Respiratory Diseases, Genetics, and Rheumatoid Arthritis Risk

呼吸系统疾病、遗传学和类风湿关节炎风险

• 批准号: 9810123
• 负责人: Jeffrey Andrew Sparks
• 金额: $ 8.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-03 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9810123
• 关键词: Adult; Affect; Asthma; Autoantibodies; Boston; Bronchiectasis; Case-Control Studies; Chronic; Chronic Obstructive Airway Disease; Clinic; Clinical; Complement; Data; Data Analyses; Data Set; Development; Diagnosis; Disease; Dyspnea; Epidemiology; Excess Mortality; Exposure to; Familiarity; Fibrosis; First Degree Relative; Funding; General Hospitals; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Goals; Hospitals; Image; Individual; Inflammatory Arthritis; Inhalant dose form; Interstitial Lung Diseases; Intervention; Investigation; Joints; Lead; Life Style; Longitudinal Studies; Lung; Lung diseases; Lymphoid; Massachusetts; Measures; Mediating; Mediator of activation protein; Medical Records; Medicine; Methodology; Methods; Mission; Morbidity - disease rate; Mucous Membrane; Musculoskeletal; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Nested Case-Control Study; Newly Diagnosed; Nurses' Health Study; Outcome; Pain; Participant; Pathogenesis; Pathway interactions; Patient Recruitments; Patient-Focused Outcomes; Patients; Phenotype; Play; Positioning Attribute; Predisposition; Prevention strategy; Prospective cohort; Prospective cohort study; Proteins; Proxy; Pulmonary function tests; Research; Respiratory physiology; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Risk Factors; Role; Serological; Serum; Single Nucleotide Polymorphism; Site; Smoker; Smoking; Sputum; Statistical Methods; Structural Models; Structure; Surface; Symptoms; Testing; United States National Institutes of Health; Woman; Work; base; biobank; chest computed tomography; chronic autoimmune disease; chronic pain; cyclic citrullinated peptide; disability; follow-up; genome wide association study; idiopathic pulmonary fibrosis; improved; medical schools; mortality; multidisciplinary; neoantigens; pleiotropism; prevent; professor; pulmonary function; repository; respiratory; secondary analysis; seropositive; systemic autoimmune disease

Project Summary Rheumatoid arthritis (RA) is a systemic autoimmune disease affecting nearly 1% of adults that causes a painful, destructive inflammatory arthritis with long-term serious consequences including chronic pain, disability, accumulation of morbidities, and excess mortality. Cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) are elevated in the serum of two-thirds of RA patients. Seropositive RA patients are more likely to develop serious respiratory outcomes including interstitial lung disease and chronic obstructive pulmonary disease (COPD). Patients with seropositive RA have 3-fold excess respiratory mortality compared to the general population. Lung involvement is known to be an important contributor to excess RA morbidity and mortality, however less is known about its role in RA risk. Previous studies suggest that mucosal surfaces of the lung may be an initiating site, after smoking or exposure to other inhalants, where CCP and RF may be formed years before joint symptoms first develop. Therefore, patients with respiratory diseases such as asthma and COPD may be more likely to develop RA. These investigations will study whether individuals with respiratory diseases are more likely to develop RA. In the first aim, we will perform a prospective cohort study within the Nurses’ Health Studies, two longitudinal studies with up to 40 years of follow-up where we have we have already identified women who developed RA and collected data including RA serologic status. We will investigate whether women with asthma or COPD are more likely to develop RA overall, and by serologic status, compared to women without these diseases while adjusting for important confounders or mediators such as smoking. In the second aim, we will perform a case- control study in the Partners Biobank and replicated in the Nurses’ Health Studies to test whether genetic factors related to respiratory diseases and function are related to RA risk. The Partners Biobank is a large research repository recruited from patients seen at Brigham and Women’s Hospital, Massachusetts General Hospital, and affiliated satellite clinics in Boston, Massachusetts. We will analyze genotype data that has already been collected in the Partners Biobank and the Nurses’ Health Studies. Dr. Jeffrey Sparks (the PI) is an Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School. He has made significant progress in his ongoing K23 studies funded by NIAMS that are investigating RA-specific factors and subsequent respiratory outcomes. These proposed studies will complement those findings by using RA as the outcome instead of the exposure thereby describing a bi- directional association between respiratory diseases and RA. These will be secondary analyses of data already collected in datasets that the PI has access to and familiarity with analyzing. Together, the results of these studies will provide strong preliminary data supporting an R01 application to further investigate the effect of RA-related autoantibodies on respiratory function, structure, and outcomes.

项目摘要 风湿性关节炎（RA）是一种全身性自身免疫性疾病，影响近1%的成年人， 疼痛的、破坏性的炎症性关节炎，具有长期的严重后果，包括慢性疼痛， 残疾、发病率累积和死亡率过高。环瓜氨酸肽与类风湿 因子（RF）在三分之二的RA患者的血清中升高。血清阳性的RA患者更有可能 发生严重的呼吸系统疾病，包括间质性肺病和慢性阻塞性肺疾病 疾病（COPD）。血清阳性RA患者的呼吸道死亡率是对照组的3倍。 一般人口。已知肺受累是RA发病率过高的重要原因， 死亡率，但其在RA风险中的作用知之甚少。先前的研究表明， 在吸烟或暴露于其他吸入剂后，肺可能是CCP和RF可能 在关节症状出现前几年就形成了因此，哮喘等呼吸道疾病患者 COPD更容易发展为RA。 这些调查将研究患有呼吸系统疾病的人是否更容易患上RA。在 第一个目标，我们将在护士健康研究中进行一项前瞻性队列研究， 在长达40年的随访研究中，我们已经发现了患RA的女性， 并收集包括RA血清学状态的数据。我们将调查患有哮喘或COPD的女性是否 与没有这些疾病的女性相比， 调整重要的混杂因素或介质，如吸烟。在第二个目标中，我们将执行一个案例- 在合作伙伴生物库中进行对照研究，并在护士健康研究中进行复制，以测试基因是否 与呼吸系统疾病和功能相关的因素与RA风险有关。合作伙伴生物银行是一个大型的 从马萨诸塞州布里格姆妇女医院的病人中招募的研究资料库 医院和附属卫星诊所在波士顿，马萨诸塞州。我们将分析基因型数据， 已经被收集在伙伴生物银行和护士健康研究中。 博士杰弗里·斯帕克斯（PI）是布里格姆妇女医院的医学助理教授， 哈佛医学院。他在NIAMS资助的K23研究中取得了重大进展， 正在研究RA特异性因素和随后的呼吸结果。这些拟议的研究将 通过使用RA作为结局而不是暴露来补充这些发现，从而描述了一个双- 呼吸系统疾病与类风湿关节炎之间的定向关联。这些将是数据的二次分析 PI可以访问并熟悉分析的数据集中已经收集的数据。在一起， 这些研究将提供强有力的初步数据，支持R01的应用，以进一步研究其影响 RA相关自身抗体对呼吸功能、结构和结局的影响。