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

• Published in: The American journal of clinical nutrition Vol. 109; no. 4; pp. 1197 - 1206
• Main Authors: Zhao, Jie V, Kwok, M K, Schooling, C Mary
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2019; Oxford University Press; American Society for Clinical Nutrition, Inc
• Subjects: Amino acids; Androgens; aspartate; Aspartic Acid - administration & dosage; Biological evolution; Blood Pressure; Cardiovascular disease; Cardiovascular diseases; Confidence intervals; Coronary artery disease; Diabetes; Diabetes mellitus; Diabetes Mellitus - drug therapy; Diabetes Mellitus - genetics; Dietary Supplements - analysis; Female; Fertility; Genetic analysis; Genetic diversity; Genetic variance; Genetics; Genome-Wide Association Study; Genomes; Glutamic Acid - administration & dosage; Health risk assessment; Heart diseases; Humans; Ischemia; ischemic heart disease; Male; Mendelian randomization; Mendelian Randomization Analysis; Myocardial infarction; Myocardial Ischemia - drug therapy; Myocardial Ischemia - genetics; Myocardial Ischemia - physiopathology; Polymorphism, Single Nucleotide; Randomization; Sensitivity analysis; United Kingdom > UK; blood pressure; RCT; GWAS; IHD; MR; ischemic heart disease; Mendelian randomization; IVW; CVD; SNP; WM; LD; aspartate; diabetes; DIAGRAM
• ISSN: 0002-9165; 1938-3207
• DOI: 10.1093/ajcn/nqy362

Evolutionary biology suggests reproduction trades off against longevity. Genetic selection in favor of fertility and ischemic heart disease (IHD) exists in humans. Observationally, soy protects against IHD. Soy amino acids, glutamate and aspartate, may lower androgens. No large randomized controlled trials testing their health effects exist. Using Mendelian randomization, we assessed how genetically predicted glutamate and aspartate affected IHD, blood pressure, and diabetes. A separate sample instrumental variable analysis with genetic instruments was used to obtain unconfounded estimates using genetic variants strongly (P < 5 × 10−8) and solely associated with glutamate or aspartate applied to an IHD case (n ≤76,014)–control (n ≤ 264,785) study (based on a meta-analysis of CARDIoGRAMplusC4D 1000 Genomes, UK Biobank CAD SOFT GWAS and Myocardial Infarction Genetics and CARDIoGRAM Exome), blood pressure from the UK Biobank (n ≤ 361,194), and the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)–control (n = 132,532) study. A weighted median and MR-Egger were used for a sensitivity analysis. Glutamate was not associated with IHD, blood pressure, or diabetes after correction for multiple comparisons. Aspartate was inversely associated with IHD (odds ratio (OR) 0.92 per log-transformed standard deviation (SD); 95% confidence interval (CI) 0.88, 0.96) and diastolic blood pressure (−0.03; 95% CI −0.04, −0.02) using inverse variance weighting, but not diabetes (OR 1.00; 95% CI 0.91, 1.09). Associations were robust to the sensitivity analysis. Our findings suggest aspartate may play a role in IHD and blood pressure, potentially underlying cardiovascular benefits of soy. Clarifying the mechanisms would be valuable for IHD prevention and for defining a healthy diet.