Abstract
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.
Highlights
Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, the genotype at four functional PON1 polymorphisms is not
We have consistently found that the PON1Q192R, PON1M55L, PON1–108C/T, and PON1–162A/G genotypes fail to predict carotid artery disease (CAAD) in modest sample sizes, when PON1 activities are predictive of CAAD [2, 3]
It has been proposed that the disconnect between PON1 activity, but not genotype, and prediction of vascular disease might be explained by unknown common functional variation in the PON1/2/3 cluster that impacts disease risk. We addressed this by extending the study of the PON1 genotype to all common variation in the PON1/2/3 cluster using a tagging single-nucleotide polymorphism approach and evaluating the prediction of PON1 activity and CAAD status
Summary
Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, the genotype at four functional PON1 polymorphisms is not. 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. TagSNP analyses of the PON gene cluster: effects on PON1 activity, LDL oxidative susceptibility, and vascular disease. PON1 has four known common functional polymorphisms, two that change amino acids (PON1Q192R, PON1M55L), and two that alter promoter activity (PON1–108C/T and PON1–162A/G). We have consistently found that the PON1Q192R, PON1M55L, PON1–108C/T, and PON1–162A/G genotypes fail to predict carotid artery disease (CAAD) in modest sample sizes, when PON1 activities are predictive of CAAD [2, 3].
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