Genetic determinants of circulating glycine levels and risk of coronary artery disease
Jia, Qiong; Han, Yi; Huang, Pin; Woodward, Nicholas C.; Gukasyan, Janet; Kettunen, Johannes; Ala‐Korpela, Mika; Anufrieva, Olga; Wang, Qin; Perola, Markus; Raitakari, Olli; Lehtimäki, Terho; Viikari, Jorma; Järvelin, Marjo‐Riitta; Boehnke, Michael; Laakso, Markku; Mohlke, Karen L.; Fiehn, Oliver; Wang, Zeneng; Tang, W.H. Wilson; Hazen, Stanley L.; Hartiala, Jaana A.; Allayee, Hooman (2019-05-09)
Jia, Q., Han, Y., Huang, P., Woodward, N., Gukasyan, J., Kettunen, J., Ala‐Korpela, M., Anufrieva, O., Wang, Q., Perola, M., Raitakari, O., Lehtimäki, T., Viikari, J., Järvelin, M., Boehnke, M., Laakso, M., Mohlke, K., Fiehn, O., Wang, Z., Tang, W., Hazen, S., Hartiala, J., Allayee, H. (2019) Genetic Determinants of Circulating Glycine Levels and Risk of Coronary Artery Disease. Journal of the American Heart Association, 8 (10), e011922. https://doi.org/10.1161/JAHA.119.011922
© 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
https://creativecommons.org/licenses/by-nc-nd/4.0/
https://urn.fi/URN:NBN:fi-fe2020042722654
Tiivistelmä
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,COX18‐ADAMTS3,PSPH,TRIB1,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.
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