RA is a complex autoimmune disease thought to develop in genetically predisposed individuals whenexposed to certain environmental factors. Epidemiologic research has produced convincing data linkingcigarette smoking and female reproductive factors to risk of RA. We have recently discovered increased riskof 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 studiesfrom our group and others are identifying new alleles associated with RA. The study of interactions betweengenetic and environmental risk factors in the development of RA is rapidly expanding and has already led tonew insights into the pathogenesis of RA. For example, smoking and HLA-DRB1 genotypes have beenshown to interact to influence the risk of anti-cyclic citrullinated peptide (CCP) antibody positive, but not CCPantibody negative RA. The current application is the first international collaborative study of a substantialnumber of cases and controls where environmental exposure assessment and clinical/immunologicalphenotyping have been rigorously performed. We propose to: 1) Investigate particulate air pollution as a riskfactor 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 EpidemiologicalInvestigation of RA (EIRA), a case-control study with 2800 men and women in Sweden. We will study thegeospatial variation in RA incidence and examine the longitudinal association between exposure toparticulate air pollution using residential geocodes linked with national air pollution databases and risk of RAin 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, 600matched controls) and in EIRA (1400 incident cases/1400 matched controls). Further, we will use geneticdata from whole genome association studies by our collaborators at the Broad Institute and NARAC andothers, to investigate new susceptibility alleles replicated by strict criteria for interactions with environmentalexposures; and 3) Investigate interactions between RA risk alleles and environmental exposures indetermining the risk of certain RA phenotypes (RF+, CCP+, and erosive RA), and age at onset of RA in theNHS and EIRA cohorts.Public Health Relevance: RA affects 1% of the world's population. This is the first international effort tostudy RA etiology, genes, and environmental exposures in a comprehensive way. The proposed studies ofgene-environment interactions in RA susceptibility could identify new etiological pathways, thereby leading tohew strategies to prevent and treat RA.
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