Associations of Plasma Branched‐Chain Amino Acids With Incident Atherosclerotic Cardiovascular Disease by Sex and Type 2 Diabetes Status Among Chinese Adults

BACKGROUND: Evidence on associations between branched-chain amino acids (BCAAs) and atherosclerotic cardiovascular disease (ASCVD) remains limited, particularly in Chinese populations. We investigated associations between BCAAs and ASCVD and whether they differed by sex and Type 2 diabetes (T2D). MATERIALS AND METHODS: Using a case-cohort design within a Chinese prospective cohort, we included a random subcohort (n = 2163) and incident ASCVD cases (n = 674). Plasma BCAA concentrations were quantified by ultra-performance liquid chromatography-tandem mass spectrometry. Associations of BCAAs with incident ASCVD were evaluated using Prentice-weighted Cox proportional hazards models, with stratified analyses and interaction tests by sex and T2D. Mediation analyses assessed the contribution of BCAAs to associations between T2D and ASCVD. RESULTS: During a median follow-up of 10.3 years, plasma BCAAs were positively associated with ASCVD. Associations appeared more pronounced among female participants, although interaction tests by sex were not statistically significant. Among female participants, significant associations were only observed in those with T2D, with hazard ratios (95% CIs) of 2.014 (1.185-3.423), 1.867 (1.142-3.052), 1.814 (1.071-3.078) and 2.030 (1.197-3.442) per standard deviation increment in ln-transformed total BCAA, isoleucine, leucine and valine, respectively. Additive interactions with T2D were detected for total BCAA and leucine. For male participants, no significant associations were observed, regardless of T2D status. Notably, total BCAA, leucine and valine partially mediated the association between T2D and ASCVD among female participants, with mediated proportions of 7.89%, 7.68% and 6.76%, respectively. CONCLUSIONS: Higher plasma BCAA concentrations were associated with increased incident ASCVD risk, supporting their potential role as metabolic markers of ASCVD.