{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T02:41:04Z","timestamp":1773888064669,"version":"3.50.1"},"reference-count":163,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To systematically synthesize Mendelian randomization (MR) evidence exploring causal associations between various exposures and rheumatoid arthritis (RA).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Systematic searches were conducted to identify eligible two-sample MR studies evaluating causal links between exposures and RA. Data extraction encompassed exposure types, genetic instruments, and analytical methods. The quality of evidence was evaluated based on STROBE-MR guidelines and evidence strength grades. Meta-analyses were performed using random-effects model with restricted maximum likelihood estimation and Hartung-Knapp-Sidik-Jonkman confidence intervals to summarize causal estimates.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 117 studies were included, comprising 496\u00a0MR associations across 248 unique exposures. Of these, 200 exposure-RA associations across 65 unique exposures were eligible for meta-analysis. The primary analysis identified smoking behavior (OR = 1.39, 95% CI 1.30\u20131.49) and hypothyroidism (OR = 1.55, 1.34\u20131.81) as significant risk factors with high-quality evidence. While television viewing (OR = 2.27, 1.77\u20132.90) and cholangitis (OR = 1.14, 1.06\u20131.23) showed nominal positive associations. Conversely, cognitive function (OR = 0.74, 0.68\u20130.81) and Interleukins-1 receptor antagonist (OR = 0.82, 95% CI 0.73\u20130.92) were identified as a nominally protective factor. In subtype analyses, basal metabolic rate emerged as a potential shared risk factor for both seropositive and seronegative RA. Overall, 7.66% and 26.01% of all associations were classified as providing Robust (I) and Probable (II) evidence, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This comprehensive review clarifies the causal landscape of RA by distinguishing between significant causal drivers and potential associations. The findings highlight smoking cessation and thyroid function management as critical, evidence-based targets for RA prevention. However, the high proportion of low-quality evidence underscores the need for future high-quality MR studies to validate weaker signals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD42024573056<\/jats:ext-link>\n                      , identifier CRD42024573056.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1774582","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T22:10:19Z","timestamp":1773871819000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Causal risk and protective factors for rheumatoid arthritis: a comprehensive mendelian randomization systematic review and meta-analysis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xu","family":"Han","sequence":"first","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenzhen","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The First Affiliated Hospital of Henan University of CM","place":["Zhengzhou, Henan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The First Affiliated Hospital of Henan University of CM","place":["Zhengzhou, Henan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yafei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The First Affiliated Hospital of Henan University of CM","place":["Zhengzhou, Henan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The First Affiliated Hospital of Henan University of CM","place":["Zhengzhou, Henan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The First Affiliated Hospital of Henan University of CM","place":["Zhengzhou, Henan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinlong","family":"Yu","sequence":"additional","affiliation":[{"name":"National Data Center of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danyang","family":"Cui","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]},{"name":"General Hospital of Northern Theater Command","place":["Shenyang, Liaoning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxia","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiazhu","family":"Jin","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Data Center of Traditional Chinese Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongtao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, The First Affiliated Hospital of Henan University of CM","place":["Zhengzhou, Henan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1579","DOI":"10.1093\/rheumatology\/kex239","article-title":"Female hormonal factors and the development of anti-citrullinated protein antibodies in women at risk of rheumatoid arthritis","volume":"56","author":"Alpizar-Rodriguez","year":"2017","journal-title":"Rheumatol. 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