The associations of genetically predicted plasma alanine with coronary artery disease (CAD) and CAD risk factors: a Mendelian randomization study

Abstract

<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>Using Mendelian randomization (MR), we assessed the unconfounded associations of plasma alanine with CAD and CAD risk factors.</p><p><strong>Methods: </strong>We applied single nucleotide polymorphisms (SNPs) that were strongly (P<5 ×10^-8) associated with plasma alanine as genetic instruments to large genome-wide association studies (GWASs) of CAD (63,108 cases; 296,901 controls), diabetes (90,612 cases; 583,493 controls), glucose (515,538 participants), lipids (LDL cholesterol, HDL cholesterol, triglycerides, total cholesterol and apolipoprotein B) (more than 1.1 million participants), blood pressure (757,601 participants) and BMI (682,137 participants). Given the potential sex disparity, we also conducted the sex-specific analyses. MR estimates per SD increase in alanine concentrations were obtained using inverse-variance weighting, followed by sensitivity analyses using weighted median, MR-Egger, MR-PRESSO, and MR-RAPS.</p><p><strong>Results: </strong>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 (beta =0.11, 95% CI: 0.02-0.19), LDL-cholesterol (beta =0.08, 95% CI:0.04-0.12), triglycerides (beta =0.25, 95% CI:0.13-0.38), total cholesterol (beta =0.14, 95% CI:0.08-0.20), apolipoprotein B (beta =0.12, 95% CI:0.03-0.21), and blood pressure (beta =1.17, 95% CI:0.31-2.04 for systolic BP; beta =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 females than in males.</p><p><strong>Conclusions: </strong>Alanine or factors affecting alanine may have causal effects on diabetes, blood glucose, lipid profiles and blood pressure, but not on CAD. Further studies are needed to clarify possible mechanisms.</p>