title: Genetic variants at chromosome 9p21 and risk of first versus subsequent coronary heart disease events: a systematic review and meta-analysis.
abstract: OBJECTIVE
  The purpose of this analysis was to compare the association between variants at the chromosome 9p21 locus (Ch9p21) and risk of first versus subsequent coronary heart disease (CHD) events through systematic review and meta-analysis.
  
  
  BACKGROUND
  Ch9p21 is a recognized risk factor for a first CHD event. However, its association with risk of subsequent events in patients with established CHD is less clear.
  
  
  METHODS
  We searched PubMed and EMBASE for prospective studies reporting association of Ch9p21 with incident CHD events and extracted information on cohort type (individuals without prior CHD or individuals with established CHD) and effect estimates for risk of events.
  
  
  RESULTS
  We identified 31 cohorts reporting on 193,372 individuals. Among the 16 cohorts of individuals without prior CHD (n = 168,209), there were 15,664 first CHD events. Ch9p21 was associated with a pooled hazard ratio (HR) of a first event of 1.19 (95% confidence interval: 1.17 to 1.22) per risk allele. In individuals with established CHD (n = 25,163), there were 4,436 subsequent events providing >99% and 91% power to detect a per-allele HR of 1.19 or 1.10, respectively. The pooled HR for subsequent events was 1.01 (95% confidence interval: 0.97 to 1.06) per risk allele. There was strong evidence of heterogeneity between the effect estimates for first and subsequent events (p value for heterogeneity = 5.6 × 10(-11)). We found no evidence for biases to account for these findings.
  
  
  CONCLUSIONS
  Ch9p21 shows differential association with risk of first versus subsequent CHD events. This has implications for genetic risk prediction in patients with established CHD and for mechanistic understanding of how Ch9p21 influences risk of CHD.
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, United Kingdom; Department of Cardiology, The Heart Hospital, University College London NHS Trust, London, United Kingdom; Genetic Epidemiology Group, Department of Epidemiology and Public Health, Institute of Cardiovascular Science, University College London, London, United Kingdom. Electronic address: riyaz.patel@ucl.ac.uk.
authors.forename: Riyaz S
authors.initials: RS
authors.lastname: Patel
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, Institute of Cardiovascular Science, University College London, London, United Kingdom; Department of Cardiology, Division of Heart & Lungs, University Medical Center, Utrecht, the Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, the Netherlands.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Medicine, Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
authors.affiliation: Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, United Kingdom.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Chris I
authors.initials: CI
authors.lastname: Finan
authors.affiliation: Department of Cardiology, Division of Heart & Lungs, University Medical Center, Utrecht, the Netherlands.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Tragante
authors.affiliation: National Institute for Cardiovascular Outcome Research, University College London, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Deanfield
authors.affiliation: Department of Epidemiology and Public Health, University College London, London, United Kingdom.
authors.forename: Harry
authors.initials: H
authors.lastname: Hemingway
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, Institute of Cardiovascular Science, University College London, London, United Kingdom.
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.affiliation: Genetic Epidemiology Group, Department of Epidemiology and Public Health, Institute of Cardiovascular Science, University College London, London, United Kingdom; Department of Surgery, Division of Transplantation, and Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
mesh_terms: D000818:Animals; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D003327:Coronary Disease / Q000175:diagnosis / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
keywords: 9p21; coronary heart disease; genomics; incident; subsequent