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

Long Wen; Jingwen Fan; Xuezhong Shi; Huiping Zhou; Yongli Yang; Xiaocan Jia

doi:10.1016/j.archger.2024.105348

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

Arch Gerontol Geriatr. 2024 Jan 24:122:105348. doi: 10.1016/j.archger.2024.105348. Online ahead of print.

Authors

Long Wen¹, Jingwen Fan¹, Xuezhong Shi¹, Huiping Zhou¹, Yongli Yang², Xiaocan Jia³

Affiliations

¹ Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China.
² Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China. Electronic address: ylyang377@zzu.edu.cn.
³ Department of Epidemiology and Biostatistics, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China. Electronic address: jxc@zzu.edu.cn.

PMID: 38460264
DOI: 10.1016/j.archger.2024.105348

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Frailty index; Fried frailty score; Inflammatory cytokines; Mendelian randomization; Rheumatoid arthritis.