Association of clinical phenotype and genetic burden in coeliac disease

Coeliac disease (CD) is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to a gluten containing diet in genetically predisposed individuals. The clinical presentation of CD is highly heterogeneous, ranging from severe intestinal symptoms such as diarrhoea and weight loss to subclinical or silent forms of the disease. Many studies have reported a change in the clinical phenotypic presentation of CD in recent years, with an increase in the prevalence of a non-classical and subclinical phenotype at diagnosis as well as the median age of diagnosis. The co-existence of CD with other immune-mediated conditions (IMC) has been well reported in the literature. It is recommended that patients with type 1 diabetes mellitus (T1DM) and autoimmune thyroid disease (ATD) are screened for CD. There is a paucity of data regarding the clinical presentation of CD in the Republic of Ireland (ROI). Genome wide association studies (GWAS) have helped elucidate the polygene architecture of CD, with HLA and non-HLA genes known to contribute to the development of the condition. Little is currently known as to the effects of genotype on clinical phenotype in CD. The use of polygene risk scores (PRS) in CD, combining HLA and non-HLA predisposing loci, have been shown to improve the identification of potential CD patients. However, whilst correlation of PRS with overall disease risk has been well explored, the association of the genotype with CD clinical phenotype has not been extensively investigated. Therefore, studies combining clinical phenotypes with genetic information could potentially explain differences in disease presentation and development. This thesis aimed to provide an updated description of the clinical phenotype of CD in Ireland at present, and to report any potential changes in the presentation of the condition over time. Furthermore, we wanted to explore the ability of PRS to predict differences in disease presentation and prognosis. Our results have corroborated findings reported internationally, that the clinical profile of the disease has changed radically over the past 55 years. Among the changes we found were an increased median age at diagnosis in adulthood, a higher prevalence of non-classical CD at diagnosis, an equal prevalence of patients diagnosed in childhood (