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A Prospective Population Study

Heather Ward, MSc; Panagiota N. Mitrou, PhD; Richard Bowman, BSc; Robert Luben, BSc; Nicholas J. Wareham, MB, PhD; Kay-Tee Khaw, MBBChir; Sheila Bingham, PhD

Arch Intern Med. 2009;169(15):1424-1429.

Background  The risk of coronary heart disease (CHD) may be related to genetic mutations in the production of apolipoprotein E via alterations to the metabolism of CHD-related blood lipids such as low-density lipoprotein cholesterol and triglycerides.

Methods  The relationship between APOE genotype (*E3/*E3, *E3/*E4, *E2/*E3, *E4/*E4, *E2/*E4, and *E2/*E2) and fatal and nonfatal CHD was examined among 10 035 men and 12 134 women, aged 440 to 79 years, from the Norfolk, England, arm of the European Prospective Into Nutrition and Cancer Study (1993-2007). During an average of 11 years of follow-up, 2712 CHD events were documented.

Results  The hazard ratio for CHD was 0.88 (95% confidence interval, 0.77-0.99) for *E2 carriers (*E2/*E2 and *E2/*E3) and 1.09 (1.00-1.19) for *E4 carriers (*E3/*E4 and *E4/*E4) compared with homozygous *E3/*E3 individuals after age and sex adjustment. Similar values were obtained when systolic blood pressure, body mass index, diabetes mellitus, alcohol intake, physical activity, and smoking were added to the model. After additional adjustment for baseline levels of the ratio of low- to high-density lipoprotein cholesterol, the hazard ratios (and 95% confidence intervals) for *E2 and *E4 carriers were 0.97 (0.85-1.10) and 1.06 (0.97-1.15), respectively, when compared with *E3 homozygotes. No interactions by sex, smoking status, or age groups were observed.

Conclusion  In the largest prospective cohort study to date, CHD risk was not associated with APOE genotype after controlling for a variety of cardiovascular risk factors, particularly the ratio of low- to high-density lipoprotein cholesterol.

Author Affiliations: Medical Research Council (MRC) Centre for Nutritional Epidemiology in Cancer Prevention and Survival (Ms Ward), Department of Public Health and Primary Care (Dr Mitrou), and European Prospective Investigation of Cancer (Mr Luben and Drs Wareham, Khaw, and Bingham), Institute of Public Health, University of Cambridge, Cambridge, England; World Cancer Research Fund International, London, England (Dr Mitrou); MRC Dunn Human Nutrition Unit, Cambridge (Mr Bowman and Dr Bingham); and MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge (Dr Wareham). Mr Bowman is now with the Institute for Cancer Research, University of London.

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