Atherosclerosis 177 (2004) 105–112 No APOE4 effect on coronary heart disease risk in a cohort with low smoking prevalence: the Whitehall II study Philippa J. Talmud a,∗ , Sarah J. Lewis b , Emma Hawe a , Steve Martin a , Jayshree Acharya a , Michael G. Marmot b , Steve E. Humphries a , Eric J. Brunner b a British Heart Foundation Laboratories, Department of Medicine, Centre for Cardiovascular Genetics, Rayne Building, University College London, 5 University Street, London WC1E 6JF, UK b Department of Epidemiology, International Centre for Health and Society, University College London, 1-19 Torrington Place, London WC1E 6BT, UK Received 28 January 2004; accepted 22 June 2004 Available online 9 August 2004 Abstract Carriers of the APOE4 allele have consistently shown higher, and 2 carriers have lower, plasma cholesterol and coronary heart disease (CHD) risk compared with 3 homozygotes. An 4:smoking interaction was observed in NPHSII, consistent with context dependency of the 4 effect on CHD risk. In this study, APOE genotype was determined in 3787 male British civil servants followed for fatal and non-fatal myocardial infarction for median of 5.8 years, with 159 validated CHD events. APOE genotype was associated with expected effects on lipid traits (all P < 0.0001). We tested the hypothesis that APOE4 was not a risk factor for CHD among non-smokers. In non-smokers, the odds ratio (OR) for 2 and 4 carriers were 0.51 (0.27, 0.97) and 0.70 (0.46, 1.08), respectively, compared with 3 homozygotes. Thus 2 carriers showed expected risk-protection, but despite 80% power to detect an OR in 4 subjects of 1.71 (i.e. of magnitude increase reported in prospective studies), the 4 non-smokers showed no increased risk compared with 3 homozygotes. Smoking prevalence in this study was low (12.8%), but smokers had higher CHD risk which was of similar magnitude in risk in all genotypes [(OR 1.57 (1.03, 2.40)]. These data, therefore, provide strong corroborative evidence that there is no elevated risk of CHD in 4 non-smokers, but failed to confirm the 4:smoking interaction on risk. This supports the context dependency of the 4 risk effect, but the low smoking incidence in the Whitehall men reduced our ability to examine a smoking:genotype interaction. © 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: APOE; Smoking; CHD risk; Gene:environment interaction 1. Introduction Apolipoprotein (apo) E with its variant alleles 2, 3 and 4 has been the subject of intense interest because of the reported predisposition of 4 carriers (4+) to both early on- set of Alzheimer’s disease [1,2] and coronary heart disease (CHD). The meta-analysis assessing the impact of APOE variants on CHD risk, undertaken by Wilson et al. [3], con- sidered 14 published studies, primarily with a case–control design, examining both clinical CHD and angiographically ∗ Corresponding author. Tel.: +44 207 679 6968; fax: +44 207 679 6212. E-mail address: p.talmud@ucl.ac.uk (P.J. Talmud). defined CHD. Compared with 3 homozygotes, the sum- mary estimates of the odds ratios on CHD events, for both sexes combined, showed 4 to have an OR = 1.26 (95% CI: 1.13–1.41) which was similar when men and women were considered separately. However, CHD is a multifactorial dis- ease, caused by the additive and interactive effects of genetic and environmental factors, and none of the above studies considered environmental factors as potential genotype-risk modifiers, but instead corrected for non-lipid risk factors, amongst them smoking, when examining the risk association of APOE genotype and CHD. Several studies since the meta-analysis [3] demonstrate the context dependency of APOE genotype on CHD risk. 0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.06.008