Carriers of the APOEԑ4 allele have consistently shown higher, and ԑ2 carriers have lower, plasma cholesterol and coronary heart disease (CHD) risk compared with ԑ3 homozygotes. An ԑ4:smoking interaction was observed in NPHSII, consistent with context dependency of the ԑ4 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 APOEԑ4 was not a risk factor for CHD among non-smokers. In non-smokers, the odds ratio (OR) for ԑ2 and ԑ4 carriers were 0.51 (0.27, 0.97) and 0.70 (0.46, 1.08), respectively, compared with ԑ3 homozygotes. Thus ԑ2 carriers showed expected risk-protection, but despite 80% power to detect an OR in ԑ4 subjects of 1.71 (i.e. of magnitude increase reported in prospective studies), the ԑ4 non-smokers showed no increased risk compared with ԑ3 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 ԑ4 non-smokers, but failed to confirm the ԑ4:smoking interaction on risk. This supports the context dependency of the ԑ4 risk effect, but the low smoking incidence in the Whitehall men reduced our ability to examine a smoking:genotype interaction.
