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Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease

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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.

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Acknowledgments

This study was supported by grants-in-aid from the HeartSearch WA (to C.C and J.B) and National Heart Foundation grant-in-aid G97P 5002. The authors thank the Busselton Population Medical Research Foundation for access to the survey.

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Authors and Affiliations

  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

    Pamela A. McCaskie & Lyle J. Palmer

  2. Clinical Biochemistry, PathWest, Laboratory Medicine Western Australian, Perth, WA, Australia

    John P. Beilby & Caroline M. L. Chapman

  3. School of Surgery and Pathology, University of Western Australia, Perth, WA, Australia

    John P. Beilby & Peter L. Thompson

  4. Sir Charles Gairdner Hospital Campus of the Heart Research Institute of Western Australia, Perth, WA, Australia

    Joseph Hung, Brendan M. McQuillan & Peter L. Thompson

  5. School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia

    Joseph Hung, Brendan M. McQuillan & Lyle J. Palmer

Authors
  1. Pamela A. McCaskie
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  2. John P. Beilby
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  3. Caroline M. L. Chapman
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  4. Joseph Hung
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  5. Brendan M. McQuillan
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  6. Peter L. Thompson
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  7. Lyle J. Palmer
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Correspondence to Pamela A. McCaskie.

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Pamela A. McCaskie and John P. Beilby contributed equally to this work.

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McCaskie, P.A., Beilby, J.P., Chapman, C.M.L. et al. Cholesteryl ester transfer protein gene haplotypes, plasma high-density lipoprotein levels and the risk of coronary heart disease. Hum Genet 121, 401–411 (2007). https://doi.org/10.1007/s00439-007-0326-2

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  • DOI: https://doi.org/10.1007/s00439-007-0326-2

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