Effect of glutamate and aspartate on ischaemic heart disease, blood pressure, and diabetes: a Mendelian randomisation study

Background Evolutionary biology suggests that reproduction trades off against longevity. Genetic selection in favour of fertility and ischaemic heart disease (IHD) exists in humans. Observational studies suggest that soy protects against IHD. Soy amino acids, glutamate and aspartate, may lower androgens. However, no large randomised controlled trials testing their health effects exist. Using Mendelian randomisation, we assessed how genetically predicted glutamate and aspartate affected IHD, blood pressure, and diabetes. Methods Separate sample instrumental variable analysis with genetic instruments was used to obtain unconfounded estimates. Genetic variants strongly (p<0.0001) and solely associated with glutamate or aspartate were selected and used in an IHD case-control study (n=<76 014 cases, n=<264 785 controls) based on meta-analysis of CARDIoGRAMplusC4D 1000 Genomes, UK Biobank CAD SOFT GWAS, and Myocardial Infarction Genetics and CARDIoGRAM Exome data, on blood pressure data (from the UK Biobank, n=317 754), and the DIAbetes Genetics Replication And Meta-analysis case-control study (n=26 676 cases, n=132 532 controls). Principal components analysis, a weighted median and MR-Egger were used for sensitivity analysis. Findings Glutamate was not clearly associated with IHD, blood pressure, or diabetes. Aspartate was inversely associated with IHD (odds ratio [OR] 0·96 per log-transformed standard deviation, 95% CI 0·94–0·98) and blood pressure (using inverse variance weighting), but not diabetes. Associations were robust to sensitivity analysis. Interpretation Although the effects of serum glutamate and aspartate may differ from dietary exposures, our findings suggest that aspartate may have a protective effect against IHD and high blood pressure, potentially underlying the cardiovascular benefits of soy. Clarifying the mechanisms would be valuable for IHD prevention, and for defining a healthy Asian diet. Funding No funding.