The Associations of Genetically Predicted Plasma Alanine with Coronary Artery Disease and its Risk Factors: A Mendelian Randomization Study

Alanine is an amino acid commonly used as a nutritional supplement and plays a key role in the glucose-alanine cycle. Plasma alanine has been associated in observational studies with a higher risk of coronary artery disease (CAD) and unhealthier lipid profiles. However, evidence from large randomized controlled trials is lacking. Using Mendelian randomization (MR), we assessed the unconfounded associations of plasma alanine with CAD and CAD risk factors. We applied single nucleotide polymorphisms that were strongly (P < 5 ×10-8) associated with plasma alanine as genetic instruments to large genome-wide association studies of CAD (63,108 cases; 296,901 controls), diabetes (90,612 cases; 583,493 controls), glucose (515,538 participants), lipids (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, triglycerides, total cholesterol, and apolipoprotein B) (>1.1 million participants), blood pressure (BP) (757,601 participants), and body mass index (682,137 participants). Given the potential sex disparity, we also conducted sex-specific analyses. MR estimates per standard deviation increase in alanine concentrations were obtained using inverse variance weighting followed by sensitivity analyses using weighted median, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier, and MR-Robust Adjusted Profile Score. Genetically predicted plasma alanine was not associated with CAD but with a higher risk of diabetes (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.06, 1.72), higher glucose (β: 0.11; 95% CI: 0.02, 0.19), LDL cholesterol (β: 0.08; 95% CI: 0.04, 0.12), triglycerides (β: 0.25; 95% CI: 0.13, 0.38), total cholesterol (β: 0.14; 95% CI: 0.08, 0.20), apolipoprotein B (β: 0.12; 95% CI: 0.03, 0.21), and BP (β: 1.17; 95% CI: 0.31, 2.04 for systolic BP: β: 0.97; 95% CI: 0.49, 1.45 for diastolic BP) overall. The positive associations of serum alanine with LDL cholesterol and triglycerides were more notable in women than in men. Alanine or factors affecting alanine may have causal effects on diabetes, blood glucose, lipid profiles, and BP but not on CAD. Further studies are needed to clarify possible mechanisms.