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Papers In Press, published online ahead of print June 1, 2007
J. Lipid Res., doi:10.1194/jlr.P600012-JLR200

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Journal of Lipid Research, Vol. 48, 1409-1416, June 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Patient-Oriented Research

Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL

Aino Soro-Paavonen^1,*,, Jussi Naukkarinen^1,,**, Miriam Lee-Rueckert, Hiroshi Watanabe^*, Elina Rantala, Sanni Soderlund^*, Anne Hiukka^*, Petri T. Kovanen, Matti Jauhiainen, Leena Peltonen^,**, and Marja-Riitta Taskinen^2,*

^* Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
Danielle Alberti Memorial Centre for Diabetes Complications, Baker Heart Research Institute, Melbourne, Australia
Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland
^** Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Wihuri Research Institute, Helsinki, Finland
Broad Institute, Massachusetts Institute of Technology, Boston, MA

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

Published, JLR Papers in Press, March 19, 2007.

¹ A. Soro-Paavonen and J. Naukkarinen contributed equally to this work.

² To whom correspondence should be addressed. e-mail: marja-riitta.taskinen{at}helsinki.fi

ABSTRACT

HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.

Supplementary key words ATP binding cassette transporter A1 • high density lipoprotein • ABCG1

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