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: 7267517
• 负责人: ELIZABETH W KARLSON
• 金额: $ 31.44万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-20 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7267517
• 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，被认为是在遗传易感个体中发展， 暴露于某些环境因素。流行病学研究已经产生了令人信服的数据， 吸烟和女性生殖因素对RA的危险性。我们最近发现 RA在美国空气污染严重的地区。遗传学研究发现HLA-DRB 1 “共享表位”等位基因和PTPN 22作为RA的强风险因素，以及全基因组关联研究 和其他人正在鉴定与RA相关的新等位基因。之间相互作用的研究 遗传和环境风险因素在RA发展中的作用正在迅速扩大， RA发病机制的新见解。例如，吸烟和HLA-DRB 1基因型已经被 已证明相互作用会影响抗环瓜氨酸肽（CCP）抗体阳性的风险，但不会影响CCP 抗体阴性RA。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 严格进行了表型分析。我们建议：1）将颗粒空气污染作为一种风险进行调查 使用来自世界上最大的风湿病环境流行病学研究的数据， 护士健康研究队列（NHS和NHSII），在美国有224，314名女性，流行病学研究 RA调查（EIRA），一项在瑞典对2800名男性和女性进行的病例对照研究。我们会研究 RA发病率的地理空间变化，并检查暴露于 使用与国家空气污染数据库和RA风险相关的居住区地理编码的颗粒空气污染 在美国和瑞典; 2）调查已建立的遗传风险因素与吸烟的相互作用， 颗粒空气污染，女性生殖因素，在国民保健服务队列（600例事件，600 匹配对照组）和EIRA（1400例事件病例/1400例匹配对照组）。此外，我们将使用遗传 来自布罗德研究所和NARAC的合作者的全基因组关联研究的数据， 其他人，调查新的易感等位基因复制的严格标准与环境的相互作用， 研究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+和糜烂性RA）的风险，以及RA发病时的年龄。 NHS和EIRA队列。 公共卫生相关性：类风湿性关节炎影响世界人口的1%。这是第一次国际努力， 全面研究RA病因、基因和环境暴露。拟议的研究 RA易感性中的基因-环境相互作用可以识别新的病因学途径，从而导致 制定防治RA策略。