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Association of Apolipoprotein E Genotypes With Lipid Levels and Coronary Risk

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(11):1300-1311. doi:10.1001/jama.298.11.1300.
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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.

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Figure 2. Differences in Lipid Levels by Apolipoprotein E Genotypes in Studies With 1000 or More Healthy Individuals, Using People With the ε3/ε3 Genotype as the Reference Group
Graphic Jump Location

Sizes of data markers are proportional to the inverse of the variance of the weighted mean difference (ε3/ε3 is represented by a square with an arbitrary fixed size) and the vertical lines represent 95% confidence intervals (CIs). To convert total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol from mmol/L to mg/dL, divide values by 0.0259; triglycerides from mmol/L to mg/dL, divide values by 0.0113.

Figure 3. Odds Ratios for Coronary Disease With Apolipoprotein E Genotype in 17 Studies With at Least 500 Cases
Graphic Jump Location

Assessment of heterogeneity: ε2 carriers vs ε3/ε3: I 2=72% (95% confidence interval [CI], 54%-83%; P<.001). ε4 carriers vs ε3/ε3: I 2=44% (95% CI, 2%-68%; P=.03). Size of data markers indicates the weight of each study in the analysis.
aAlthough these studies did not previously report on apolipoprotein E genotypes and coronary risk, principal investigators have provided the references shown to describe the methods used in their study.

Figure 4. Odds Ratios for Coronary Disease With Apolipoprotein E Genotypes Using Individuals With the ε3/ε3 Genotype as the Reference Group, Based on Data From 21 331 Cases and 47 467 Controls in Studies With 500 or More Cases
Graphic Jump Location

Size of data markers is proportional to the inverse of the variance of the odds ratios (ε3/ε3 is represented by a square with arbitrarily fixed size) and vertical lines represent 95% confidence intervals (CIs).

Figure 5. Odds Ratios for Coronary Disease With Apolipoprotein E Genotypes in Studies With 500 or More Cases
Graphic Jump Location

CHD indicates coronary heart disease; CI confidence interval; MI, myocardial infarction; PCR, polymerase chain reaction; phenotype, use of isoelectric methods to classify apolipoprotein E genotype; and PI, principal investigator of study. Exploration of potential sources of heterogeneity yielded P >.05 for location, publication status, and genotyping method, P =.03 for study design, and P=.003 for data source in ε2 carriers. All corresponding P values were >.05 in ε4 carriers. Size of the data markers is proportional to the inverse of the variance of the odds ratios.
aTotal number for exposed and reference groups.
bIncludes 1 Australian study.
cRefers to status of the source study at the time of current analysis.

Figure 6. Odds Ratios for Coronary Disease With Apolipoprotein E Genotypes in Studies With Fewer Than 500 Cases
Graphic Jump Location

CHD indicates coronary heart disease; CI, confidence interval; MI, myocardial infarction; PCR, polymerase chain reaction; phenotype, use of isoelectric methods to classify apolipoprotein E genotype; and PI, principal investigator of study. Several characteristics explained a considerable part of the heterogeneity, including study location (P<.001), design (P<.001), publication status (P=.004), data source (P<.001), and type of journal (P<.001). Size of data markers is proportional to the inverse of the variance of the odds ratios.
aTotal number for exposed and reference groups.
bRefers to status of the source study by January 2007.
cGenotype-specific data was not available from 3 studies.
d The weighted average of these strata-specific odds ratios (and the numbers of participants contributing to them) does not equal the overall odds ratio because only partial data were available on these characteristics since they were provided as tabular data by only a subset of relevant studies.

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