Circulating Apolipoprotein E Concentration and Cardiovascular Disease Risk: Meta-analysis of Results from Three Studies

<div><p>Background</p><p>The association of <i>APOE</i> 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.</p><p>Methods and Findings</p><p>To 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, <i>p <</i> 0.001, in both ELSA and NPHSII), total cholesterol (correlation coefficient 0.46 and 0.34 in ELSA and NPHSII, respectively; both <i>p <</i> 0.001), low-density lipoprotein cholesterol (correlation coefficient 0.30 and 0.14, respectively; both <i>p <</i> 0.001), high-density lipoprotein (correlation coefficient 0.16 and −0.14, respectively; both <i>p <</i> 0.001), and triglycerides (correlation coefficient 0.43 and 0.46, respectivly; both <i>p <</i> 0.001). In NPHSII, ApoE concentration was additionally associated with apolipoprotein B (correlation coefficient 0.13, <i>p =</i> 0.001) and lipoprotein(a) (correlation coefficient −0.11, <i>p <</i> 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.</p><p>Conclusions</p><p>In 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 <i>APOE</i> genotype with CVD events may be explained by isoform-specific functions as well as other mechanisms, rather than circulating concentrations of ApoE.</p></div

Cross-sectional association between geometric mean of ApoE concentration and haemoglobin, ferritin, and fibrinogen measured in ELSA, by gender.

<p>Male (circles) and female (square) mean log ApoE concentration was calculated for each decile of the associated variable and plotted to visualise the shape of the association. Bars give 95% CIs.</p

Baseline characteristics of studies included.

<p>Baseline characteristics of studies included.</p

Cross-sectional association between geometric mean of ApoE concentration and C-reactive protein measured in ELSA, by gender.

<p>Male (circles) and female (square) mean log ApoE concentration was calculated for each decile of the associated variable and plotted to visualise the shape of the association. Bars give 95% CIs.</p

Kaplan-Meier plot for tertiles of ApoE concentration in individuals with ε3ε3 genotype.

<p>This analysis was conducted to overcome any effect of isoform or structural change in the circulating protein. High concentrations are indicated in blue, intermediate in red, and low in green. Precise time-to-event measures are available in NPHSII, and therefore analyses are restricted to this study. There is a marginally statistically significant relationship between ApoE concentration and time to CVD event; however, given that this analysis is restricted to one study, which included only men, it has to be interpreted with caution. CVD, cardiovascular disease.</p

Cross-sectional association between geometric mean of ApoE concentration and glucose, body mass index, and waist-to-hip ratio measured in ELSA, by gender.

<p>Male (circles) and female (square) mean log ApoE concentration was calculated for each decile of the associated variable and plotted to visualise the shape of the association. Bars give 95% CIs.</p

Cross-sectional association between geometric mean of ApoE concentration and total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides measured in ELSA, by gender.

<p>Male (circles) and female (square) mean log ApoE concentration was calculated for each decile of the associated variable and plotted to visualise the shape of the association. Bars give 95% CIs.</p

Cross-sectional association between geometric mean of ApoE concentration and age, systolic blood pressure, diastolic blood pressure, and pulse pressure measured in ELSA, by gender.

<p>Male (circles) and female (square) mean log ApoE concentration was calculated for each decile of the associated variable and plotted to visualise the shape of the association. Bars give 95% CIs.</p

Summary estimates for the association of log ApoE concentration with cardiovascular events from the three studies.

<p>Summary estimates for the association of log ApoE concentration with cardiovascular events from the three studies.</p

Bivariate associations of circulating ApoE with measured markers in the population-based studies, ELSA and NPHSII.

<p>Bivariate associations of circulating ApoE with measured markers in the population-based studies, ELSA and NPHSII.</p