Genetic association and potential mediators between metabolic syndrome and chronic obstructive pulmonary disease: A Mendelian randomization study

Chronic obstructive pulmonary disease (COPD) is a common and serious health issue. Epidemiological studies indicate a significant link between metabolic syndrome (MetS) and its components with the risk of developing COPD. However, observational studies are prone to confounding and reverse causation, so the causal relationship and underlying mechanisms between MetS and COPD remain unclear. This study used 2-sample Mendelian randomization (MR) to examine the causal relationship between MetS, its components, and COPD. Univariable Mendelian randomization identified causal links, followed by multivariable Mendelian randomization (MVMR) to assess regulatory effects of risk factors. A 2-step MR approach further explored mediation mechanisms. Genetic data were obtained from large genome-wide association study consortia of European populations. Genetically predicted MetS significantly increased COPD risk (OR = 1.53; 95% CI: 1.37-1.70; P = 6.63e-15). Among its components, waist circumference and hypertension were key contributors, while higher fasting glucose appeared protective. MVMR analysis revealed that the association between MetS and COPD is primarily mediated by body mass index (BMI), as the association was no longer significant after adjusting for BMI. Two-step MR confirmed BMI mediated most (86-94%) of MetS and waist circumference effects on COPD, with alcohol consumption having a smaller, opposite mediating effect. No evidence supported a reverse causal effect of COPD on MetS. This study demonstrates that genetically predicted MetS, particularly obesity and hypertension, causally increases COPD risk, with BMI as a key mediator. Proactive weight management could effectively prevent COPD in MetS patients.