Biological mechanisms underlying the cardiovascular effects of branched-chain amino acids: A proteome-wide Mendelian Randomization Study.
BACKGROUND Ischemic heart disease (IHD) is the leading cause of morbidity and mortality. Branched-chain amino acids (BCAAs) are associated with higher IHD risk, but the underlying biological pathways remain unclear. OBJECTIVE This study aims to explore these pathways using two-step proteome-wide Mendelian randomization. METHODS We examined the associations between genetic proxies for BCAAs and 2,922 proteins in the UK Biobank Pharma Proteomics Project (UKB-PPP), supplemented by a meta-analysis with data from deCODE to identify proteins associated with BCAAs. Then we tested their effects on IHD risk using CARDIoGRAMplusC4D (122,733 cases, 424,528 controls) and replicated in FinnGen (31,640 cases, 187,152 controls). We conducted sensitivity analyses using genetic instruments from deCODE. Proteins associated with IHD risk and, in a consistent direction, with genetically predicted BCAAs were considered potential mediators. RESULTS Genetic proxies for BCAAs were associated with 40 proteins. Among these, six proteins showed consistent evidence of mediation, including complement component 1s (C1S), coagulation factor II (F2), granulin (GRN), proprotein convertase subtilisin/kexin type 9 (PCSK9), sex hormone-binding globulin (SHBG) and V-set and transmembrane domain-containing Protein 2 Like (VSTM2L). These proteins are involved in inflammation, coagulation, lipid metabolism and cellular stress response. All associations were robust across different analytical methods and replicated in independent datasets. Mediation analysis showed that these proteins accounted for 6.5% to 32.1% of the association between BCAAs and IHD risk. CONCLUSIONS This study identified six proteins that potentially link BCAAs to IHD, implicating pathways related to inflammation, coagulation, lipid metabolism, and cellular stress responses. These findings provide novel mechanistic insights into the BCAA-IHD relationship and highlight potential protein targets for future prevention and intervention strategies.