Exploring the causal relationship between inflammatory cytokines and inflammatory arthritis: A Mendelian randomization study

Abstract

Objectives: Previous studies have reported an association between inflammatory cytokines and inflammatory arthritis, including Ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriatic arthritis (PsA). This study aims to explore the causal relationship between inflammatory cytokines and AS, RA, and PsA using Mendelian randomization (MR).

Methods: We conducted a bidirectional two-sample MR analysis using genetic summary data from a publicly available genome-wide association study (GWAS) that included 41 genetic variations of inflammatory cytokines, as well as genetic variant data for AS, RA, and PsA from the FinnGen consortium. The main analysis method used was Inverse variance weighted (IVW) to investigate the causal relationship between exposure and outcome. Additionally, other methods such as MR Egger, weighted median (WM), simple mode, and weighted mode were employed to strengthen the final results. Sensitivity analysis was also performed to ensure the reliability of the findings.

Results: The results showed that macrophage colony-stimulating factor (MCSF) was associated with an increased risk of AS (OR = 1.163, 95 % CI = 1.016-1.33, p = 0.028). Conversely, high levels of TRAIL and beta nerve growth factor (β-NGF) were associated with a decreased risk of AS (OR = 0.892, 95 % CI = 0.81-0.982, p = 0.002; OR = 0.829, 95 % CI = 0.696-0.988, p = 0.036). Four inflammatory cytokines were found to be associated with an increased risk of PsA: vascular endothelial growth factor (VEGF) (OR = 1.161, 95 % CI = 1.057-1.275, p = 0.002); Interleukin 12p70 (IL12p70) (OR = 1.189, 95 % CI = 1.049-1.346, p = 0.007); IL10 (OR = 1.216, 95 % CI = 1.024-1.444, p = 0.026); IL13 (OR = 1.159, 95 % CI = 1.05-1.28, p = 0.004). Interleukin 1 receptor antagonist (IL-1rα) was associated with an increased risk of seropositive RA (OR = 1.181, 95 % CI = 1.044-1.336, p = 0.008). Similarly, genetic susceptibility to inflammatory arthritis was found to be causally associated with multiple inflammatory cytokines. Lastly, the sensitivity analysis supported the robustness of these findings.

Conclusions: This study provides additional insights into the relationship between inflammatory cytokines and inflammatory arthritis, and may offer new clues for the etiology, diagnosis, and treatment of inflammatory arthritis.

Keywords: Bidirectional; GWAS; Inflammatory arthritis; Inflammatory cytokines; Mendelian randomization.