The autoimmune puzzle - shared and specific genetics of immune-related diseases

Abstract

Immune-mediated disorders are common diseases affecting 5-10% of the population. They include two sets of diseases: the classical autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis and coeliac disease; and inflammatory diseases, such as inflammatory bowel disease, psoriasis, asthma and others. All these diseases have a complex genetic background, meaning that the combination of an unknown number of genes, each with a moderate or small individual effect, and one or more environmental factors are required for the disease to develop. The major genetic risk factor for all these diseases is the HLA locus on chromosome 6p21. The studies described in this thesis were aimed at unravelling the shared genetic aspects of autoimmunity and at characterising the shared and specific non-HLA risk factors in immune-related diseases that may explain the co-morbidity seen for these diseases. In part one of this thesis the overview of genetic studies in complex diseases is presented. In part two, the studies performed using the candidate gene- and candidate- pathway approaches are reported. The innate immune pathways screen led to the discovery of two variants associated to inflammatory bowel disease. Part three describes the genome-wide association strategy on the example of coeliac disease. Two steps of extended replication of the initial GWAS led to the discovery of 10 non-HLA genes in coeliac disease. Part four is focused on the shared and specific genetic aspects and the molecular pathways underlying immune-related diseases. We also zoom specifically to the shared genetics of coeliac disease and rheumatoid arthritis. In the discussion part, the studies described in the thesis are put in to prospective, and the past, present and future of genetic research in to complex immune-related diseases is discussed