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Originally published In Press as doi:10.1194/jlr.M600405-JLR200 on December 28, 2006 Originally published In Press as doi:10.1194/jlr.M600405-JLR200 on December 27, 2006

Papers In Press, published online ahead of print March 1, 2007
J. Lipid Res., doi:10.1194/jlr.M600405-JLR200
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Journal of Lipid Research, Vol. 48, 674-682, March 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Cholesteryl ester transfer protein and hyperalphalipoproteinemia in Caucasiansboxs

Wim A. van der Steeg1,*, G. Kees Hovingh1,*, Anke H. E. M. Klerkx*, Barbara A. Hutten{dagger}, Inge C. Nootenboom*, Johannes H. M. Levels*, Arie van Tol§, Gees M. Dallinga-Thie§, Aeilko H. Zwinderman{dagger}, John J. P. Kastelein* and Jan Albert Kuivenhoven2,*

* Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
{dagger} Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands
§ Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands

boxs The online version of this article (available at http://www.jlr.org) contains supplemental data in the form of four tables and two figures.

Published, JLR Papers in Press, December 28, 2006.

1 W. A. van der Steeg and G. K. Hovingh contributed equally to this work.

2 To whom correspondence should be addressed. e-mail: j.a.kuivenhoven{at}amc.uva.nl

It is unclear whether cholesteryl ester transfer protein (CETP) contributes to high density lipoprotein cholesterol (HDL-C) levels in hyperalphalipoproteinemia (HALP) in Caucasians. Moreover, even less is known about the effects of hereditary CETP deficiency in non-Japanese. We studied 95 unrelated Caucasian individuals with HALP. No correlations between CETP concentration or activity and HDL-C were identified. Screening for CETP gene defects led to the identification of heterozygosity for a novel splice site mutation in one individual. Twenty-five heterozygotes for this mutation showed reduced CETP concentration (–40%) and activity (–50%) and a 35% increase of HDL-C compared with family controls. The heterozygotes presented with an isolated high HDL-C, whereas the remaining subjects exhibited a typical high HDL-C/low-triglyceride phenotype. The increase of HDL-C in the CETP-deficient heterozygotes was primarily attributable to increased high density lipoprotein containing apolipoprotein A-I and A-II (LpAI:AII) levels, contrasting with an increase in both high density lipoprotein containing apolipoprotein A-I only and LpAI:AII in the other group. This study suggests the absence of a relationship between CETP and HDL-C levels in Caucasians with HALP. The data furthermore indicate that genetic CETP deficiency is rare among Caucasians and that this disorder presents with a phenotype that is different from that of subjects with HALP who have no mutation in the CETP gene.

Supplementary key words deficiency • mutation • CETP-IVS7+1

Abbreviations: apoC-III, apolipoprotein C-III; BMI, body mass index; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; HALP, hyperalphalipoproteinemia; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; LpAI, high density lipoprotein containing apolipoprotein A-I only; LpAI:AII, high density lipoprotein containing apolipoprotein A-I and A-II


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