Abstract
BackgroundIn 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/PrincipalOutcome 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/SignificanceWe 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.
Highlights
There is growing interest in the notion that functional properties of high-density lipoprotein (HDL) [1,2,3] are important factors contributing to protection against cardiovascular disease (CVD) risk in addition to HDL quantity
As anti-atherogenic properties of HDL are thought to derive from multiple HDL particle constituents including [7] apolipoproteins, enzymes (paraoxonase-1, lecithin-cholesterol acyltransferase (LCAT), and glutathione peroxidase), and lipid transfer proteins (cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP)), we recently studied and reported findings focusing on apolipoprotein E (apoE) in this context
Results of multivariable Cox regression demonstrated non-significance (p = 0.17) for peak versus base subjects in a model adjusted for gender, age, BMI, hypertension, metabolic syndrome, smoking, and levels of apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), apoB, apoE, total cholesterol, C-reactive protein (CRP), HDL cholesterol (HDL-C), and triglycerides
Summary
There is growing interest in the notion that functional properties of high-density lipoprotein (HDL) [1,2,3] are important factors contributing to protection against cardiovascular disease (CVD) risk in addition to HDL quantity. Evidence is accumulating to suggest that HDL atheroprotective functionality may be degraded in the setting of inflammation and oxidative stress; and that such conditions may result in dysfunctional transformation of HDL from anti-atherogenic to pro-atherogenic [4,5,6,7,8] To investigate this notion in human populations, we have been studying incident and recurrent CVD risk in individuals with concurrently high levels of C-reactive protein (CRP), reflective of inflammatory status, and HDL cholesterol (HDL-C). 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 (HDLC). To assess whether apolipoprotein A-II (apoA-II) plays a role in apoE-associated risk in the two female groups
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