Mendelian Randomization Study in East Asian Populations Supports the Causal Relationship Between Blood Metabolites and COPD: Insights from Amino Acids, Phospholipids, Vitamin D, and Trace Elements

Background: Chronic obstructive pulmonary disease (COPD) is the most common respiratory disease among middle-aged and older adults worldwide, and its etiology remains incompletely understood. As intermediate products of biochemical reactions, blood metabolites have a debated role in the pathogenesis of COPD, with observational studies yielding conflicting results. Most existing genetic studies are based on European cohorts, whereas East Asian populations differ substantially in genetic architecture and environmental exposures, limiting the generalizability of current findings. Methods: We performed two-sample Mendelian randomization (MR) leveraging the most recently released summary statistics from large-scale genome-wide association studies (GWAS) in East Asian populations. Independent SNPs significantly associated with circulating metabolite levels were selected from multiple East Asian datasets as instrumental variables (3432 Chinese participants, 2022). Outcome data were obtained from two independent East Asian COPD GWAS cohorts: ebi-a-GCST90018587 (4017 cases, 162,653 controls, BioBank Japan, 2021) and bbj-a-103 (3315 cases, 201,592 controls, BioBank Japan, 2019). Inverse-variance weighting (IVW) served as the primary estimator, with sensitivity analyses conducted using MR-Egger regression, the weighted median, and additional complementary approaches. Results: Seven blood metabolites showed suggestive causal links with COPD. In the ebi-a-GCST90018587 cohort, genetically predicted platelet count was positively associated with COPD risk (OR = 1.51, 95% CI 1.01– 2.27, P = 0.0467), and in the bbj-a-103 cohort higher genetically predicted manganese levels likewise indicated increased risk (OR = 1.27, 95% CI 1.00– 1.62, P = 0.0460). Conversely, higher genetically predicted levels of leucine (OR = 0.56, 95% CI 0.34– 0.91, P = 0.0197), alpha-aminoadipic acid (OR = 0.75, 95% CI 0.59– 0.96, P = 0.0208), serum-alanine-transaminase (ALT)(OR = 0.87, 95% CI 0.76– 0.99, P = 0.0345), phosphoethanolamine (OR=0.75, 95% CI 0.56– 1.00, P = 0.0500), and 25-hydroxyvitamin-D2 (OR = 0.81, 95% CI 0.70– 0.94, P = 0.0045) were associated with lower COPD risk, with phosphoethanolamine and 25-hydroxyvitamin-D2 showing concordant directions and comparable effect sizes across the two independent COPD GWAS cohorts. For all exposures, Cochran’s Q tests and MR-Egger intercepts indicated no significant heterogeneity ( P > 0.05 ), and Steiger directionality tests ( P< 0.05 ) did not suggest reverse causation. Conclusion: Leveraging large East Asian cohorts, this study provides MR evidence implicating amino-acid metabolism, phospholipid metabolism, vitamin D status, and selected trace elements in COPD pathophysiology. The replicated protective signals for phosphoethanolamine and 25(OH)D 2 , and the risk signals for platelet count and manganese, offer East Asian–specific genetic support for metabolically oriented prevention and precision interventions.