RA is a complex autoimmune disease thought to develop in genetically predisposed individuals when exposed to certain environmental factors. Epidemiologic research has produced convincing data linking cigarette smoking and female reproductive factors to risk of RA. We have recently discovered increased risk of RA in areas with heavy air pollution within the United States. Genetic studies have identified HLA-DRB1 "shared epitope" alleles and PTPN22 as strong risk factors for RA, and whole genome association studies from our group and others are identifying new alleles associated with RA. The study of interactions between genetic and environmental risk factors in the development of RA is rapidly expanding and has already led to new insights into the pathogenesis of RA. For example, smoking and HLA-DRB1 genotypes have been shown to interact to influence the risk of anti-cyclic citrullinated peptide (CCP) antibody positive, but not CCP antibody negative RA. The current application is the first international collaborative study of a substantial number of cases and controls where environmental exposure assessment and clinical/immunological phenotyping have been rigorously performed. We propose to: 1) Investigate particulate air pollution as a risk factor for RA using data from the largest rheumatic disease environmental epidemiology studies in the world, the Nurses' Health Study Cohorts (NHS and NHSII) with 224,314 women in the US, and the Epidemiological Investigation of RA (EIRA), a case-control study with 2800 men and women in Sweden. We will study the geospatial variation in RA incidence and examine the longitudinal association between exposure to particulate air pollution using residential geocodes linked with national air pollution databases and risk of RA in the US and Sweden; 2) Investigate interactions of established genetic risk factors with cigarette smoking, particulate air pollution, and female reproductive factors, in the NHS cohorts (600 incident cases, 600 matched controls) and in EIRA (1400 incident cases/1400 matched controls). Further, we will use genetic data from whole genome association studies by our collaborators at the Broad Institute and NARAC and others, to investigate new susceptibility alleles replicated by strict criteria for interactions with environmental exposures; and 3) Investigate interactions between RA risk alleles and environmental exposures in determining the risk of certain RA phenotypes (RF+, CCP+, and erosive RA), and age at onset of RA in the NHS and EIRA cohorts. Public Health Relevance: RA affects 1% of the world's population. This is the first international effort to study RA etiology, genes, and environmental exposures in a comprehensive way. The proposed studies of gene-environment interactions in RA susceptibility could identify new etiological pathways, thereby leading to hew strategies to prevent and treat RA.