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September 19, 2007

Association of Apolipoprotein E Genotypes With Lipid Levels and Coronary Risk

Author Affiliations

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).

JAMA. 2007;298(11):1300-1311. doi:10.1001/jama.298.11.1300

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 ε2/ε2 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 ε4/ε4 genotype. There were approximately linear relationships of apoE genotypes (when ordered ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, ε4/ε4) 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 ε2/ε2 genotype. Compared with ε3/ε3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in ε2 carriers and was 1.06 (95% CI, 0.99-1.13) in ε4 carriers.

Conclusions There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the ε3/ε3 genotype, ε2 carriers have a 20% lower risk of coronary heart disease and ε4 carriers have a slightly higher risk.