Exploring the Role of Glycine Metabolism in Coronary Artery Disease: Insights from Human Genetics and Mouse Models

Background: Circulating glycine levels have been associated with reduced risk of coronary artery disease (CAD) in humans but these associations have not been observed in all studies. We evaluated whether the relationship between glycine levels and atherosclerosis was causal using genetic analyses in humans and feeding studies in mice. Methods: Serum glycine levels were evaluated for association with risk of CAD in the UK Biobank. Genetic determinants of glycine levels were identified through a genome-wide association study (GWAS) and used to evaluate the causal relationship between glycine and risk of CAD by Mendelian randomization (MR). A dietary supplementation study was carried out with atherosclerosis-prone apolipoprotein E deficient (ApoE−/−) mice to determine the effects of increased circulating glycine levels on cardiometabolic traits and aortic lesion formation. Results: Among 105,718 UK Biobank subjects, elevated serum glycine levels were associated with significantly reduced risk of prevalent CAD (Quintile 5 vs. Quintile 1 OR = 0.76, 95% CI 0.67–0.87; p < 0.0001) and incident CAD (Quintile 5 vs. Quintile 1 HR = 0.70, 95% CI 0.65–0.77; p < 0.0001) after adjustment for age, sex, ethnicity, anti-hypertensive and lipid-lowering medications, blood pressure, kidney function, and diabetes. A GWAS meta-analysis with 230,947 subjects identified 61 loci for glycine levels, of which 26 were novel. MR analyses provided modest evidence that genetically elevated glycine levels were causally associated with reduced systolic blood pressure and risk of type 2 diabetes, but did not provide significant evidence for an association with decreased risk of CAD. Glycine supplementation in mice had no effects on cardiometabolic traits or atherosclerotic lesion development. Conclusions: While expanding the genetic architecture of glycine metabolism, MR analyses and in vivo feeding studies did not provide evidence that the clinical association of this amino acid with atherosclerosis represents a causal relationship.