Causal association of rheumatoid arthritis with frailty and the mediation role of inflammatory cytokines: a Mendelian randomization study

Previous observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design. Summary-level data for RA (N=58,284), frailty index (FI) (N=175,226), Fried frailty score (FFS) (N=386,565), and 41 inflammatory cytokines (N=8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR. Univariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95% CI: 0.012, 0.03; p=2.2 × 10−6) and FFS (beta=0.011; 95%CI: 0.007, 0.015; p=8.811 × 10−8). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8% (95%CI: 4.76%, 19.05%), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6% (95%CI: 0%, 18.18%) and 8.44% (95%CI: 0%, 18.18%), respectively. This study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty.