Mendelian randomization study to investigate the causal relationship between plasma homocysteine and chronic obstructive pulmonary disease.

BACKGROUND: Several observational studies have shown an association between homocysteine (Hcy) levels and chronic obstructive pulmonary disease (COPD), but causal relationships are not clear. Our study aimed to explore the causal relationship between plasma Hcy and COPD by two-sample Mendelian randomization (MR). METHODS: A two-sample MR study was performed to infer the causal link. Genetically predicted plasma Hcy was selected as an instrumental variable (IV) from published genome-wide association study (GWAS) meta-analyses. COPD with different etiologies was extracted as outcome variables from other GWAS meta-analyses. The main MR analysis was performed using the inverse-variance weighted (IVW) method. Additional analyses were further performed using Cochran's Q-test and MR-Egger regression to evaluate the heterogeneity or horizontal pleiotropy of our findings. RESULTS: MR analysis showed no significant association between plasma Hcy and COPD. The results of the groups were consistent with the sensitivity analysis and repeated analysis, without heterogeneity or horizontal pleiotropy. The IVW results showed COPD hospital admissions (odds ratio [OR] 1.06, 95% confidence interval [CI] 0.91-1.24, P=0.42), asthma/COPD (OR 0.97, 95% CI 0.89-1.06, P=0.55), COPD-related chronic infection (OR 1.50, 95% CI 0.57-3.99, P=0.41), COPD/asthma/interstitial lung disease (ILD)-related pneumonia or pneumonia-derived septicemia (OR 0.93, 95% CI 0.86-1.02, P=0.13), and COPD-related respiratory insufficiency (OR 1.00, 95% CI 0.7-1.44, P=0.99). CONCLUSION: There is no direct causal relationship between plasma Hcy and COPD in our study. As Hcy is known to have deleterious effects on endothelial function and vascular homeostasis, further studies are needed to investigate whether additional factors mediate the association between Hcy and COPD.