title: A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease.
abstract: BACKGROUND
  Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).
  
  
  RESULTS
  We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.
  
  
  CONCLUSIONS
  In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.
authors.affiliation: Department of Surgery, Division of Transplantation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Epidemiology & Public Health, University College London, London, UK. Electronic address: mvholmes@gmail.com.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Ruth
authors.initials: R
authors.lastname: Frikke-Schmidt
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Daniela
authors.initials: D
authors.lastname: Melis
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Luben
authors.affiliation: Department of Cardiology, Division Heart & Lungs, University Medical Center, Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands; Institute of Cardiovascular Science, faculty of Population Health Sciences, University College London, London, United Kingdom.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Centre for Nutrition, Prevention and Health Services, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands.
authors.forename: Jolanda M A
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Jackie
authors.initials: J
authors.lastname: Cooper
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Jutta
authors.initials: J
authors.lastname: Palmen
authors.affiliation: Department of Epidemiology & Public Health, University College London, London, UK.
authors.forename: Pia
authors.initials: P
authors.lastname: Horvat
authors.affiliation: Department of Epidemiology & Public Health, University College London, London, UK.
authors.forename: Jorgen
authors.initials: J
authors.lastname: Engmann
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Ka-Wah
authors.initials: KW
authors.lastname: Li
authors.affiliation: Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
authors.forename: N Charlotte
authors.initials: NC
authors.lastname: Onland-Moret
authors.affiliation: Department of Pediatrics, Molecular Genetics, University Medical Center Groningen and Groningen University, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Department of Epidemiology & Public Health, University College London, London, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Kumari
authors.affiliation: Department of Surgery, Division of Transplantation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Keating
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 4, 14021, Czech Republic.
authors.forename: Jaroslav A
authors.initials: JA
authors.lastname: Hubacek
authors.affiliation: Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Videnska 1958/9, Prague 4, 14021, Czech Republic.
authors.forename: Vera
authors.initials: V
authors.lastname: Adamkova
authors.affiliation: National Institute of Public Health, Srobarova 48, 10042 Prague, Czech Republic.
authors.forename: Ruzena
authors.initials: R
authors.lastname: Kubinova
authors.affiliation: Department of Epidemiology & Public Health, University College London, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Bobak
authors.affiliation: Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Børge G
authors.initials: BG
authors.lastname: Nordestgaard
authors.affiliation: Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Department of Epidemiology & Public Health, University College London, London, UK; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tybjaerg-Hansen
authors.affiliation: Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D053327:Apolipoprotein E4 / Q000235:genetics*; D015331:Cohort Studies; D003327:Coronary Disease / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
chemical_list: D053327:Apolipoprotein E4
keywords: APOE genotype; Coronary heart disease; Gene–environment interaction; Smoking