Genetic Determinants of Circulating Glycine Levels and Risk of Coronary Artery Disease

Abstract

Background Recent studies have revealed sexually dimorphic associations between the carbamoyl‐phosphate synthase 1 locus, intermediates of the metabolic pathway leading from choline to urea, and risk of coronary artery disease ( CAD ) in women. Based on evidence from the literature, the atheroprotective association with carbamoyl‐phosphate synthase 1 could be mediated by the strong genetic effect of this locus on increased circulating glycine levels. Methods and Results We sought to identify additional genetic determinants of circulating glycine levels by carrying out a meta‐analysis of genome‐wide association study data in up to 30 118 subjects of European ancestry. Mendelian randomization and other analytical approaches were used to determine whether glycine‐associated variants were associated with CAD and traditional risk factors. Twelve loci were significantly associated with circulating glycine levels, 7 of which were not previously known to be involved in glycine metabolism ( ACADM , PHGDH , COX 18‐ ADAMTS 3 , PSPH , TRIB 1 , PTPRD , and ABO ). Glycine‐raising alleles at several loci individually exhibited directionally consistent associations with decreased risk of CAD . However, these effects could not be attributed directly to glycine because of associations with other CAD ‐related traits. By comparison, genetic models that only included the 2 variants directly involved in glycine degradation and for which there were no other pleiotropic associations were not associated with risk of CAD or blood pressure, lipid levels, and obesity‐related traits. Conclusions These results provide additional insight into the genetic architecture of glycine metabolism, but do not yield conclusive evidence for a causal relationship between circulating levels of this amino acid and risk of CAD in humans.

ABO blood group, glycosyltransferase activity and risk of venous thromboembolism

“…Besides, since ABO antigens are also expressed on various other tissues including platelets and the vascular endothelium 20 , it could be speculated that the ABO locus may modulate VTE risk via VWF independent mechanisms. Such hypothesis is supported by several studies reporting the association of the ABO locus with different cardiovascular endophenotypes such as intercellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin [21][22][23][24][25] . Finally, the observation that plasma AGT activity can vary by a factor 1 to 3 in individuals of the same A1 blood 10 group strongly suggests that the variability in plasma AGT activity cannot be attributable only to ABO blood groups, emphasizing the need for a better assessment of the role of GTs in relation to VTE risk.…”

Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases

“…Association between the SNPs rs10206976 and rs12613336 in the CPS1 gene were also pinpointed in a genome-wide association study (GWAS) [120], which suggested that individuals with a genotype leading to higher expression of CPS1 have lower levels of circulating glycine, and the opposite also holds true. Recently, meta-analysis of GWAS in 30,118 individuals of European ancestry showed four significant loci associated with circulating glycine levels [121]: two loci at the glycine cleavage system (GCS) subunits, protein P (SNP rs71503800 at GLDC , glycine decarboxylase) and protein H (SNP rs11860711 at GCSH ); and two novel loci at enzymes involved in serine metabolism SNP rs478093 in PHGDH (phosphoglycerate dehydrogenase) and SNP rs6955423 in PSPH (phosphoserine phosphatase). In addition, GWAS revealed an association between the levels of betaine and the SNPs s499368 in the SLC6A12 gene (which codes for a betaine transporter) and rs17823642 near the BHMT gene [119], and between the levels of dimethylglycine and the SNP rs2431332 at the DMGDH locus (coding for dimethylglycine dehydrogenase) [84].…”

ABO blood group, glycosyltransferase activity and risk of Venous Thrombosis

“…Besides, since ABO antigens are also expressed on various other tissues including platelets and the vascular endothelium 20 , it could be speculated that the ABO locus may modulate VT risk via VWF independent mechanisms. Such hypothesis is supported by several studies reporting the association of the ABO locus with different cardiovascular endophenotypes such as intercellular adhesion molecule-1 (ICAM-1), P-selectin and E-selectin [21][22][23][24][25] . Finally, the observation that plasma AGT activity can vary by a factor 1 to 3 in individuals of the same A1 blood 10 group strongly suggests that the variability in plasma AGT activity cannot be attributable only to ABO blood groups, emphasizing the need for a better assessment of the role of GTs in relation to VT risk.…”