Nicotine Metabolism and Chronic Obstructive Pulmonary Disease: Mendelian Randomization and Phenotypic Characterization Analysis

Background: Smokers with similar smoking exposure show markedly different risks of chronic obstructive pulmonary disease (COPD), and it remains unclear whether genetically determined nicotine metabolism, measured by the nicotine metabolite ratio (NMR), is independently associated with COPD beyond smoking exposure. Methods: This study integrated genetic evidence and population-based phenotypic analyses. First, two-sample Mendelian randomization (MR) analyses were conducted using genome-wide association study summary statistics to evaluate the causal effect of the NMR on COPD, with colocalization analyses to assess shared causal genetic variants. Second, phenotypic analyses in the China National Tobacco Cessation Cohort Study were conducted in a cross-sectional setting to compare COPD prevalence across metabolic phenotypes under comparable smoking exposure, with mediation analyses evaluating the contribution of smoking behavior. Results: MR analysis showed a causal association between a higher NMR and increased risk of COPD (OR = 1.06, 95% CI: 1.05– 1.08). Colocalization analyses identified shared causal variants. Population-based phenotypic analyses showed that COPD prevalence was consistently higher in normal metabolizers (NMR ≥ 0.31) than slow metabolizers (NMR < 0.31), regardless of smoking exposure strata, and more importantly, remained higher within comparable levels of cumulative smoking. Mediation analysis showed that smoking behavior partially mediated this association (indirect effect β = 0.0049, P < 0.001), accounting for 14.5% of the total effect. Conclusion: Nicotine metabolism, as captured by NMR, is causally associated with COPD susceptibility. These findings suggest that incorporating nicotine metabolism into smoking exposure assessment may have potential value in improving COPD risk stratification. Keywords: COPD, nicotine metabolism, smoking behavior