Causal effects of circulating inflammatory proteins on COPD: A Mendelian randomization study

Chronic obstructive pulmonary disease (COPD) is a major public health concern due to its high prevalence, morbidity, and mortality. Although COPD is recognized as a systemic inflammatory disease, the specific circulating inflammatory proteins associated with its development and progression remain poorly understood. We performed a Mendelian randomization (MR) study to investigate the association between circulating inflammatory proteins and COPD risk. Genetic data were obtained from a genome-wide association study of 20,066 COPD cases and 338,303 controls from the FinnGen consortium and circulating inflammatory protein data were derived from a genome-wide association study of 14,824 participants. The inverse-variance weighted method was used as the primary analysis. Depending on the number of available instrumental variables, complementary methods including the Wald ratio, Weighted Median, MR-Egger, Weighted Mode, and Simple Mode were applied to assess robustness. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy using Cochran’s Q test, the MR-Egger intercept, MR-PRESSO, and leave-one-out analysis. In addition, cis-acting protein quantitative trait locus –restricted analyses were performed to further reduce potential pleiotropy. Our findings showed that higher genetically predicted levels of CCL28 (odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.69–0.99, P  = .0394), CD40 (OR = 0.94, 95% CI: 0.89–0.99, P  = .0170), and urokinase-type plasminogen activator (OR = 0.91, 95% CI: 0.85–0.99, P  = .0212) were associated with a lower risk of COPD, whereas higher levels of Flt3L (OR = 1.09, 95% CI: 1.01–1.18, P  = .0344) and CD6 (OR = 1.06, 95% CI: 1.02–1.12, P  = .0099) were associated with a higher risk. Sensitivity analyses showed no evidence of heterogeneity or directional pleiotropy, and leave-one-out analyses indicated that the results were not driven by any single nucleotide polymorphism. These findings suggest that circulating inflammatory proteins, including CCL28, CD40, urokinase-type plasminogen activator, Flt3L, and CD6, may be involved in COPD pathogenesis. Further studies are needed to validate these findings and clarify their potential biological relevance.