Abstract
BackgroundThe ɛ2, ɛ3, and ɛ4 alleles of the apolipoprotein E gene (APOE) encode three isoforms, apoE2, E3, and E4, respectively. The apoE isoforms circulate in different plasma concentrations, but plasma concentrations of the same isoform also differ between individuals. Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown. Methods and FindingsWe assessed APOE genotypes, plasma levels of apoE, cardiovascular risk factors, and mortality in a population-based sample of 546 individuals aged 85 y who participated in the Leiden 85-plus Study and were prospectively followed for specific causes of death for 5 y. Participants in the highest tertile of apoE levels suffered a twofold-increased risk of cardiovascular mortality (hazard ratio compared to lowest tertile, 2.08; 95% confidence interval [CI], 1.30 to 3.33). Among the 324 participants with the ɛ3ɛ3 genotype, the hazard from cardiovascular disease was threefold increased (highest versus lowest tertile 3.01; 95% CI 1.60 to 5.66), with similar estimates for men and women. Other causes of death were not increased significantly. Plasma levels of apoE in ɛ3ɛ3 participants were positively correlated with total cholesterol ( p < 0.001), low-density lipoprotein cholesterol ( p < 0.001) and triglycerides ( p < 0.001) and negatively with high-density lipoprotein cholesterol levels ( p = 0.010). Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent. The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile ( p interaction < 0.001). Among participants from the lowest tertile of CRP levels, those with a high apoE levels had a significantly steeper increase in CRP than those with low apoE levels ( p = 0.020). Similar cardiovascular mortality risks as in ɛ3ɛ3 participants were found in ɛ2 and ɛ4 carriers. ConclusionsIn old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.
Highlights
The apolipoprotein E (APOE) gene influences lipid metabolism and disease risk
High plasma apoE levels precede an increase of circulating C-reactive protein (CRP) and strongly associates with cardiovascular mortality, independent of apolipoprotein E gene (APOE) genotype and plasma lipids
Levels of high-density lipoprotein (HDL) cholesterol, triglycerides, and circulating CRP did not differ between the various genotypes
Summary
The apolipoprotein E (APOE) gene influences lipid metabolism and disease risk. It was shown recently that apoE mediates the presentation of lipid antigens to the immune system and in this way influences the inflammatory process [11]. Both lipids and inflammation are involved in the pathogenesis of atherosclerosis, but the relation of plasma apoE levels and cardiovascular disease risk has not yet been reported. Different people have different levels of apoE in their blood, depending on which version of the APOE gene (which codes for the apoE protein) they have as well as other factors
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