Association Between Metabolically Different Adiposity Subtypes and Osteoarthritis: A Mendelian Randomization Study

Objective In this Mendelian randomization (MR) study, the objective was to investigate the causal effect of metabolically different adiposity subtypes on osteoarthritis. Methods We performed 2-sample MR using summary-level data for osteoarthritis (10,083 cases and 40,425 controls) from a genome-wide association using the UK Biobank, and for site-specific osteoarthritis from the Arthritis Research UK Osteoarthritis Genetics consortium. We used 3 classes of genetic instruments, which all increase body mass index but are associated with different metabolic profiles (unfavorable, neutral, and favorable). Primary analysis was performed using inverse variance weight (IVW), with additional sensitivity analysis from different MR methods. We further applied a nonlinear MR using UK Biobank data to understand the nature of the adiposity-osteoarthritis relationship. Results Greater metabolically unfavorable and metabolically neutral adiposity were associated with higher odds of osteoarthritis (IVW odds ratio [OR] 1.56 [95% confidence interval (95% CI) 1.31, 1.85] and OR 1.60 [95% CI 1.15, 2.23], respectively). The estimate for the association between metabolically favorable adiposity and osteoarthritis was similar, although with notable imprecision (OR 1.55 [95% CI 0.70, 3.41]). Using site-specific osteoarthritis, metabolically unfavorable, neutral, and favorable adiposity were all associated with higher odds of knee osteoarthritis (OR 1.44 [95% CI 1.04, 1.98], OR 2.28 [95% CI 1.04, 4.99], and OR 6.80 [95% CI 2.08, 22.19], respectively). We found generally consistent estimates with a wider confidence interval crossing the null from other MR methods. The nonlinear MR analyses suggested a nonlinear relationship between metabolically unfavorable adiposity and osteoarthritis (P-nonlinear = 0.003). Conclusion Metabolic abnormalities did not explain the association between greater adiposity and the risk of osteoarthritis, which might suggest that the association is largely due to a mechanical effect on the joints.

Automated summary

This Mendelian randomization study investigates the causal effect of different metabolically defined adiposity subtypes on osteoarthritis. The results show that metabolically unfavorable and metabolically neutral adiposity are associated with increased odds of osteoarthritis, while the association with metabolically favorable adiposity is less clear. Furthermore, all three metabolically defined adiposity subtypes are associated with increased odds of knee osteoarthritis. Nonlinear analyses suggest a nonlinear relationship between metabolically unfavorable adiposity and osteoarthritis.