August 28, 2001 Access past issues

Reviewed by: Teri Manolio Division of Epidemiology and Clinical Applications, NHLBI, NIH

The Health Outcome

Coronary heart disease (CHD) is the leading cause of death in most developed countries.  Likewise, the incidence of CHD is increasing in developing countries, as is the mortality rate attributed to this condition. Although smoking, hypertension, hyperlipidemia, obesity, and physical inactivity have long been recognized as environmental risk factors for CHD, family history is also a powerful CHD risk factor.  The search for genetic determinants of CHD risk to date has revealed little information, other than to identify rare single-gene determinants such as familial hypercholesterolemia, hereditary homocystinuria, and monogenic forms of hypertension.  Researchers currently are investigating whether potential genetic modifiers of environmental risk might explain the epidemic of CHD in the mid- to late-20th century and the familial aggregation it demonstrates.

The Finding

The association of APOE genotype with CHD incidence has been reported in several studies (1-4) and presumably is due both to their higher low-density lipoprotein (LDL) cholesterol levels and to the decreased protection afforded by the 4 variant against LDL oxidation.  Smoking increases CHD risk through a number of pathways, among which are increased oxidation of LDL particles that increases their atherogenicity (5).  An early  study of 300 elderly Finnish men showed smoking to be an important predictor of coronary mortality in 4 carriers but not in 3 homozygotes.  In the current study, men aged 50-61 years were recruited from nine general practices in England and Scotland.   Blood was drawn in the nonfasting state and stored at -40 ^oC prior to analysis for APOE genotype and lipid levels.  Coronary events were assessed in subsequent annual visits for an estimated average follow-up duration of 8.3 years. (a detailed abstraction of this article is available online as part of the HuGE Net e-journal club).

The study demonstrated an increased CHD risk in smokers regardless of genotype, as would be expected with its larger sample size, but showed that the risk gradient was particularly large for carriers of the 4 allele.  When compared to all neversmokers who did not differ in CHD risk by genotype, current smokers with the 3/3 genotype had a 1.68-fold increased risk of CHD, 2 carriers had a nonsignificant 1.18-fold increased risk, and 4 carriers had a 3.17-fold increased risk (95% CI 1.82-5.51).  The increased risk in 4 carriers remained after adjustment for clinic; baseline age; body mass index (BMI); systolic blood pressure; and cholesterol, triglyceride and fibrinogen levels (adjusted hazard ratio = 2.79, 95% CI 1.59-4.91).  Findings in ex-smokers were less conclusive, with 3/3 homozygotes having a 1.74-fold increased CHD risk (95% CI 1.10-2.77) compared to all neversmokers.  However, 2 carriers had a nonsignificant 52% reduced risk (hazard ratio = 0.48, 95% CI 0.12-2.02) and 4 carriers had a 16% reduced risk (hazard ratio = 0.84, 95% CI 0.40-1.75).  Tests of heterogeneity of genotype effect on risk in ex-smokers and smokers were significant (p < 0.04) before and after adjustment for other risk factors.

Public Health Implications

This study adds to a growing body of literature suggesting that carriers of the APOE*4 allele are more susceptible to adverse effects of other CHD risk factors compared to noncarriers of the APOE*4 allele.  Whether this susceptibility is modulated through reduced resistance to lipoprotein oxidation or through other mechanisms remains a subject of active study.  Elucidation of the mechanism of increased CHD risk in 4 carriers may shed light on mechanisms of atherosclerosis development and progression and on potential preventive and therapeutic interventions.  Carriers of the APOE*4 allele, however, may be well advised to pay particular attention to prevention and control of other CHD risk factors, though the effectiveness of such approaches in reducing their APOE*4-associated CHD risk remains to be proven.

References

1. Davignon J, Gregg RE, Sing CF.  Apolipoprotein E polymorphism and atherosclerosis.  Arteriosclerosis 1988;8:1-21.
2. Wilson PW, Schaefer EJ, Larson MG, Ordovas JM.  Apolipoprotein E alleles and risk of coronary disease: a meta-analysis.  Arterioscler Thromb Vasc Biol 1996;16:1250-5.
3. Gerdes LU, Gerdes C, Kervinen K, et al.  The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: a substudy of the Scandinavian simvastatin survival study.  Circulation 2000;101:1366-71.
4. Hixson JE.  Apolipoprotein E polymorphisms affect atherosclerosis in young males.  Arterioscler Thromb 1991;11:1237-44.
5. Fickl H, Van Antwerpen VL, Richards GA, et al.  Increased levels of autoantibodies to cardiolipin and oxidised low-density lipoprotein are inversely associated with plasma vitamin C status in cigarette smokers.  Atherosclerosis 1996;124:75-81.