Several observational studies have indicated an association between high serum levels of branched-chain amino acids (BCAAs) and an increased risk of cardiovascular disease (CVD). To assess whether theses associations reflect causality, we carried out two-sample Mendelian randomization (MR). Single-nucleotide polymorphisms (SNPs) associated with BCAA were evaluated in 10 studies, including 24,925 participants. The association between SNPs and coronary artery disease (CAD) were assessed using summary estimates from the CARDIoGRAMplusC4D consortium. Further MR analysis of BCAAs and seven CVD outcomes was performed. The BCAA-raising gene functions were also analyzed. MR analyses revealed a risk-increasing causal relationship between serum BCAA concentrations and CAD (odds ratio 1.08; 95% confidence interval (CI) 1.02-1.14), which was partly mediated by blood pressure and type 2 diabetes. BCAA also demonstrated a causal relationship with ischemic CVD events induced by plaque rupture and thrombosis (false discovery rate <0.05). Two BCAA-raising genes (MRL33 and CBLN1) were preferentially associated with myocardial infarction risk in the presence of atherosclerosis (p < 0.003). Functional analysis of the BCAA-raising genes suggested the causal involvement of two pathophysiological pathways, including glucose metabolism (PPM1K and TRMT61A) related to plaque progression, and the newly discovered neuroendocrine disorders regulating blood pressure (MRPL33, CBLN1, and C2orf16) related to plaque rupture and thrombosis. This comprehensive MR analysis provided insights into the potential causal mechanisms linking BCAA with CVD risk and suggested targeting neuroendocrine disorders as a potential strategy for the prevention of CVD. These results warrant further studies to elucidate the mechanisms underlying these reported causal associations.

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