Genome-wide association study and targeted metabolomics identifies sex-specific association of CPS1 with coronary artery disease

Jaana A. Hartiala, W. H. Wilson Tang, Zeneng Wang, Amanda L. Crow, Alexandre F. R. Stewart, Robert Roberts, Ruth McPherson, Jeanette Erdmann, Christina Willenborg, Stanley L. Hazen and Hooman Allayee ()
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Jaana A. Hartiala: USC Keck School of Medicine
W. H. Wilson Tang: Cleveland Clinic
Zeneng Wang: Cleveland Clinic
Amanda L. Crow: USC Keck School of Medicine
Alexandre F. R. Stewart: John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute
Robert Roberts: John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute
Ruth McPherson: John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute
Jeanette Erdmann: 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
Christina Willenborg: 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
Stanley L. Hazen: Cleveland Clinic
Hooman Allayee: USC Keck School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10558

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