Year: 2019
Type: article
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 , 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.
Authors: 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 Tang, Stanley L. Hazen, Jaana A. Hartiala, Hooman Allayee
Institutions: University of Southern California, Central South University, Finnish Institute for Health and Welfare, University of Oulu, Baker Heart and Diabetes Institute, University of Eastern Finland, University of Bristol, MRC Integrative Epidemiology Unit, University of Helsinki, Institute for Molecular Medicine Finland, University of Tartu, University of Turku, Turku University Hospital, Tampere University, Fimlab (Finland), Oulu University Hospital, MRC Centre for Environment and Health, Imperial College London, University of Michigan, University of North Carolina at Chapel Hill, University of California, Davis, Cleveland Clinic
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,750
Funders: University of Bristol, Academy of Finland, Novo Nordisk, State Government of Victoria, Novo Nordisk Fonden, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences
Awards: Genetic and Environmental Determinants of Asthma Endophenotypes, Targeted Genetic Analysis of T2D and Quantitative Traits, AB/SCIEX QTrap 6500 Mass Spectrometer Metabolic profiling system, Identifying Genes for Type 2 Diabetes: FUSION, Role of Glycine Metabolism in Cardiovascular Disease, Nitrative stress in heart failure, Southern California Children's Enviromental Health Center (SC-CEHC), G3521192838, Functional Cardio-Metabolomics, Oxidation in Inflammation and Cardiovascular Disease, HDL Structure and its Function in Atherosclerosis, INTEGRATIVE GENETIC APPROACHES TO GENE-AIR POLLUTION INTERACTIONS IN ASTHMA, Gut Flora metabolism of dietary carnitine and cardiovascular disease, Michigan Diabetes Research Center (MDRC), Genetic epidemiology of rare and regulatory variants for metabolic traits, Southern California Clinical and Translational Science Institute, Identifying Genes for Type 2 Diabetes: FUSION
OpenAlex ID: W2944006800