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

Lancet. 2001 Jul 14;358(9276):115-9. doi: 10.1016/S0140-6736(01)05330-2.


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 investigated whether the effect of smoking on coronary heart disease risk is affected by APOE genotype.

Methods: We enrolled 3052 middle-aged men who were free of coronary heart disease for prospective cardiovascular surveillance in the second Northwick Park Heart Study (NPHSII). Smoking habit was ascertained at baseline and yearly by questionnaire. APOE genotype was identified by PCR and restriction enzyme digestion. Endpoints were fatal coronary heart disease, non-fatal myocardial infarction, and coronary artery surgery and silent myocardial infarction at follow-up.

Findings: During 18836 person years of surveillance, 96 men had an acute myocardial infarction, 26 needed coronary artery surgery, and 14 had silent myocardial 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 1.94 (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. Risk in men homozygous for the epsilon3 allele was 1.74 (1.10-2.77) in ex-smokers 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 no significant differences in risk in the epsilon2 carriers. For the epsilon3 group, the genotype effect on risk was no longer significant after adjustment for classic risk factors (including plasma lipids). However, even after adjustment, smokers who were carriers of the epsilon4 allele, showed significantly raised risk of coronary heart disease compared with the non-smoking 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apolipoprotein E4
  • Apolipoproteins E / genetics*
  • Coronary Disease / epidemiology
  • Coronary Disease / etiology*
  • Coronary Disease / genetics*
  • Gene Frequency / genetics
  • Genetic Carrier Screening
  • Genotype
  • Homozygote
  • Humans
  • Male
  • Middle Aged
  • Polymerase Chain Reaction
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Factors
  • Smoking / adverse effects*
  • Surveys and Questionnaires
  • Survival Analysis
  • United Kingdom / epidemiology


  • Apolipoprotein E4
  • Apolipoproteins E