Genetic influence of BCAA metabolism on type 2 diabetes and coronary artery disease, independent of traditional risk factors

Abstract Type 2 diabetes (T2D) and cardiovascular disease are major global health burdens. Branched-chain amino acid (BCAA) metabolism has been implicated as a potential therapeutic target, but it remains unclear whether its associations with disease risk are independent of traditional risk factors such as obesity and dyslipidemia. We leveraged genomic structural equation modeling of large-scale genome-wide association studies (GWAS) from European and East Asian populations, including the largest East Asian GWAS of BCAA levels (n = 42,826). We identified a genetic factor influencing BCAA metabolism independently of body mass index and circulating lipid levels. A cross-population polygenic score derived from this factor was associated with hemoglobin A1c, blood glucose, and the onset of both T2D and coronary artery disease. These findings provide the first genetic insight in humans that BCAA metabolism is involved in T2D and CAD beyond traditional risk factors, highlighting its clinical relevance and therapeutic potential.