Date Published: October 18, 2016
Publisher: Public Library of Science
Author(s): Reecha Sofat, Jackie A. Cooper, Meena Kumari, Juan P. Casas, Jacqueline P. Mitchell, Jayshree Acharya, Simon Thom, Alun D. Hughes, Steve E. Humphries, Aroon D. Hingorani, Kazem Rahimi
Abstract: BackgroundThe association of APOE genotype with circulating apolipoprotein E (ApoE) concentration and cardiovascular disease (CVD) risk is well established. However, the relationship of circulating ApoE concentration and CVD has received little attention.Methods and FindingsTo address this, we measured circulating ApoE concentration in 9,587 individuals (with 1,413 CVD events) from three studies with incident CVD events: two population-based studies, the English Longitudinal Study of Ageing (ELSA) and the men-only Northwick Park Heart Study II (NPHSII), and a nested sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). We examined the association of circulating ApoE with cardiovascular risk factors in the two population-based studies (ELSA and NPHSII) and the relationship between ApoE concentration and coronary heart disease and stroke in all three studies. Analyses were carried out within study, and, where appropriate, pooled effect estimates were derived using meta-analysis. In the population-based samples, circulating ApoE was associated with systolic blood pressure (correlation coefficient 0.08, p < 0.001, in both ELSA and NPHSII), total cholesterol (correlation coefficient 0.46 and 0.34 in ELSA and NPHSII, respectively; both p < 0.001), low-density lipoprotein cholesterol (correlation coefficient 0.30 and 0.14, respectively; both p < 0.001), high-density lipoprotein (correlation coefficient 0.16 and −0.14, respectively; both p < 0.001), and triglycerides (correlation coefficient 0.43 and 0.46, respectivly; both p < 0.001). In NPHSII, ApoE concentration was additionally associated with apolipoprotein B (correlation coefficient 0.13, p = 0.001) and lipoprotein(a) (correlation coefficient −0.11, p < 0.001). In the pooled analysis of ASCOT, ELSA, and NPHSII, there was no association of ApoE with CVD events; the odds ratio (OR) for CVD events per 1-standard-deviation higher ApoE concentration was 1.02 (95% CI 0.96, 1.09). After adjustment for cardiovascular risk factors, the OR for CVD per 1-standard-deviation higher ApoE concentration was 0.97 (95% CI 0.82, 1.15). Limitations of these analyses include a polyclonal method of ApoE measurement, rather than isoform-specific measurement, a moderate sample size (although larger than any other study to our knowledge and with a long lag between ApoE measures), and CVD events that may attenuate an effect.ConclusionsIn the largest study to date on this question, we found no evidence of an association of circulating ApoE concentration with CVD events. The established association of APOE genotype with CVD events may be explained by isoform-specific functions as well as other mechanisms, rather than circulating concentrations of ApoE.
Partial Text: Apolipoprotein E (ApoE) is a 34-kDa liver-derived multifunctional protein found associated with triglyceride-rich chylomicrons and very low density lipoproteins (VLDLs), their remnants, and a subset of high-density lipoprotein particles [1,2]. One of ApoE’s major physiological roles is in lipid metabolism; ApoE mediates high-affinity binding of ApoE-containing lipoproteins to the low-density lipoprotein receptor (LDL-R) and LDL receptor related protein 1 (LRP1), facilitating clearance of triglyceride-rich lipoproteins from the circulation. It is this mechanism that is thought to confer protection from atherogenesis. ApoE is a polymorphic protein with three major circulating isoforms, E2, E3, and E4 , and lipid metabolism is isoform dependent. Isoforms are determined by a combination of two common non-synonymous single nucleotide polymorphisms (SNPs rs7412 and rs429358) in exon 4 of the APOE gene on Chromosome 19 . The most commonly observed, and the reference, isoform is E3. E3 has a cysteine residue at 112 and an arginine residue at 158, and is present in ~79% of the population. E4 (rs429358), the next most commonly encountered isoform (~14%), has an arginine residue substituting cysteine at 112. Finally, E2 (rs7412) is present at a frequency of ~7% and has a cysteine substituting arginine at residue 158. The resultant six common genotypes, in order of observed frequency, are ε3/ε3, ε3/ε4, ε2/ε3 ε2/ε4, ε4/ε4, and ε2/ε2. The most common genotype group is ε3/ε3, which serves as the reference category.
Studies contributed to the analyses in different ways, summarised in S1 Table.