Impact of birth weight on cardiovascular disease and mediating role of metabolic traits: a Mendelian randomisation study.

BACKGROUND: Birth weight (BW) has been linked to cardiometabolic diseases, but causal associations with a comprehensive range of cardiovascular outcomes and underlying metabolic mechanisms remain unclear. METHODS: We applied a two-sample Mendelian randomisation (MR) approach to evaluate causal relationships between genetically predicted BW and 16 distinct cardiovascular diseases (CVD). We further conducted a two-step MR mediation analysis to quantify the mediating roles of 24 metabolic traits covering body composition, glucose metabolism, lipid metabolism, blood pressure, fatty acids and amino acids. RESULTS: Genetically lower BW was associated with higher risks of coronary heart disease (OR 0.72, 95% CI 0.65 to 0.81), myocardial infarction (OR 0.71, 95% CI 0.63 to 0.80) and angina pectoris (OR 0.81, 95% CI 0.72 to 0.90). These effects were partly mediated by type 2 diabetes, systolic blood pressure, total cholesterol and triglycerides, explaining 11.76-33.33% of the total associations. In contrast, genetically higher BW increased the risk of aortic aneurysm (OR 1.46, 95% CI 1.21 to 1.75), venous thromboembolism (OR 1.22, 95% CI 1.09 to 1.36) and atrial fibrillation (OR 1.34, 95% CI 1.21 to 1.48). These associations were partly explained by body composition traits, with appendicular lean mass and body mass index mediating 10.53-26.32% of the effect on aortic aneurysm, 15.79-68.42% of the effect on venous thromboembolism and 10.34-58.62% of the effect on atrial fibrillation. CONCLUSIONS: Our study provides robust evidence of distinct causal pathways linking BW with adult cardiovascular risks through specific metabolic mediators. These findings highlight the importance of optimal fetal growth and lifelong metabolic health management as critical strategies to reduce CVD burden.