Re-Evaluating the Relationship Between Insulin Resistance and Chronic Obstructive Pulmonary Disease: Evidence from NHANES and Mendelian Randomization

Background and Purpose: Observational studies suggest an association between insulin resistance (IR) and chronic obstructive pulmonary disease (COPD), but this link is susceptible to confounding and reverse causality. This study integrated cross-sectional analysis with Mendelian Randomization (MR) to systematically evaluate their potential causal relationship. Methods: Using NHANES data, we employed complex sampling weighting and multivariable logistic regression to assess the observational association between IR (measured by HOMA-IR) and COPD. For genetic analysis, genetic variants strongly associated with IR were selected as instrumental variables from GWAS summary data. Two-sample MR analyses were conducted using inverse-variance weighted (IVW), weighted median, and MR-Egger regression, with rigorous testing for pleiotropy and heterogeneity. Results: Observational analysis showed no significant association before confounder adjustment (P=0.166). After adjustment, moderate IR levels (third quintile) were associated with increased COPD risk (OR=2.24, 95% CI: 1.15-4.37, P=0.018). MR analysis revealed inconsistent estimates: IVW suggested a weak risk effect (OR=1.009, P