Abstract
Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a case-control study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A final stepwise regression considering both nongenetic and genetic variables identified the combination of covariates that explained maximal PLTPa variance. PLTPa was significantly associated with CAAD (7.90 × 10(-9)), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10(-5)), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10(-7)), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.
Highlights
Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL
Even in transgenic LDLRϪ/Ϫ mice with normal systemic Phospholipid transfer protein (PLTP) and APOAI gene expression, it was found that PLTP-mediated macrophage atheroprotection could still be derived following bone marrow transplant [34]. These findings suggest that the physiologic context of PLTP expression is an important factor in determining its effects on atherosclerosis, with atherosclerotic lesion-based PLTP activity (PLTPa) likely being atheroprotective and systemic PLTPa possibly being atherogenic [35], though conflicting results have been reported with macrophage PLTPa not being associated with an increase in reverse cholesterol transport (RCT) [29]
The studied subset of Carotid Lesion Epidemiology and Risk (CLEAR) (n = 1,115) was comprised of two groups: those who had been previously analyzed by Jarvik et al [40] (n = 87) and those who were newly phenotyped for PLTPa for this study (n = 1,028)
Summary
Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10؊5), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10؊7), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. We report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.—Kim, D. Activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity. Cholesterol carried on HDL (HDL-C) has long been believed to be cardioprotective, based on consistent epidemiologic findings of an inverse relationship between incident CVD and HDL-C levels in subjects healthy at baseline [1, 2].
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