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Originally published In Press as doi:10.1194/jlr.M500476-JLR200 on December 30, 2005

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Journal of Lipid Research, Vol. 47, 787-793, April 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Bradley E. Aouizerat*,{dagger},1, Mary B. Engler*,{dagger}, Yanina Natanzon*, Medha Kulkarni*,§, James Song§, Celeste Eng§, Jarkko Huuskonen§, Christopher Rivera§, Annie Poon§, Matt Bensley**, Amy Sehnert**, Christian Zellner§, Mary Malloy§, John Kane{dagger},§ and Clive R. Pullinger*,§

* Department of Physiological Nursing, School of Nursing, University of California San Francisco, San Francisco, CA 94143
{dagger} Center for Human Genetics, University of California San Francisco, San Francisco, CA 94143
§ Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143
** Department of Pediatrics, School of Medicine, University of California San Francisco, San Francisco, CA 94143

Published, JLR Papers in Press, December 30, 2005.

* To whom correspondence should be addressed. e-mail: bradley.aouizerat{at}nursing.ucsf.edu

Phospholipid transfer protein (PLTP) participates in key processes in lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. The impact of PLTP on reverse cholesterol transport suggests that the gene may harbor sequence anomalies that contribute to disorders of HDL metabolism. The human PLTP gene was screened for sequence anomalies by DNA melting analysis in 276 subjects with hypoalphalipoproteinemia (HA) and 364 controls. The association with plasma lipid parameters was evaluated. We discovered 18 sequence variations, including four missense mutations and a novel polymorphism (c.-34G>C). In healthy controls, the c.-34G>C minor allele was associated with higher high density lipoprotein-cholesterol (HDL-C) and was depleted in subjects with HA. Linear regression models predict that possession of the rare allele decreases plasma triglyceride (TG) and TG/HDL-C and increases HDL-C independent of TG. Decreased PLTP activity was observed in one (p.R235W) of four (p.E72G, p.S119A, p.S124Y, and p.R235W) mutations in an in vitro activity assay. These findings indicate that PLTP gene variation is an important determinant of plasma lipoproteins and affects disorders of HDL metabolism.

Supplementary key words dyslipidemia • genetic polymorphism • atherosclerosis • cardiovascular diseases • phospholipid transfer protein


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