Identification of genetic and epigenetic factors in autoimmune disease etiology and treatment response

Multiple sclerosis and rheumatoid arthritis are complex autoimmune disease of unknown etiology. Each are result of exposure to a combination of genetic and environmental risk factors. Effective treatments that reduce the rate that normal tissues are attacked by the immune system have been developed; however, the mechanisms underlying disease pathogenesis and treatment response are not completely understood. In this dissertation, I used a combination of epidemiologic, bioinformatic, and computational methods to study the role of gene and environmental interactions, the vitamin D pathway, and DNA methylation in multiple sclerosis and rheumatoid arthritis. Chapter one introduces the genetic, environmental, and epigenetic factors in multiple sclerosis and rheumatoid arthritis. Chapter two describes results from an investigation into gene and environment interaction between genetic risk factors and pregnancy for multiple sclerosis susceptibility finding no evidence for effect modification between genetic susceptibility and pregnancy. Chapter three uses mendelian randomization methods to identify evidence that variation in vitamin D receptor binding is associated with MS susceptibility. Chapter four shows that changes cell-specific DNA methylation are associated with response to treatment with methotrexate among treatment naïve rheumatoid arthritis patients