Metformin Treatment Reduces the Incidence of Rheumatoid Arthritis: A Two-Sample Mendelian Randomized Study

Several studies have shown that rheumatologic patients can benefit from metformin, but it remains unclear whether metformin treatment is causally associated with the risk of rheumatoid arthritis (RA). A two-sample Mendelian randomization (MR) study was conducted to investigate the causal relationship between metformin treatment and the incidence of rheumatoid arthritis. The genome-wide significant (p < 5 × 10^-8) single-nucleotide polymorphisms (SNPs) associated with metformin use were selected as instrumental variables (IVs). Summary statistics on RA were extracted from a large genome-wide association study (GWAS) meta-analysis. The inverse variance-weighted (IVW) method was used as the determinant of the causal effects of metformin treatment on RA. Cochran's Q was used to detect heterogeneity. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test and MR-Egger regression were used to detect horizontal pleiotropy. A total of 34 SNPs significantly associated with metformin treatment were obtained. Thirty-two SNPs were selected as IVs after removing two SNPs for being palindromic with intermediate allele frequencies (rs11658063 and rs4930011). The IVW results showed a negative causal association between metformin treatment and RA (OR = 0.0232, 95% CI 1.6046 × 10^-3 - 0.3368; p = 0.006). Meanwhile, no heterogeneity or pleiotropy was detected, indicating that the results were reliable. This study indicated a negative causality between metformin treatment and RA, indicating that the treatment of metformin can prevent the pathogenesis of RA.