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). METHODS AND 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and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts.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 In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified.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.

Center for Experimental Medicine Institute for Clinical and Experimental Medicine Videnska 1958 9 Prague 4 14021 Czech Republic

Centre for Cardiovascular Genetics Institute of Cardiovascular Science University College London London UK

Centre for Nutrition Prevention and Health Services National Institute for Public Health and the Environment PO Box 1 3720 BA Bilthoven The Netherlands

Department of Cardiology Division Heart and 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

Department of Clinical Biochemistry Herlev Hospital Copenhagen University Hospital Copenhagen Denmark

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

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

Department of Epidemiology and Public Health University College London London UK

Department of Epidemiology and Public Health University College London London UK; MRC Epidemiology Unit Institute of Metabolic Science University of Cambridge UK

Department of Pediatrics Molecular Genetics University Medical Center Groningen and Groningen University Groningen The Netherlands

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Surgery Division of Transplantation Perelman School of Medicine University of Pennsylvania Philadelphia PA USA

Department of Surgery Division of Transplantation Perelman School of Medicine University of Pennsylvania Philadelphia PA USA; Department of Epidemiology and Public Health University College London London UK

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht The Netherlands

National Institute of Public Health Srobarova 48 10042 Prague Czech Republic

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

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