underlying this wide clinical heterogeneity remain obscure.

For many people nowadays, suspicion of coeliac disease is closely connected to known familial history of the disease. These familial cases are in the majority, but not every patient has affected relatives and such patients are considered sporadic. Where coeliac disease heredity is concerned, HLA-DQ2.5 is the best-known genetic component. However, numerous loci outside the HLA region have also been associated with the disease.

The studies presented in this dissertation focused in investigating whether there are genetic and/or phenotypic differences between familial and sporadic coeliac disease and whether the dose of HLA-DQ2.5 or the presence of genetic variants outside HLA region, including the ones within candidate genes CCR9 and CCL25, contributes to the clinical picture of the disease.

The findings of this dissertation managed to describe sporadic coeliac disease as an independent entity with a distinct HLA-DQ genotype even though not many significant phenotypic differences were observed between familial and sporadic coeliac disease. Nevertheless, the sporadic cases had more severe clinical phenotype at diagnosis as well as poorer overall health even after dietary treatment. Moreover, HLA-DQ2.5-negative coeliac disease patients were observed to present with classical phenotype at diagnosis as well as with persistent symptoms after dietary treatment more often than patients heterozygous or homozygous for high-risk HLA- DQ2.5. These findings will hopefully encourage physicians to pay special attention to both these patient groups. Four distinct non-HLA variants were associated with increased risk for familial coeliac disease, but the associations need to be confirmed in future studies. The contribution of HLA-DQ2.5 dose as well as non-HLA single nucleotide polymorphisms (SNPs) within CCR9 and CCL25 to the clinical picture of coeliac disease was found to be only modest.