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J Am Heart Assoc. 2019 May 21;8(10):e011922. doi: 10.1161/JAHA.119.011922.

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

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1 Department of Preventive Medicine Keck School of Medicine, University of Southern California Los Angeles CA.
2 Department of Biochemistry & Molecular Medicine Keck School of Medicine, University of Southern California Los Angeles CA.
3 Xiangya School of Medicine Central South University Hunan China.
4 Computational Medicine Faculty of Medicine University of Oulu and Biocenter Oulu Oulu Finland.
5 National Institute for Health and Welfare Helsinki Finland.
6 Systems Epidemiology Baker Heart and Diabetes Institute Melbourne Victoria Australia.
7 NMR Metabolomics Laboratory School of Pharmacy University of Eastern Finland Kuopio Finland.
9 Population Health Science Bristol Medical School University of Bristol United Kingdom.
10 Medical Research Council Integrative Epidemiology Unit at the University of Bristol United Kingdom.
11 Department 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.
12 Estonian Genome Center University of Tartu Estonia.
13 Institute for Molecular Medicine (FIMM) University of Helsinki Finland.
14 Research Centre of Applied and Preventive Cardiovascular Medicine University of Turku Finland.
17 Department of Clinical Physiology Turku University Hospital Turku Finland.
18 Department of Clinical Chemistry Fimlab Laboratories and Faculty of Medicine and Health Technology Finnish Cardiovascular Research Center-Tampere Tampere University Tampere Finland.
15 Department of Medicine University of Turku Finland.
16 Division of Medicine Turku University Hospital Turku Finland.
19 Department of Epidemiology and Biostatistics School of Public Health MRC-PHE Centre for Environment and Health Imperial College London London United Kingdom.
20 Center for Life Course and Systems Epidemiology University of Oulu Finland.
21 Unit of Primary Care Oulu University Hospital Oulu Finland.
22 Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor MI.
8 School of Medicine University of Eastern Finland Kuopio Finland.
23 Department of Genetics University of North Carolina Chapel Hill NC.
24 Genome Center University of California Davis CA.
25 Department of Cardiovascular Medicine Cleveland Clinic Cleveland OH.
26 Department of Cellular & Molecular Medicine Cleveland Clinic Cleveland OH.


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.


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

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