title: Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease.
abstract: Metabolites derived from dietary choline and L-carnitine, such as trimethylamine N-oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identified two significantly associated loci on chromosomes 2q34 and 5q14.1. The lead variant on 2q24 (rs715) localizes to carbamoyl-phosphate synthase 1 (CPS1), which encodes a mitochondrial enzyme that catalyses the first committed reaction and rate-limiting step in the urea cycle. Rs715 is also significantly associated with decreased levels of urea cycle metabolites and increased plasma glycine levels. Notably, rs715 yield a strikingly significant and protective association with decreased risk of CAD in only women. These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis.
authors.affiliation: Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.|Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.
authors.forename: Jaana A
authors.initials: JA
authors.lastname: Hartiala
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.|Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.|Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.|Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Crow
authors.affiliation: John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.affiliation: John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada K1Y 4W7.
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, University Heart Center Luebeck, 23562 Lübeck, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: Institute for Integrative and Experimental Genomics, University of Lübeck, DZHK (German Research Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, University Heart Center Luebeck, 23562 Lübeck, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Willenborg
authors.affiliation: Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.|Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Preventive Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.|Institute for Genetic Medicine, USC Keck School of Medicine, Los Angeles, California 90033, USA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
mesh_terms: D001622:Betaine / Q000097:blood; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics / Q000378:metabolism*; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D055432:Metabolomics; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors
chemical_list: D001622:Betaine; D002222:Carbamoyl-Phosphate Synthase (Ammonia)
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