University of Oulu

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

Genetic determinants of circulating glycine levels and risk of coronary artery disease

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Author: Jia, Qiong1,2; Han, Yi1,2; Huang, Pin1,2,3;
Organizations: 1Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
2Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
3Xiangya School of Medicine, Central South University, Hunan, China
4Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
5National Institute for Health and Welfare, Helsinki, Finland
6Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
7NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
8Population Health Science, Bristol Medical School, University of Bristol, United Kingdom
9Medical Research Council Integrative Epidemiology Unit at the University of Bristol, United Kingdom
10Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Victoria, Australia
11Estonian Genome Center, University of Tartu, Estonia
12Institute for Molecular Medicine (FIMM), University of Helsinki, Finland
13Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Finland
14Department of Clinical Physiology, Turku University Hospital, Turku, Finland
15Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Health Technology, Finnish Cardiovascular Research Center–Tampere, Tampere University, Tampere, Finland
16Department of Medicine, University of Turku, Finland
17Division of Medicine, Turku University Hospital, Turku, Finland
18Department of Epidemiology and Biostatistics, School of Public Health, MRC‐PHE Centre for Environment and Health, Imperial College London, London, United Kingdom
19Center for Life Course and Systems Epidemiology, University of Oulu, Finland
20Unit of Primary Care, Oulu University Hospital, Oulu, Finland
21Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI
22School of Medicine, University of Eastern Finland, Kuopio, Finland
23Department of Genetics, University of North Carolina, Chapel Hill, NC
24Genome Center, University of California, Davis, CA
25Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH
26Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, OH
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2020042722654
Language: English
Published: John Wiley & Sons, 2019
Publish Date: 2020-04-27
Description:

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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Series: Journal of the American Heart Association
ISSN: 2047-9980
ISSN-E: 2047-9980
ISSN-L: 2047-9980
Volume: 8
Issue: 10
Article number: e011922
DOI: 10.1161/JAHA.119.011922
OADOI: https://oadoi.org/10.1161/JAHA.119.011922
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
3111 Biomedicine
Subjects:
Funding: This work was supported, in part, by NIH grants R01HL133169, R01ES021801, R01ES025786, R01HL103866, P20HL113452, R01DK062370, and S10OD016346 and Transatlantic Networks of Excellence Awards from Foundation Leducq. The GeneBank study was supported, in part, by NIH grants P01HL098055, P01HL076491, and R01HL103931. Mass Spectrometry instrumentation used for the GeneBank study was housed in a facility supported, in part, through a Shimadzu Center of Excellence Award. Kettunen is supported through funds from the Academy of Finland (Grant Nos. 297338 and 307247) and Novo Nordisk Foundation (Grant No. NNF17OC0026062). Ala‐Korpela is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia (APP1158958) and also works in a unit that is supported by the University of Bristol and the UK Medical Research Council (MC_UU_12013/1). The Baker Institute is supported, in part, by the Victorian Government's Operational Infrastructure Support Program.
Academy of Finland Grant Number: 297338
307247
Detailed Information: 297338 (Academy of Finland Funding decision)
307247 (Academy of Finland Funding decision)
Copyright information: © 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/