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.