Identification of functional common and rare variants in the CD40 signalling pathway in Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a common, chronic autoimmune disease, affecting approximately 1% of the population worldwide. Although its causes are largely unknown, it is clear that there is a considerable heritable component. In 2007, three genome-wide association studies (GWAS) as well as candidate gene approaches successfully increased the number of RA gene loci from two to five. To enhance the discovery of additional genes, a meta-analysis of these GWAS has recently been completed by Dr. Plenge (Nature Genetics, in press). The most significant finding outside of the known RA risk loci was of a common polymorphism near the CD40 gene (odds ratio (OR) = 0.87, p=5.1x10-9). While this represents a true disease gene, several questions remain to be answered to fully comprehend its fundamental involvement in the disease pathway. 1) What is the exact causal common mutation? 2) Are there rare mutations that independently contribute to the risk of disease? 3) What is the biological function of the common and rare risk alleles? My proposed research will address these three critical questions by applying next-generation genetic technologies (e.g., Solexa sequencing) in large RA case-control collections together with hypothesis-driven immunological experiments to elucidate the role of CD40 mutations in RA.