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March 21, 2026Open Access

Causal risk and protective factors for rheumatoid arthritis: a comprehensive mendelian randomization systematic review and meta-analysis

XHXu HanChina Academy of Chinese Medical Sciences ZHZhenzhen HanFirst Affiliated Hospital of Henan University of Traditional Chinese Medicine SWSiyu WangFirst Affiliated Hospital of Henan University of Traditional Chinese Medicine

Key Points

To explore causal associations between various exposures and rheumatoid arthritis using Mendelian randomization.
Conducted systematic searches for two-sample MR studies on exposures linked to RA.
Extracted data on exposure types, genetic instruments, and analytical methods.
Performed meta-analyses using random-effects models with confidence intervals.
Included 117 studies with 496 MR associations across 248 exposures.
Identified smoking behavior and hypothyroidism as significant risk factors for RA.
Found cognitive function and interleukins-1 receptor antagonist to be protective factors.
Classified 7.66% of associations as providing robust evidence and 26.01% as probable evidence.

Abstract

Objective To systematically synthesize Mendelian randomization (MR) evidence exploring causal associations between various exposures and rheumatoid arthritis (RA). Methods 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. Results A total of 117 studies were included, comprising 496 MR 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 1.30–1.49) and hypothyroidism (OR = 1.55, 1.34–1.81) as significant risk factors with high-quality evidence. While television viewing (OR = 2.27, 1.77–2.90) and cholangitis (OR = 1.14, 1.06–1.23) showed nominal positive associations. Conversely, cognitive function (OR = 0.74, 0.68–0.81) and Interleukins-1 receptor antagonist (OR = 0.82, 95% CI 0.73–0.92) 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. Conclusion 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. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD42024573056 , identifier CRD42024573056.

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