A strong association with the MHC (major histocompatibility complex) is the most important known genetic predisposition factor of human autoimmune diseases, including rheumatoid arthritis (RA). The MHC alone, however, seems to be insufficient for the induction of a polygenic autoimmune disease, because non-MHC-linked genetic factors control susceptibility, severity, or other clinical and immunological traits of the disease. Proteoglycan (aggrecan)-induced arthritis (PGIA) is a novel autoimmune animal model which shares many similarities with RA, including systemic and local inflammatory reactions and genetics. During the current project period, we have genome-scanned over 2,200 F2 hybrid (including 665 arthritic) mice of five different genetic intercrosses using over 150 simple sequence length polymorphic (SSLP) markers for each cross. As a result of these genome-wide screening studies, we have identified a total of 29 genetic loci (Pgia) linked to PGIA, and 15 quantitative trait loci (QTLs) linked to collagen-induced arthritis (CIA) in mice (mCia). Many of the arthritis-associated clinical and immunological QTLs shared chromosome regions, being common in both PGIA and CIA, and co-localized with QTLs of other autoimmune models and their corresponding human diseases. In the continuation of this project we propose to (i) perform genome screening and identify possibly a single arthritis susceptibility locus in two, genetically (almost) identical, murine subcolonies (C3H/HeJ vs. C3H/HeJCr), (ii) select the most critical genetic loci (QTLs) using congenic and sub-congenic lines, and (iii) reduce the size of selected chromosomal regions to be suitable for positional candidate gene cloning. Potentially, sequences of candidate genes in arthritis-susceptible parental strains and disease-affected F2 hybrids can be compared with corresponding sequences in arthritis-resistant strains and/or individuals.
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