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

Abstract

Background: 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.

Objectives: Using Mendelian randomization (MR), we assessed the unconfounded associations of plasma alanine with CAD and CAD risk factors.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: Mendelian randomization; alanine; blood pressure; coronary artery disease; diabetes; glucose; lipids.