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Papers In Press, published online ahead of print August 1, 2008
J. Lipid Res., doi:10.1194/jlr.P800011-JLR200

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Journal of Lipid Research, Vol. 49, 1846-1854, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients^*,

Clive R. Pullinger^1,*,, Bradley E. Aouizerat^,, Irina Movsesyan^*, Vincent Durlach^**, Eric J. Sijbrands, Katsuyuki Nakajima, Annie Poon^*, Geesje M. Dallinga-Thie^***, Hiroaki Hattori, Lauri L. Green, Pui-Yan Kwok^*, Richard J. Havel^*, Philip H. Frost^*,, Mary J. Malloy^*, and John P. Kane^*,,****

^* Cardiovascular Research Institute, University of California, San Francisco, CA
Department of Physiological Nursing, University of California, San Francisco, CA
Institute for Human Genetics, University of California, San Francisco, CA
Department of Medicine, University of California, San Francisco, CA
^**** Department of Biochemistry and Biophysics, University of California, San Francisco, CA
^** Service d'Endocrinologie, Maladies Métabolique, et Médicine Interne, Hôpital Robert Debré, Reims Cedex, France
Department of Cardiovascular Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
Japan Immunoresearch Laboratories Co., Takasaki Gunma, Japan
^*** Laboratory of Experimental Vascular Medicine, Academisch Medisch Centrum, Amsterdam, The Netherlands
Department of Advanced Medical Technology and Development, BML, Inc., Kawagoe, Saitama, Japan

^* This work was supported by grants from the American Heart Association (Grants 0655195Y to C.R.P. and 0465005Y to B.E.A.), National Institutes of Health National Center for Research Resources Grant KL2 RR-024130 to B.E.A., a Hellman Family Award (to C.R.P. and B.E.A), a UCSF Academic Senate Award (to C.R.P.), the Leducq Foundation, the Joseph Drown Foundation (to M.J.M.), and by gifts from Donald Yellon and the Mildred V. Strouss Charitable Trust.

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

Published, JLR Papers in Press, April 25, 2008.

¹To whom correspondence should be addressed. e-mail: clive.pullinger{at}ucsf.edu

Apolipoprotein A-V (apoA-V) is an important regulator of plasma levels of triglyceride (TG) in mice. In humans, APOA5 genetic variation is associated with TG in several populations. In this study, we determined the effects of the p.185Gly>Cys (c.553G>T; rs2075291) polymorphism on plasma TG levels in subjects of Chinese ancestry living in the United States and in a group of non-Chinese Asian ancestry. The frequency of the less common cysteine allele was 4-fold higher (15.1% vs. 3.7%) in Chinese high-TG subjects compared with a low-TG group (Chi-square = 20.2; P < 0.0001), corresponding with a 4.45 times higher risk of hypertriglyceridemia (95% confidence interval, 2.18–9.07; P < 0.001). These results were replicated in the non-Chinese Asians. Heterozygosity was associated, in the high-TG group, with a doubling of TG (P < 0.001), mainly VLDL TG (P = 0.014). All eleven TT homozygotes had severe hypertriglyceridemia, with mean TG of 2,292 ± 447 mg/dl. Compared with controls, carriers of the T allele had lower postheparin lipoprotein lipase activity but not hepatic lipase activity. In Asian populations, this common polymorphism can lead to profound adverse effects on lipoprotein profiles, with homozygosity accounting for a significant number of cases of severe hypertriglyceridemia. This specific apoA-V variant has a pronounced effect on TG metabolism, the mechanism of which remains to be elucidated.

Supplementary key words polymorphism • Chinese Americans • triglycerides • heart disease • lipoprotein lipase • high density lipoprotein • haplotypes • single nucleotide polymorphism

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