Genetic causality between modifiable risk factors and the risk of rheumatoid arthritis: Evidence from Mendelian randomization

Objectives: Emerging research has investigated the potential impact of several modi-fiable risk factors on the risks of rheumatoid arthritis (RA), but the findings did not yield consistent results. This study aimed to comprehensively explore the genetic causality between modifiable risk factors and the susceptibility of RA risk using the Mendelian randomization (MR) approach. Methods: Genetic instruments for modifiable risk factors were selected from severalgenome-wide association studies at the genome-wide significance level (p< 5 x 10(-8)), respectively. Summary- level data for RA were sourced from a comprehensive meta- analysis. The causal estimates linking modifiable risk factors to RA risk were assessed using MR analysis with inverse variance weighting (IVW), MR- Egger, weighted, and weighted median methods. Results: After Bonferroni correction for multiple tests, we found the presence of cau-sality between educational attainment and RA, where there were protective effects of educational attainment (college completion) (odds ratio [OR] = 0.50, 95% CI = 0.36, 0.69, p= 2.87E-05) and educational attainment (years of education) (OR = 0.93, 95% CI = 0.90, 0.96, p= 4.18E-06) on the lower RA risks. Nevertheless, smoking initiation was observed to be associated with increased RA risks (OR = 1.27, 95% CI = 1.09, 1.47, p= .002). Moreover, there was no indication of horizontal pleiotropy of genetic vari-ants during causal inference between modifiable risk factors and RA. Conclusions: Our study reveals the genetic causal impacts of educational attainmentand smoking on RA risks, suggesting that the early monitoring and recognition of modifiable risk factors would be beneficial for the preventive counseling/treatment strategies for RA.