Linking Chronic Obstructive Pulmonary Disease and Asthma with Gallstones: Evidence from a Cross-Sectional Study and Mendelian Randomization

To investigate whether chronic obstructive pulmonary disease (COPD) and asthma increase the risk of gallstones based on the National Health and Nutrition Examination Survey (NHANES) and Mendelian randomization (MR). Data from the NHANES 2017–2023 were included in the cross-sectional study. Diagnoses of COPD, asthma and gallstones were obtained from self-report questionnaires. Multivariate logistic regression, subgroup analyses and interaction tests were applied to explore these associations. Data for MR analysis were obtained from the Finnish cohort and the Integrative Epidemiology Unit (IEU). The inverse variance weighting (IVW) estimate was applied as the main approach to determine the causality of associations. A total of 8,728 participants were enrolled in the cross-sectional study. Both COPD (OR 1,842, 95% CI 1.144, 2.968, <i>p</i> = 0.015) and asthma (OR 1.434, 95% CI 1.093, 1.883, <i>p</i> = 0.012) were associated with increased gallstone risk before and after covariate adjustments, and diabetes history may interact with the COPD-gallstone association (<i>p</i> = 0.020). In MR analysis, although a causal association was observed between COPD and gallstones (OR 1.216, 95% CI 1.023, 1.445; <i>p</i> = 0.026), leave-one-out analysis suggested that the causal association disappeared without serpin family A member 1 (<i>SERPINA1</i>). No causal association was observed between asthma and gallstones (OR 1.016, 95% CI 0.932, 1.108; <i>p</i> = 0.718). Although both COPD and asthma were positively associated with gallstones based on NHANES, the COPD-gallstone association was largely driven by <i>SERPINA1</i>, and no causality was observed in asthma-gallstone association. The available evidence provided limited support for causal associations between obstructive lung diseases and gallstones.