Association between serum copper and COPD: Insights from NHANES 2011-2016 and Mendelian randomization study

Chronic obstructive pulmonary disease (COPD) affects 390 million people globally, with oxidative stress playing a key pathogenic role. Smoking and other forms of tobacco exposure are major COPD drivers and important sources of systemic oxidative stress, and potentially interact with metal homeostasis. Copper exhibits dual effects in lung homeostasis, as a cofactor for antioxidant enzymes and a potential catalyst for reactive oxygen species. However, the causal relationship between serum copper levels and COPD remains unclear. This study aimed to assess their association using a combination of observational and genetic approaches.

In stage one, we used multivariate regression to analyze the association between serum copper and COPD in 3166 participants in the National Health and Nutrition Examination Survey (NHANES), 2011-2016. Models adjusted for demographic and clinical covariates including smoking-related variables, and stratified analyses by smoking status. Stage two utilized Mendelian randomization (MR) analysis to explore a potential cause-and-effect link between copper levels in serum determined by genetics and COPD.

Observational analysis showed increased COPD risk in the highest serum copper tertile (T3 vs T1, OR=1.65; 95% CI: 1.09-2.49; p-trend=0.0245). The association remained after adjustment for smoking-related covariates. However, MR analyses using both FinnGen and UK Biobank data suggested no causal effect (FinnGen IVW, OR=1.01; 95% CI: 0.98-1.04, p=0.37; UK Biobank IVW, OR=1.00; 95% CI: 1.00-1.00, p=0.55), with sensitivity analyses confirming result robustness.

While elevated serum copper is associated with COPD prevalence observationally, the null MR finding suggests it may reflect tobacco-related systemic oxidative stress or reverse causation rather than being a direct causal driver. Therefore, serum copper may be more useful as a biomarker of smoking-induced redox disturbance than as a therapeutic target. These results underscore the importance of integrating tobacco exposure metrics in future studies examining metal biology in COPD.