Causal effects of circulating inflammatory proteins on knee and hip osteoarthritis: A two sample Mendelian randomization study

Abstract

Introduction: Numerous circulating proteins are linked to the presence or severity of joint inflammation. However, traditional studies could not explain whether these protein biomarkers are proximate to disease progression.

Method: We conducted a study to explore the causal effects of 91 circulating inflammation-related proteins (CIPs) on knee osteoarthritis (KOA) and hip osteoarthritis (HOA), using two-sample Mendelian randomization (MR). The primary analysis utilized the inverse variance weighted (IVW) method, augmented by complementary approaches including weighted median, weighted mode, simple median, MR-Egger, and MR-PRESSO analysis. Sensitivity analysis validated the robustness of the results and ensured the absence of heterogeneity and horizontal pleiotropy.

Results: We identified 2 CIPs with a causal effect on KOA, including CXCL9 (OR = 1.249, 95% CI = 1.046-1.492, P = 0.014) and TNF-β (OR = 1.105, 95% CI = 1.014-1.204, P = 0.023). Additionally, 3 CIPs were found to have a causal effect on HOA, including CXCL6 (OR = 1.058, 95% CI = 1.004-1.116, P = 0.035), RANKL (OR = 1.067, 95% CI = 1.002-1.137, P = 0.044), and VEGFA (OR = 1.072, 95% CI = 1.008-1.140, P = 0.027).

Conclusions: In the current study, our findings indicated that CXCL9 and TNF-β had the potential to influence the risk of KOA, while CXCL6, RANKL, and VEGFA could impact the risk of HOA. These discoveries underscored the significance of these proteins as potential targets for intervention in the prevention and treatment of KOA and HOA. Key Points • We presented genetic evidence supporting a causal link between circulating inflammatory proteins associated with joint inflammation using MR methods. • 5 CIPs have demonstrated promotive effects on the occurrence of KOA and HOA.

Keywords: Causal inference; Inflammation protein; Mendelian randomization; Osteoarthritis.