Introduction and Objective: Triglyceride in low-density lipoprotein (TG-LDL) was considered a novel biomarker for coronary artery disease (CAD) from observational studies. We aimed to explore the causal relationship between TG-LDL levels and both overall and sex-specific CAD risk in individuals of European ancestry. Methods: We analyzed 487,759 European-ancestry participants from the UK Biobank and performed a genome-wide association study (GWAS) of TG-LDL using linear mixed models adjusted for age, sex, genotyping array, and ancestry principal components. Genome-wide significant variants were selected as genetic instruments for TG-LDL. CAD instruments were obtained from a multi-consortium GWAS comprising 181,522 cases among 1,165,690 predominantly European participants. Two-sample Mendelian Randomization (MR) was used to estimate the causal effect of higher TG-LDL levels on CAD risk. MR-Egger regression and the weighted median estimator were used as sensitivity analyses to evaluate the robustness of the findings. This MR framework was applied to the overall population and by sex. Results: In total, 121 SNPs for the overall population and 86 SNPs for the sex-stratified analyses were used as genetic instruments in the MR pipeline. Higher TG-LDL levels were causally associated with increased CAD risk in the overall, male, and female populations (odds ratios: 1.44, 1.50, and 1.39; 95% CIs: 1.32-1.57, 1.31-1.71, and 1.22-1.62, respectively). Sensitivity analyses showed no evidence of directional pleiotropy (p=0.09, 0.41, and 0.53, respectively). Conclusion: Our findings indicate that TG-LDL is a causal biomarker of CAD risk and highlight its relevance for both general and sex-specific risk assessment. Disclosure Y. Lu: None. Y. Yoshida: None. Funding American Diabetes Association (7-23-JDFWH-10), National Institute of General Medical Sciences of the National Institutes of Health (1P20GM152305), Administrative Supplement of the Louisiana Clinical & Translational Science Center (U54 GM104940)
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