Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease risk in women with high levels of HDL cholesterol and C-reactive protein

Abstract

Background: In a previous report by our group, high levels of apolipoprotein E (apoE) were demonstrated to be associated with risk of incident cardiovascular disease in women with high levels of C-reactive protein (CRP) in the setting of both low (designated as HR1 subjects) and high (designated as HR2 subjects) levels of high-density lipoprotein cholesterol (HDL-C). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups.

Methodology/principal: Outcome event mapping, a graphical data exploratory tool; Cox proportional hazards multivariable regression; and curve-fitting modeling were used to examine apoA-II influence on apoE-associated risk focusing on HDL particles with apolipoprotein A-I (apoA-I) without apoA-II (LpA-I) and HDL particles with both apoA-I and apoA-II (LpA-I:A-II). Results of outcome mappings as a function of apoE levels and the ratio of apoA-II to apoA-I revealed within each of the two populations, a high-risk subgroup characterized in each situation by high levels of apoE and additionally: in HR1, by a low value of the apoA-II/apoA-I ratio; and in HR2, by a moderate value of the apoA-II/apoA-I ratio. Furthermore, derived estimates of LpA-I and LpA-I:A-II levels revealed for high-risk versus remaining subjects: in HR1, higher levels of LpA-I and lower levels of LpA-I:A-II; and in HR2 the reverse, lower levels of LpA-I and higher levels of LpA-I:A-II. Results of multivariable risk modeling as a function of LpA-I and LpA-I:A-II (dichotomized as highest quartile versus combined three lower quartiles) revealed association of risk only for high levels of LpA-I:A-II in the HR2 subgroup (hazard ratio 5.31, 95% CI 1.12-25.17, p = 0.036). Furthermore, high LpA-I:A-II levels interacted with high apoE levels in establishing subgroup risk.

Conclusions/significance: We conclude that apoA-II plays a significant role in apoE-associated risk of incident CVD in women with high levels of HDL-C and CRP.

Figure 1. Flow diagram of study design.

Figure 2. Outcome event map as a function of apoA-II/apoA-I ratio and apoE ranks in the total study population of women and men with iso-contour line of risk at 5.3% superimposed.

Figure 3. Outcome event maps as a function of apoA-II/apoA-I ratio and apoE ranks in women for: A. the background subgroup (BG); B. the low HDL-C/high CRP subgroup (HR1) with iso-contour line of risk at 5.3% superimposed; and C. the high HDL-C/high CRP subgroup (HR2) with iso-contour line of risk at 5.3% superimposed.

Figure 4. Outcome event maps as a function of apoA-II/apoA-I ratio and apoE ranks in men for: A. the background subgroup (BG); B. the low HDL-C/high CRP subgroup (HR1); and C. the high HDL-C/high CRP subgroup (HR2).

Figure 5. Kaplan-Meier plots for base subjects (heavy solid line) and peak subjects (light solid line) for: A. the low female HDL-C/high CRP subgroup (HR1) (p<0.0001, log-rank); and B. the female high HDL-C/high CRP subgroup (HR2) (p<0.0001, log-rank).

Figure 6. Kaplan-Meier curves in the female high-HDL-C/high CRP subgroup (HR2) as a function of combinations of dichotomized LpA-I:A-II and apoE levels as follows: light solid line - low LpA-I:A-II and low apoE, short dashes - low LpA-I:A-II and high apoE, long dashes - high LpA-I:A-II and low apoE, and heavy solid line - high LpA-I:A-II and high apoE.