J. Lipid Res.
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A more recent version of this article appeared on April 1, 2006

Papers In Press, published online ahead of print December 30, 2005
J. Lipid Res., doi:10.1194/jlr.M500476-JLR200
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Submitted on October 31, 2005
Revised on December 6, 2005
Accepted on December 30, 2005

Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Bradley E. Aouizerat, Mary B. Engler, Yanina Natanzon, Medha V. Kulkarni, James Song, Celeste Eng, Jarkko Huuskonen, Christopher Rivera, Annie Poon, Matt Bensley, Amy Sehnert, Christian Zellmer, Mary J. Malloy, John P. Kane, and Clive R. Pullinger

Physiological Nursing, University of California San Francisco, San Francisco, CA 94143-0160

Corresponding Author: bradley.aouizerat{at}nursing.ucsf.edu

Background: Phospholipid Transfer Protein (PLTP) participates in key processes in lipoprotein metabolism including inter-particle 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 the gene may harbor sequence anomalies that contribute to disorders of HDL metabolism. Methods and Results: 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. Results: We discovered 18 sequence variations, including 4 missense mutations and a novel polymorphism (c.-34G>C). In healthy controls, the c.-34G>C minor allele was associated with higher HDL-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 elevates 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. Conclusions: These findings indicate that PLTP gene variation is an important determinant of plasma lipoproteins and impacts disorders of HDL metabolism.


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