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Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Howson JMM 1 , Zhao W 2 , Barnes DR 1 , Ho WK 1 , Young R 1 , Paul DS 1 Show all authors , Waite LL 3 , Freitag DF 1 , Fauman EB 4 , Salfati EL 5 , Sun BB 1 , Eicher JD 6 , Johnson AD 6 , Sheu WHH 7 , Nielsen SF 8 , Lin WY 1 , Surendran P 1 , Malarstig A 9 , Wilk JB 10 , Tybjærg-Hansen A 11 , Rasmussen KL 8 , Kamstrup PR 8 , Deloukas P 12 , Erdmann J 13 , Kathiresan S 14 , Samani NJ 15 , Schunkert H 16 , Watkins H 17 , CARDIoGRAMplusC4D , Do R 18 , Rader DJ 19 , Johnson JA 20 , Hazen SL 21 , Quyyumi AA 22 , Spertus JA 23 , Pepine CJ 24 , Franceschini N 25 , Justice A 25 , Reiner AP 26 , Buyske S 27 , Hindorff LA 28 , Carty CL 29 , North KE 25 , Kooperberg C 29 , Boerwinkle E 30 , Young K 25 , Graff M 25 , Peters U 29 , Absher D 3 , Hsiung CA 31 , Lee WJ 32 , Taylor KD 33 , Chen YH 31 , Lee IT 34 , Guo X 33 , Chung RH 31 , Hung YJ 35 , Rotter JI 36 , Juang JJ 37 , Quertermous T 5 , Wang TD 37 , Rasheed A 38 , Frossard P 38 , Alam DS 39 , Majumder AAS 40 , Di Angelantonio E 1 , Chowdhury R 1 , EPIC-CVD , Chen YI 33 , Nordestgaard BG 8 , Assimes TL 5 , Danesh J 1 , Butterworth AS 1 , Saleheen D 1

Affiliations 

  • 1 MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 2 Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 3 HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA
  • 4 Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA
  • 5 Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA
  • 6 National Heart, Lung, and Blood Institute, Population Sciences Branch, Bethesda, Maryland, USA
  • 7 Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
  • 8 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  • 9 Pfizer Worldwide Research and Development, Stockholm, Sweden
  • 10 Pfizer Worldwide Research and Development, Human Genetics, Cambridge, Massachusetts, USA
  • 11 Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 12 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  • 13 Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
  • 14 Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  • 15 Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
  • 16 Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
  • 17 Radcliffe Department of Medicine, University of Oxford, Oxford, UK
  • 18 Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  • 19 Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 20 University of Florida College of Pharmacy, Gainesville, Florida, USA
  • 21 Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio, USA
  • 22 Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA
  • 23 Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA
  • 24 College of Medicine, University of Florida, Gainesville, Florida, USA
  • 25 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA
  • 26 Department of Epidemiology, University of Washington, Seattle, Washington, USA
  • 27 Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA
  • 28 Division of Genomic Medicine, National Human Genome Research Institute, US National Institutes of Health, Bethesda,Maryland, USA
  • 29 Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  • 30 Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA
  • 31 Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan
  • 32 Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
  • 33 Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA
  • 34 School of Medicine, Chung Shan Medical University, Taichung, Taiwan
  • 35 College of Medicine, National Defense Medical Center, Taipei, Taiwan
  • 36 Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA
  • 37 Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
  • 38 Centre for Non-Communicable Disease, Karachi, Pakistan
  • 39 School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada
  • 40 National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Bangladesh
Nat Genet, 2017 Jul;49(7):1113-1119.
PMID: 28530674 DOI: 10.1038/ng.3874

Abstract

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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