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Originally published In Press as doi:10.1194/jlr.M500517-JLR200 on February 11, 2006

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Journal of Lipid Research, Vol. 47, 1014-1024, May 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease

Christopher S. Carlson*, Patrick J. Heagerty{dagger}, Thomas S. Hatsukami§, Rebecca J. Richter**, Jane Ranchalis**, Julieann Lewis**, Tamara J. Bacus**, Laura A. McKinstry**, Gerard D. Schellenberg§§§, Mark Rieder***, Deborah Nickerson***, Clement E. Furlong**,***, Alan Chait{dagger}{dagger} and Gail P. Jarvik1,**,***

* The Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, The University of Washington
{dagger} Department of Biostatistics, Seattle, WA
§ Puget Sound Veterans Affairs Health Care System, Seattle, WA
** Department of Medicine (Divisions of Medical Genetics), Seattle, WA
§§ Department of Neurology, Seattle, WA
*** Department of Genome Sciences, Seattle, WA
{dagger}{dagger} Department of Medicine (Metabolism, Endocrinology , and Nutrition), Seattle, WA

Published, JLR Papers in Press, February 11, 2006.

1 To whom correspondence should be addressed. e-mail: pair{at}u.washington.edu

Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, although the genotype at four functional PON1 polymorphisms is not. To address this inconsistency, we investigated the role of all common PON1 genetic variability, as measured by tagging single-nucleotide polymorphisms (tagSNPs), in predicting PON1 activity for phenylacetate hydrolysis, LDL susceptibility to oxidation ex vivo, plasma homocysteine (Hcy) levels, and carotid artery disease (CAAD) status. The biological goal was to establish whether additional common genetic variation beyond consideration of the four known functional SNPs improves prediction of these phenotypes. PON2 and PON3 tagSNPs were secondarily evaluated. Expanded analysis of an additional 26 tagSNPs found evidence of previously undescribed common PON1 polymorphisms that affect PON1 activity independently of the four known functional SNPs. PON1 activity was not significantly correlated with LDL oxidative susceptibility, but genotypes at the PON1-108 promoter polymorphism and several other PON1 SNPs were. Neither PON1 activity nor PON1 genotype was significantly correlated with plasma Hcy levels. This study revealed previously undetected common functional PON1 polymorphisms that explain 4% of PON1 activity and a high rate of recombination in PON1, but the sum of the common PON1 locus variation does not explain the relationship between PON1 activity and CAAD.

Supplementary key words paraoxonase • carotid artery disease • LDL oxidation • haplotype • genotype • tagging single-nucleotide polymorphism

Abbreviations: AIC, Akaike's Information Criterion; CAAD, carotid artery disease; CVD, cardiovascular disease; Hcy, homocysteine; PON, paraoxonase; tagSNP, tagging single-nucleotide polymorphism


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