Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke:a prospective study

Background The common isoforms of apolipoprotein E (apoE), E2, E3, and E4, are important determinants of plasma lipid concentrations, and the epsilon4 allele is associated with raised risk of coronary heart disease. We invest igated whether the effect of smoking on coronary heart disease risk is affe cted by APOE genotype. Methods We enrolled 3052 middle-aged men who were free of coronary heart di sease for prospective cardiovascular surveillance in the second Northwick P ark Heart Study (NPHSII). Smoking habit was ascertained at baseline and yea rly by questionnaire. APOE genotype was identified by PCR and restriction e nzyme digestion. Endpoints were fatal coronary heart disease, non-fatal myo cardial infarction, and coronary artery surgery and silent myocardial infar ction at follow-up. Findings During 18 836 person years of surveillance, 96 men had an acute my ocardial infarction, 26 needed coronary artery surgery, and 14 had silent m yocardial infarctions. Compared with never-smokers, risk of coronary heart disease in ex-smokers was 1.34 (95% CI 0.86-2.08) and in smokers it was 1.9 4 (1.25-3.01). This risk was independent of other classic risk factors. In never-smokers, risk was closely similar in men with different genotypes. Ri sk in men homozygous for the epsilon3 allele was 1.74 (1.10-2.77) in ex-smo kers and 1.68 (1.01-2.83) in smokers, whereas in men carrying the epsilon4 allele risk was 0.84 (0.40-1.75) and 3.17 (1.82-5.50), respectively, with n o significant differences in risk in the epsilon2 carriers. For the epsilon 3 group, the genotype effect on risk was no longer significant after adjust ment for classic risk factors (including plasma lipids). However. even afte r adjustment. smokers who were carriers of the epsilon4 allele, showed sign ificantly raised risk of coronary heart disease compared with the non-smoki ng group (2.79, 1.59-4.91, epsilon4-smoking interaction p=0.007). Interpretation Smoking increases the risk of coronary heart disease in men of all genotypes but particularly in men carrying the epsilon4 allele.