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Anna M. Bennet, PhD; Emanuele Di Angelantonio, MD, MSc; Zheng Ye, PhD; Frances Wensley, MSc; Anette Dahlin, BSc; Anders Ahlbom, PhD; Bernard Keavney, MD, FRCP; Rory Collins, FRCP, FMedSci; Björn Wiman, MD, PhD; Ulf de Faire, MD, PhD; John Danesh, MSc, DPhil, FRCP

JAMA. 2007;298:1300-1311.

Context  Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases.

Objective  To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk.

Data Sources  We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies.

Study Selection  Eighty-two studies of lipid levels (86 067 healthy participants) and 121 studies of coronary outcomes (37 850 cases and 82 727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes.

Data Extraction  Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators.

Results  In the most extreme comparison, people with the 2/2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the 4/4 genotype. There were approximately linear relationships of apoE genotypes (when ordered 2/2, 2/3, 2/4, 3/3, 3/4, 4/4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the 2/2 genotype. Compared with 3/3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in 2 carriers and was 1.06 (95% CI, 0.99-1.13) in 4 carriers.

Conclusions  There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the 3/3 genotype, 2 carriers have a 20% lower risk of coronary heart disease and 4 carriers have a slightly higher risk.

Author Affiliations: Department of Public Health and Primary Care, University of Cambridge, Cambridge, England (Drs Bennet, Di Angelantonio, Ye, and Danesh and Ms Wensley); Division of Clinical Chemistry, Department of Molecular Medicine and Surgery (Ms Dahlin and Dr Wiman), Department of Cardiology (Dr de Faire) Karolinska University Hospital, and Divisions of Epidemiology (Dr Ahlbom) and Cardiovascular Epidemiology (Dr de Faire), Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Institute of Human Genetics, Newcastle University, Central Parkway, Newcastle, England (Dr Keavney); and Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, England (Dr Collins).

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