Interleukins and rheumatoid arthritis: bi-directional Mendelian randomization investigation

Abstract

Objectives: To assess the causality of the associations between interleukins (ILs) and rheumatoid arthritis (RA) using Mendelian randomization (MR) design.

Methods: Genetic instruments and summary-level data for ten ILs were obtained from three genome-wide association meta-analyses. Corresponding data on RA were obtained from a meta-analysis of 22 genome-wide association studies (14,361 cases and 43,923 controls) and the FinnGen consortium (6236 cases, 4596 seropositive cases, 1937 seronegative cases, and 172,834 controls). Forward and reverse MR analyses were performed.

Results: The odds ratios (ORs) of RA were 2.08 (95% confidence interval (CI), 1.56-2.77; p<0.001), 2.14 (95% CI, 1.85-2.49; p<0.001), and 0.95 (95% CI, 0.92-0.97; p<0.001) for one standard deviation increase in genetically predicted IL-1β, IL-6 and IL-6 receptor antagonist (IL-6ra) levels, respectively. There were suggestive associations of genetically predicted IL-1 receptor antagonist (IL-1ra) (OR, 0.85, 95% CI, 0.76, 0.96; p=0.010) and IL-18 (OR, 1.07, 95% CI, 1.00, 1.15; p=0.043) levels with RA risk. Subtype-specific associations were observed for seropositive RA (IL-1β, IL-1ra, and IL-6) and seronegative RA (IL-2 receptor alpha subunit, IL-8, and IL-18). Reverse MR analysis found a suggestive association between genetic liability to RA and IL-6 receptor antagonist (change 0.015; 95% CI, 0.003-0.028; p=0.015).

Conclusions: This MR study suggests that long-term IL-1 and IL-6 inhibition may reduce the risk of RA, particularly seropositive RA. Upregulations of ILs involved in IL-6 signaling pathways appears to be downstream effects of RA, which supports the blocking IL-6 treatment for RA.

Keywords: Mendelian randomization; interleukin; rheumatoid arthritis; seronegative; seropositive.