Environmental and Genetic Epidemiology of Rheumatoid Arthritis

类风湿关节炎是一种复杂的自身免疫性疾病，被认为在以下情况下在遗传易感性个体中发展 暴露在特定的环境因素中。流行病学研究产生了令人信服的数据联系 吸烟和女性生殖因素对类风湿性关节炎的风险。我们最近发现风险增加了 在美国境内空气污染严重的地区，风湿性关节炎的风险很高。遗传学研究已确定人类白细胞抗原DRB1 “共享表位”等位基因和PTPN22是RA的强烈危险因素，以及全基因组相关性研究 我们小组和其他人正在识别与RA相关的新等位基因。相互作用的研究 遗传和环境风险因素在类风湿关节炎的发展中迅速扩大，并已导致 对类风湿关节炎发病机制的新认识。例如，吸烟和人类白细胞抗原-DRB1基因型别 显示相互作用影响抗环瓜氨酸肽(CCP)抗体阳性的风险，但不影响CCP 抗体阴性的类风湿关节炎。目前的申请是第一个国际合作研究的实质性 环境暴露评估和临床/免疫学的病例和对照数量 已经严格地进行了表型鉴定。我们建议：1)将颗粒物空气污染作为一种风险进行调查 使用世界上最大的风湿病环境流行病学研究数据得出的类风湿性关节炎的因素， 护士健康研究队列(NHS和NHSII)包括224,314名美国妇女，以及流行病学 对瑞典2800名男性和女性进行的病例对照研究--类风湿性关节炎(Eira)调查。我们会研究 类风湿性关节炎发病的地理空间差异，并检查暴露于 使用与国家空气污染数据库相关联的住宅地理编码的颗粒物空气污染和RA风险 在美国和瑞典；2)调查已确定的遗传风险因素与吸烟的相互作用， NHS队列中的颗粒物空气污染和女性生殖因素(600个事件病例，600个 在埃拉(1400例事件病例/1400例匹配对照)。此外，我们将使用基因 来自我们在布罗德研究所和NARAC的合作者进行的全基因组关联研究的数据 其他的，通过与环境相互作用的严格标准来研究新的易感等位基因 以及3)调查RA风险等位基因与环境暴露之间的相互作用 确定某些类风湿关节炎表型(RF+、CCP+和侵蚀性类风湿关节炎)的风险，以及在 NHS和Eira的队列。 公共卫生相关性：RA影响世界1%的人口。这是国际社会第一次努力 全面研究类风湿性关节炎的病因、基因和环境暴露。建议进行的研究 在RA易感性中，基因-环境相互作用可以识别新的致病途径，从而导致 预防和治疗类风湿关节炎的策略。

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.