Genetic and genomic analysis of arthritis regulating regions in human and mouse

Sammanfattning: Identifying genes involved in the disease pathways of complex diseases such as Rheumatoid arthritis (RA) has been shown to be very difficult. Despite decades of research still only a handful of genes have been convincingly identified as risk genes. RA is a common autoimmune disorder that affects approximately 1% of the population and knowledge of the contributing genetic factors would greatly increase our understanding of the disease and thus lead to the development of effective treatments. The genetic contributing to RA is heterogeneous and the risk effect of each individual gene will be small. Thus, very large patient cohorts are required to achieve enough power to detect new risk genes. By taking advantage of the less heterogeneous genetic and environmental contribution to disease of animal models as well as the controlled genetic background of inbred strains, the power to detect new risk genes increases. In the papers presented in this thesis a combination of animal and human genetics has lead to the identification of three new risk gene candidates. In papers I and II, the association of the genes encoding the NADPH oxidase complex was investigated for association with arthritis, initiated by the finding of Ncf1 as a risk gene in animal models. In paper I, a SNP in NCF4 was found to be associated with rheumatoid factor negative RA, specifically in men, whereas copy number variation of NCF1 was found to be association with RA in paper II. Both these findings support the role of the NADPH oxidase complex in human RA. Paper III deals with the identification of candidate genes in the mice model collagen induced arthritis and introduces a new method, which identifies several new candidate genes including Ptpn22 and Chi3l3. In paper IV, a splice site SNP in the gene Slc38a1 is identified as an arthritis causative SNP in mice. Investigation of SLC38A1 in RA patients revealed two SNPs, associated with autoantibody positive disease in men. The results presented in this thesis have led to an increased knowledge of the genetic contribution to RA and will greatly enhance our understanding of the disease pathways.