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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Comprehensive Center (P60)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Zak, Agnes; Corrigan, Cassandra; Yu, Zhi et al. (2018) Barriers to treatment adjustment within a treat to target strategy in rheumatoid arthritis: a secondary analysis of the TRACTION trial. Rheumatology (Oxford) 57:1933-1937
von Heideken, Johan; Iversen, Maura D; Gerdhem, Paul (2018) Rapidly increasing incidence in scoliosis surgery over 14 years in a nationwide sample. Eur Spine J 27:286-292
MacFarlane, Lindsey A; Yang, Heidi; Collins, Jamie E et al. (2018) Relationship between patient-reported swelling and MRI-defined effusion-synovitis in patients with meniscus tears and knee osteoarthritis. Arthritis Care Res (Hoboken) :
Sparks, Jeffrey A; Lin, Tzu-Chieh; Camargo Jr, Carlos A et al. (2018) Rheumatoid arthritis and risk of chronic obstructive pulmonary disease or asthma among women: A marginal structural model analysis in the Nurses' Health Study. Semin Arthritis Rheum 47:639-648
Kreps, David J; Halperin, Florencia; Desai, Sonali P et al. (2018) Association of weight loss with improved disease activity in patients with rheumatoid arthritis: A retrospective analysis using electronic medical record data. Int J Clin Rheumtol 13:1-10
Solomon, Daniel H; Lu, Bing; Yu, Zhi et al. (2018) Benefits and Sustainability of a Learning Collaborative for Implementation of Treat-to-Target in Rheumatoid Arthritis: Results of a Cluster-Randomized Controlled Phase II Clinical Trial. Arthritis Care Res (Hoboken) 70:1551-1556
Prado, Maria G; Iversen, Maura D; Yu, Zhi et al. (2018) Effectiveness of a Web-Based Personalized Rheumatoid Arthritis Risk Tool With or Without a Health Educator for Knowledge of Rheumatoid Arthritis Risk Factors. Arthritis Care Res (Hoboken) 70:1421-1430
Lee, Moa P; Lii, Joyce; Jin, Yinzhu et al. (2018) Patterns of Systemic Treatment for Psoriatic Arthritis in the US: 2004-2015. Arthritis Care Res (Hoboken) 70:791-796
Barbhaiya, Medha; Tedeschi, Sara K; Lu, Bing et al. (2018) Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts. Ann Rheum Dis 77:196-202
Sparks, Jeffrey A; Iversen, Maura D; Yu, Zhi et al. (2018) Disclosure of Personalized Rheumatoid Arthritis Risk Using Genetics, Biomarkers, and Lifestyle Factors to Motivate Health Behavior Improvements: A Randomized Controlled Trial. Arthritis Care Res (Hoboken) 70:823-833

Showing the most recent 10 out of 444 publications