A bidirectional Mendelian randomisation study of the association between rheumatoid arthritis and frailty

Observational studies have linked rheumatoid arthritis and frailty, but confounding factors and reverse causality make it unclear if there is a causal relationship. The current study used bidirectional two-sample Mendelian randomisation (MR) to assess the bidirectional causation between rheumatoid arthritis and frailty.

The primary analysis used the latest GWAS data for rheumatoid arthritis and frailty index in pure Europeans from large genome-wide association studies. Validation analysis was done to verify the accuracy of the results. The appropriate instrumental variables (IVs) were selected based on the three MR assumptions. The MR methods used were MR-Egger, weighted median (WM), and inverse variance weighted (IVW). The effects of horizontal pleiotropy were examined using the MR-Egger intercept and the MR-PRESSO method. To avoid single SNP bias, a leave-one-out analysis was performed.

Genetic predictions suggested that there is a significant association between rheumatoid arthritis and the increased prevalence of frailty (IVW OR=1.01; 95% CI=[1.01-1.02], p=2.47 E-06). It has been verified in validation analysis that rheumatoid arthritis is also associated with frailty (IVW OR=1.03, 95% CI=[1.02-1.04], p=3.30E-17). Notably, genetic predictions suggested that frailty may be associated with the onset or development of rheumatoid arthritis (IVW β=1.25, SE=0.44, 95% CI=[0.39-2.12], p=4.58E-03).

The present study provides evidence supporting the fact that rheumatoid arthritis can increase the prevalence of frailty. Frailty may be a risk factor for rheumatoid arthritis, and whether frailty is involved in triggering the onset or progression of rheumatoid arthritis needs further study.