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Papers In Press, published online ahead of print December 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800155-JLR200

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Journal of Lipid Research, Vol. 49, 2648-2656, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Patient-Oriented and Epidemiological Research

Comprehensive evaluation of apolipoprotein H gene (APOH) variation identifies novel associations with measures of lipid metabolism in GENOA^*,

Magalie S. Leduc, Lawrence C. Shimmin, Kathy L. E. Klos, Craig Hanis, Eric Boerwinkle and James E. Hixson¹

Human Genetics Center, Division of Epidemiology, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX

^* This work was supported in part by a graduate student fellowship from the Harry S. and Isabel C. Cameron Foundation (M.S.L.), and National Institutes of Health/National Heart Lung and Blood Institute Grant HL-072810 (K.L.E.K., E.B., J.E.H.). GENOA sample collection and measurements were supported by National Institutes of Health/National Heart Lung and Blood Institute Grants HL-54504, HL-039107, HL-054457, and HL-051021.

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

Published, JLR Papers in Press, August 1, 2008.

¹ To whom correspondence should be addressed. e-mail: James.E.Hixson{at}uth.tmc.edu

Apolipoprotein H (apoH, also named β-2 glycoprotein I) is found on several classes of lipoproteins, and is involved in the activation of lipoprotein lipase in lipid metabolism. We have comprehensively investigated the association of variation in the apoH gene (APOH) with lipid traits in hepatic cholesterol transport, dietary cholesterol transport (DCT), and reverse cholesterol transport (RCT). Our study population consisted of families from the Genetic Epidemiology Network of Arteriopathy multicenter study that include African Americans, Mexican Americans, and European Americans. We individually tested 36 single-nucleotide polymorphisms (SNPs) that span the APOH locus, including nonsynonymous variants that result in known apoH charge isoforms. In addition, we constructed haplotypes from SNPs in the 5' promoter region that comprise cis-acting regulatory elements, as well as haplotypes for multiple amino acid substitutions. We found point-wise significant associations of APOH variants with various lipid measures in the three racial groups. The strongest associations were found for DCT traits (triglyceride and apoE levels) in Mexican Americans with a nonsynonymous variant (SNP 14917, Cys306Gly) that may alter apoH protein folding in a region involved in phospholipid binding. In conclusion, family-based analyses of APOH variants have identified associations with measures of lipid metabolism in three American racial groups.

Supplementary key words dietary cholesterol transport • reverse cholesterol transport • hepatic cholesterol transport • apolipoprotein E levels • triglyceride levels • HDL cholesterol • LDL cholesterol • functional polymorphisms • nonsynonymous substitutions • SNP haplotypes • protein folding

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