Abstract
Family studies have long demonstrated that rheumatoid arthritis susceptibility is linked to an underlying genetic component, both inside and outside of the major histocompatibility complex (MHC). The last decade has seen incredible advances in the discovery of risk loci for rheumatoid arthritis; now there are about 100 disease loci that have been identified. However, understanding the link between genetic loci and disease mechanism, is contingent on investigators identifying causal alleles and elucidating how they function to modify disease susceptibility. We are now just beginning to make this key step. Here we present recent work on (1) efforts to identify rheumatoid arthritis loci outside of the MHC region, (2) efforts within our own group to localize MHC effects to functional amino acid sites within HLA genes, separately for seronegative and seropositive rheumatoid arthritis, and (3) methodological advance to connect non-MHC loci to functional alleles that influence gene regulation in specific immune cell-types.
