Multi-Ancestry Mendelian Randomization Reveals Lipid-Associated Genetic Risk Factors for COPD.

Background: Previous Mendelian randomization (MR) studies investigating the causal relationship between lipid traits and chronic obstructive pulmonary disease (COPD) have primarily focused on individuals of European (EUR) ancestry, limiting the generalizability of findings. This study aimed to address this limitation.

Methods: Summary-level data for individuals of East Asian (EAS), African (AFR), and Hispanic (HIS) ancestry were obtained from large-scale genetic databases. Lipid traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC), were derived from the Global Lipids Genetics Consortium (GLGC). The discovery COPD dataset was sourced from the Global Biobank Meta-analysis Initiative (GBMI), while replication datasets came from the Million Veteran Program (MVP) and Biobank Japan (BBJ). Causal effects were assessed through meta-analysis across discovery and replication cohorts, supplemented by a series of sensitivity analyses, including the Steiger test, Causal Analysis Using Summary Effect Estimates (CAUSE), MRLap, RadialMR, Bonferroni correction, among others.

Results: In the EAS population, strong evidence supported a causal relationship between genetically predicted TC levels and reduced COPD risk (OR = 0.891, 95% CI: 0.841-0.944, P = 9.91×10^-5). Additionally, the association between TG and COPD (OR = 0.827, 95% CI: 0.739-0.925, P = 9.04×10^-4) in EAS was primarily driven by the rs7350481 variant in the MAML2 gene. Suggestive evidence also indicated a positive causal association between TG levels and increased COPD risk (OR = 1.438, 95% CI: 1.091-1.896, P = 0.009) in the AFR population. No other significant causal relationships were detected.

Conclusion: This study reveals ancestry-specific causal links between lipid traits and COPD risk. The protective effect observed for TG in EAS may reflect variant-level pleiotropy rather than a true metabolic influence, warranting cautious interpretation. These findings highlight the importance of multi-ancestry analyses in contextualizing genetic associations across diverse populations.