Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease |
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Authors: | Pamela A McCaskie John P Beilby Caroline M L Chapman Joseph Hung Brendan M McQuillan Peter L Thompson Lyle J Palmer |
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Institution: | (1) Laboratory for Genetic Epidemiology, Western Australian Institute for Medical Research, UWA Centre for Medical Research, University of Western Australia, Ground Floor, Hospital Ave, Nedlands, WA, 6009, Australia;(2) Clinical Biochemistry, PathWest, Laboratory Medicine Western Australian, Perth, WA, Australia;(3) School of Surgery and Pathology, University of Western Australia, Perth, WA, Australia;(4) Sir Charles Gairdner Hospital Campus of the Heart Research Institute of Western Australia, Perth, WA, Australia;(5) School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia |
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Abstract: | High-density lipoprotein cholesterol (HDL-C) is a known inverse predictor of coronary heart disease (CHD) and is thus a potential
therapeutic target. Cholesteryl ester transfer protein (CETP) is a key protein in HDL-C metabolism such that elevated CETP
activity is associated with lower HDL-C. Currently available HDL-C raising drugs are relatively ineffective and evidence suggesting
the role of CETP in HDL-C levels has promoted the development of CETP inhibitors as potential therapeutic agents for CHD.
We investigated three SNPs in the CETP gene in two cross-sectional community-based populations (n = 1,574 and 1,109) and a population of 556 CHD patients to determine if reduced CETP activity due to genetic variations in
the CETP gene would increase HDL-C levels and reduce the risk of CHD. CETP genotypes and haplotypes were tested for association
with lipid levels, CETP activity and risk of CHD. Multivariate analysis showed the common AAB2 haplotype defined by the G-2708A,
C-629A and TaqIB polymorphisms, was consistently associated with reduced CETP activity and increased HDL-C levels. A mean increase in HDL-C
levels of 0.16–0.24 mmol/l was observed in individuals with two copies of the AAB2 haplotype relative to non AAB2 carriers
across all three populations (P < 0.001). A case-control study of males indicated no association between single SNPs or haplotypes and the risk of CHD. These
results suggest that raising HDL-C via CETP inhibition may not alter risk of CHD. Randomized control trials are needed to
determine whether CETP inhibition will in reality reduce risk of CHD by raising HDL-C.
Pamela A. McCaskie and John P. Beilby contributed equally to this work. |
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