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

被引:28
作者
Carlson, Christopher S.
Heagerty, Patrick J.
Hatsukami, Thomas S.
Richter, Rebecca J.
Ranchalis, Jane
Lewis, Julieann
Bacus, Tamara J.
McKinstry, Laura A.
Schellenberg, Gerard D.
Rieder, Mark
Nickerson, Deborah
Furlong, Clement E.
Chait, Alan
Jarvik, Gail P. [1 ]
机构
[1] Univ Washington, Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98195 USA
[2] Univ Washington, Dept Biostat, Seattle, WA 98195 USA
[3] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA
[4] Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA
[5] Univ Washington, Dept Neurol, Seattle, WA 98195 USA
[6] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
[7] Puget Sound Vet Affairs Hlth Care Syst, Seattle, WA USA
关键词
paraoxonase; carotid artery disease; LDL oxidation; haplotype; genotype; tagging single-nucleotide polymorphism;
D O I
10.1194/jlr.M500517-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1014 / 1024
页数:11
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