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

Qiong Jia, Yi Han, Pin Huang, Nicholas C. Woodward, Janet Gukasyan, Johannes Kettunen, Mika Ala-Korpela, Olga Anufrieva, Qin Wang, Markus Perola, Olli Raitakari, Terho Lehtimäki, Jorma Viikari, Marjo Riitta Järvelin, Michael Boehnke, Markku Laakso, Karen L. Mohlke, Oliver Fiehn, Zeneng Wang, W. H.Wilson TangStanley L. Hazen, Jaana A. Hartiala, Hooman Allayee

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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.

Original languageEnglish
Pages (from-to)e011922
Number of pages27
JournalJournal of the American Heart Association
Issue number10
Early online date9 May 2019
Publication statusPublished - 21 May 2019


  • causality
  • coronary artery disease
  • genome‐wide association study
  • glycine
  • Mendelian randomization
  • meta‐analysis


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