Association of Circulating Branched-Chain Amino Acids with Cardiovascular Diseases: A Mendelian Randomization Study

There have been reports linking branched-chain amino acids (BCAAs) to the hazard of various cardiovascular diseases (CVDs); however, the causal role of this relationship is still unclear. We conducted a study using bi-directional two-sample Mendelian randomization (MR) with the aim of investigating the possible causal correlation between BCAAs and 13 types of cardiovascular diseases.

The study analyzed data of the largest genome-wide association studies (GWAS) published for the total BCAAs, encompassing isoleucine, leucine, and valine, which were obtained from the UK Biobank, as well as data for 13 cardiovascular endpoints from the MRC-IEU, the FinnGen consortium, and the EBI database. The approach of the primary dissection used became the inverse-variance-weighted (IVW) approach, with additional analyses using the MR-PRESSO global test as well as MR-Egger regression with a view to determining horizontal pleiotropy. Heterogeneity was evaluated by means of Cochran's Q test. The study also conducted logistic regression dissection for the sake of investigating the correlation between cardiovascular events and serum BCAAs in the UK biobank cohort study.

In this study, it was found that individuals with a genetic predisposition to more elevated levels for circulating total BCAAs had a higher hazard of peripheral arterial disease (OR 1.400, 95% CI 1.063, 1.844; p = 0.017) in addition to stroke (OR 1.266, 95% CI 1.012, 1.585; p = 0.039); circulating valine casually increased the risk of intracerebral hemorrhage (OR 1.760, 95% CI 1.116, 2.776; p = 0.015), along with stroke (OR 1.269, 95% CI 1.079, 1.492; p = 0.004); genetically predicted isoleucine showed a positive association with peripheral arterial disease (OR 1.466, 95% CI 1.044, 2.058; p = 0.027), along with cardioembolic stroke (OR 1.547, 95% CI 1.126, 2.124; p = 0.007); furthermore, leucine causally associated with stroke (OR 1.310, 95% CI 1.031, 1.663, p = 0.027). In the UK Biobank cohort study, we detected that total BCAAs (OR: 1.285; 95% CI: 1.009, 1.636), valine (OR: 1.287; 95% CI: 1.009, 1.642), and isoleucine (OR: 1.352; 95% CI: 1.064, 1.718) were independently linked to stroke, but not leucine (OR: 1.146; 95% CI: 0.901, 1.458). No such association was found for BCAAs with peripheral arterial disease and intracerebral hemorrhage in the cohort study.

In summary, circulating total BCAAs and valine may be causally associated with stroke. The association of BCAAs with other CVD events needs further study.