Environmental and Genetic Epidemiology of Rheumatoid Arthritis

类风湿关节炎的环境和遗传流行病学

• 批准号: 7578201
• 负责人: ELIZABETH W KARLSON
• 金额: $ 37.9万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7578201
• 关键词: Address; Adult; Affect; Age; Air Pollution; Alleles; American; Antibodies; Antigens; Area; Arthritis; Autoimmune Diseases; Breathing; CTLA4 gene; Case-Control Studies; Chronic; Cigarette; Citrulline; Clinical; Clinical Data; Clinical assessments; Collection; Complex; Data; Databases; Development; Environment; Environmental Epidemiology; Environmental Exposure; Environmental Risk Factor; Epidemiologic Studies; Epidemiologist; Epitopes; Etiology; Exposure to; Female; Genes; Genetic; Genotype; Glutathione S-Transferase; Goals; HLA-DRB1; Hormones; Hospital Nursing; Incidence; Individual; Institutes; Interdisciplinary Study; International; Investigation; Lead; Link; Literature; Lung; Minerals; Molecular; Normal Horse Serum; Numbers; Nurses' Health Study; Occupational; PTPN22 gene; Particulate; Particulate Matter; Pathogenesis; Pathway interactions; Patients; Peptide antibodies; Phenotype; Population; Predisposition; Public Health; Publishing; Reproductive History; Rheumatism; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Risk Factors; Smoke; Smoking; Subgroup; Sweden; Thinking; Toxic Environmental Substances; United States; Variant; Woman; case control; cigarette smoking; cigarette smoking; cohort; cyclic citrullinated peptide; disease phenotype; gene environment interaction; genetic epidemiology; genetic risk factor; genome wide association study; human PTPN22 protein; insight; men; novel; prevent; reproductive; toxin metabolism

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.

RA是一种复杂的自身免疫性疾病，认为在遗传易感的个体中发展 暴露于某些环境因素。流行病学研究产生了令人信服的数据链接 吸烟和女性生殖因素可能有RA的风险。我们最近发现风险增加 在美国境内有重型空气污染的地区的RA。遗传研究已经确定了HLA-DRB1 “共享表位”等位基因和PTPN22作为RA和整个基因组协会研究的强大风险因素 来自我们的小组和其他人正在识别与RA相关的新等位基因。研究之间的相互作用 RA发展中的遗传和环境风险因素正在迅速扩展，并且已经导致 对RA发病机理的新见解。例如，吸烟和HLA-DRB1基因型已经 证明可以相互作用以影响抗偶然柠檬硫化肽（CCP）抗体阳性的风险，而不是CCP 抗体阴性RA。当前的申请是对一项实质性的首次国际合作研究 环境暴露评估和临床/免疫学的病例和对照数量 表型已经严格执行。我们建议：1）研究颗粒空气污染作为风险 RA使用来自世界上最大的风湿病环境流行病学研究的数据的因素， 护士健康研究队列（NHS和NHSII）与美国224,314名妇女以及流行病学 对RA（EIRA）的调查，这是一项案件对照研究，对瑞典有2800名男性和女性。我们将研究 RA发病率的地理空间变化，并检查暴露之间的纵向关联 使用与国家空气污染数据库相关的住宅地理污染的颗粒空气污染和RA的风险 在美国和瑞典； 2）研究已建立的遗传危险因素与吸烟的相互作用， NHS队列中的颗粒空气污染和女性生殖因子（600例，600例 匹配的控件）和EIRA（1400个事件案例/1400个匹配的控件）。此外，我们将使用遗传 我们的合作者在Broad Institute和Narac和Narac和 其他，调查由严格标准与环境互动复制的新的易感性等位基因 暴露； 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RA表型（RF+，CCP+和侵蚀性RA）的风险，以及RA发作时的年龄 NHS和EIRA队列。 公共卫生相关性：RA影响世界人口的1％。这是第一个国际努力 研究RA病因，基因和环境暴露于全面的方式。提出的研究 RA易感性中的基因环境相互作用可以鉴定出新的病因途径，从而导致 HEW策略预防和治疗RA。