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

Joanna M M Howson, Wei Zhao, Daniel R Barnes, Weang-Kee Ho, Robin Young, Dirk S Paul, Lindsay L Waite, Daniel F Freitag, Eric B Fauman, Elias L Salfati, Benjamin B Sun, John D Eicher, Andrew D Johnson, Wayne H H Sheu, Sune F Nielsen, Wei-Yu Lin, Praveen Surendran, Anders Malarstig, Jemma B Wilk, Anne Tybjærg-HansenKatrine L Rasmussen, Pia R Kamstrup, Panos Deloukas, Jeanette Erdmann, Sekar Kathiresan, Nilesh J Samani, Heribert Schunkert, Hugh Watkins, Ron Do, Daniel J Rader, Julie A Johnson, Stanley L Hazen, Arshed A Quyyumi, John A Spertus, Carl J Pepine, Nora Franceschini, Anne Justice, Alex P Reiner, Steven Buyske, Lucia A Hindorff, Cara L Carty, Kari E North, Charles Kooperberg, Eric Boerwinkle, Kristin Young, Mariaelisa Graff, Ulrike Peters, Devin Absher, Chao A Hsiung, Børge G Nordestgaard, CARDIoGRAMplusC4D

224 Citations (Scopus)

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.

Original languageEnglish
JournalNature Genetics
Volume49
Issue number7
Pages (from-to)1113-1119
Number of pages7
ISSN1061-4036
DOIs
Publication statusPublished - Jul 2017

Keywords

  • Arteries
  • Atherosclerosis
  • Cell Adhesion
  • Chemotaxis, Leukocyte
  • Coronary Artery Disease
  • Energy Metabolism
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Histone Code
  • Humans
  • Male
  • Muscle, Smooth, Vascular
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Risk Factors
  • Journal Article
  • Meta-Analysis

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