Identification of Arthritis Susceptibility Genes in Mice and Humans
Abstract: Rheumatoid arthritis (RA) is a chronic autoimmune disease with a largely unknown aetiology. The risk of developing RA is partly dependent on genetic factors, which has motivated extensive efforts to identify the disease regulating genes as away to understand disease pathogenesis. However, identifying genes controlling complex diseases such as RA has proven extremely difficult and to date only a few risk factors have been identified. An alternative strategy is to identify genes regulating an animal model of the disease of interest and subsequently test if the identified genes have the same effect in humans. Numerous methods have been developed to map genes in rodents. This thesis is based on five papers in which we use a number of different strategies to map genes controlling collagen-induced arthritis (CIA) in mice, including congenic inbred strains, partial advanced intercrosses and a heterogeneous stock inbred-outbred cross. We identify 14 new quantitative trait loci regulating CIA and fine-map two of them. One locus, Cia38, is mapped down to only six candidate genes that will require further investigation to determine which one is the susceptibility gene. The second locus is mapped down to a single gene that affects amino acid-uptake and CIA susceptibility mainly in male mice. The gene is also shown to be associated with RA susceptibility in a patient cohort. Interestingly, the effect is male-predominant in both mice and humans. The results demonstrate the effectiveness of the used strategies, and illustrate some of the complications of gene-mapping in complex traits.
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