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Nat Genet. 2017 Jul;49(7):1113-1119. doi: 10.1038/ng.3874. Epub 2017 May 22.

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

Author information

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
Department of Applied Mathematics, University of Nottingham Malaysia Campus, Semenyih, Malaysia.
4
Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
5
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USA.
6
Pfizer Worldwide Research and Development, Cambridge, Massachusetts, USA.
7
Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, California, USA.
8
Stanford Cardiovascular Institute, Stanford University, Stanford, California, USA.
9
National Heart, Lung, and Blood Institute, Population Sciences Branch, Bethesda, Maryland, USA.
10
NHLBI and Boston University's The Framingham Heart Study, Framingham, Massachusetts, USA.
11
Division of Endocrine and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
12
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
13
College of Medicine, National Defense Medical Center, Taipei, Taiwan.
14
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
15
Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
16
Pfizer Worldwide Research and Development, Stockholm, Sweden.
17
Pfizer Worldwide Research and Development, Human Genetics, Cambridge, Massachusetts, USA.
18
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
19
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
20
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
21
Centre for Genomic Health, Queen Mary University of London, London, UK.
22
Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany.
23
DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, Lübeck, Germany.
24
University Heart Center Lübeck, Lübeck, Germany.
25
Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
26
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
27
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
28
NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
29
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
30
DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
31
Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
32
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
33
Charles Bronfman Institute for Personalized Medicine, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
34
Departments of Genetics, Medicine, and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
35
University of Florida College of Pharmacy, Gainesville, Florida, USA.
36
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland, Ohio, USA.
37
Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USA.
38
Saint Luke's Mid America Heart Institute, Kansas City, Missouri, USA.
39
Department of Biomedical and Health Informatics, University of Missouri-Kansas City, Kansas City, Missouri, USA.
40
College of Medicine, University of Florida, Gainesville, Florida, USA.
41
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, USA.
42
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
43
Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA.
44
Division of Genomic Medicine, National Human Genome Research Institute, US National Institutes of Health, Bethesda,Maryland, USA.
45
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
46
Carolina Center for Genome Sciences, Chapel Hill, North Carolina, USA.
47
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.
48
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
49
Division of Biostatistics and Bioinformatics, Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan.
50
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
51
Institute for Translational Genomics and Population Sciences, Department of Pediatrics, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
52
School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
53
Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
54
Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, California, USA.
55
Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
56
National Taiwan University College of Medicine, Taipei, Taiwan.
57
Centre for Non-Communicable Disease, Karachi, Pakistan.
58
School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
59
National Institute of Cardiovascular Diseases, Sher-e-Bangla Nagar, Bangladesh.
60
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK.
61
Wellcome Trust Sanger Institute, Hinxton, UK.
62
British Heart Foundation Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge, UK.

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.

PMID:
28530674
PMCID:
PMC5555387
DOI:
10.1038/ng.3874
[Indexed for MEDLINE]
Free PMC Article

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