Ignite Creation Date:
2024-05-05 @ 11:23 AM
Last Modification Date:
2024-10-26 @ 9:06 AM
Study NCT ID:
NCT00011258
Status:
COMPLETED
Last Update Posted:
2009-01-21
First Post:
2001-02-14
Brief Title:
Paraoxonase and LDL Oxidation in Carotid Artery Disease
Sponsor:
US Department of Veterans Affairs
Organization:
VA Office of Research and Development
Study Overview
Official Title:
Paraoxonase and LDL Oxidation in Carotid Artery Disease
Status:
COMPLETED
Status Verified Date:
2004-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Atherosclerosis of the carotid arteries is a common cause of stroke The prevalence and progression of carotid atherosclerosis are believed to be influenced by genetically inherited variations in lipoprotein metabolism This study investigates the specific role of paraoxonase an enzyme thought to detoxify atherogenic oxidized low-density lipoprotein This study compares veterans who have significant carotid atherosclerosis on ultrasound examination with controls without carotid atherosclerosis Both paraoxonase activity and genotype will be determined and compared between groups The results may eventually make it possible to screen for a paraoxonase allele that confers high risk of atherosclerosis and to diminish the risk by early treatment
Detailed Description:
Primary Objective
Atherosclerosis of the carotid arteries is a common cause of stroke The prevalence and progression of carotid atherosclerosis are believed to be influenced by genetically inherited variations in lipoprotein metabolism This study investigates the specific role of paraoxonase an enzyme thought to detoxify atherogenic oxidized low-density lipoprotein This study compares veterans who have significant carotid atherosclerosis on ultrasound examination with controls without carotid atherosclerosis Both paraoxonase activity and genotype will be determined and compared between groups The results may eventually make it possible to screen for a paraoxonase allele that confers high risk of atherosclerosis and to diminish the risk by early treatment
Study Abstract
The general aim of the proposed research is to evaluate the contribution and mechanism of paraoxonase PON1 genotypic and phenotypic variation PON1 status in risk and progression of carotid artery disease CAAD We propose to study moderately affected individuals currently being enrolled in a longitudinal 3-year magnetic resonance imaging MR study to evaluate components of MR image as predictors of CAAD progression We will study the role of PON1 in CAAD progression in this cohort We will also collect age- sex- race- and hospital- matched controls to test hypotheses related to the presence or absence of CAAD We plan to consider the complex genetic architecture of both vascular disease and PON1 effects in vascular disease In addition to evaluating known paraoxonase PON1 polymorphisms we will evaluate PON1 hydrolysis phenotypes We have shown that these intervening phenotypes can be superior to known genotypes in CAAD prediction We will also evaluate PON1 polymorphisms that we have recently detected and shown to affect PON1 expression as well as consider haplotype effects The specific aims are to 1 test for PON1 effects in CAAD progression evaluated by 3 year magnetic resonance image follow-up of percent lumen stenosis 2 test for PON1 effects in moderate CAAD vs control prediction including independence of PON1 from traditional cardiovascular risk factors and 3 evaluate the possible mechanisms of PON1s association with carotid artery disease specifically PON1s relationship with the susceptibility of LDL to oxidation and variation in LDL density
Two paraoxonase PON1 polymorphisms PON1-Q192R and PON1-L55M have been inconsistently associated with vascular disease However plasma PON1 activity phenotypes vary markedly within genotypes Thus activity was expected to add to the informativeness of genotype for predicting vascular disease The case-control study included 212 age and race matched men with mean age 664 yr range 49-82 yr 95 were Caucasian The 106 carotid artery disease CAAD cases had 80 carotid stenosis and the 106 controls had 15 stenosis Two PON1 substrate hydrolysis rates paraoxon POase diazoxon DZOase were significantly lower in cases than in controls and were significant predictors of CAAD using logistic regression POase p0005 25 reduced DZOase p0019 16 reduced POase and DZOase were both significant when included in the same model DZOase predicted vascular disease independently of lipoprotein profile HDL subfractions apoAI and smoking The marginal effects of PON1-192 p075 and PON1-55 p083 genotypes or haplotype 070 did not predict case-control status However when phenotype was included as a predictor both PON1-192 and PON1-55 genotypes or haplotypes were significant predictors at the 005 level The common methodology of examining PON1-192 andor PON1-55 genotypes alone may lead to the erroneous conclusion that there is no PON1 role in CAAD This may have broad implications for the utility of the genotype only approach These results support the benefit of a level crossing approach that includes intervening phenotypes in the study of complexly inherited disease
Atherosclerosis of the carotid arteries is a common cause of stroke The prevalence and progression of carotid atherosclerosis are believed to be influenced by genetically inherited variations in lipoprotein metabolism This study investigates the specific role of paraoxonase an enzyme thought to detoxify atherogenic oxidized low-density lipoprotein This study compares veterans who have significant carotid atherosclerosis on ultrasound examination with controls without carotid atherosclerosis Both paraoxonase activity and genotype will be determined and compared between groups The results may eventually make it possible to screen for a paraoxonase allele that confers high risk of atherosclerosis and to diminish the risk by early treatment
Study Abstract
The general aim of the proposed research is to evaluate the contribution and mechanism of paraoxonase PON1 genotypic and phenotypic variation PON1 status in risk and progression of carotid artery disease CAAD We propose to study moderately affected individuals currently being enrolled in a longitudinal 3-year magnetic resonance imaging MR study to evaluate components of MR image as predictors of CAAD progression We will study the role of PON1 in CAAD progression in this cohort We will also collect age- sex- race- and hospital- matched controls to test hypotheses related to the presence or absence of CAAD We plan to consider the complex genetic architecture of both vascular disease and PON1 effects in vascular disease In addition to evaluating known paraoxonase PON1 polymorphisms we will evaluate PON1 hydrolysis phenotypes We have shown that these intervening phenotypes can be superior to known genotypes in CAAD prediction We will also evaluate PON1 polymorphisms that we have recently detected and shown to affect PON1 expression as well as consider haplotype effects The specific aims are to 1 test for PON1 effects in CAAD progression evaluated by 3 year magnetic resonance image follow-up of percent lumen stenosis 2 test for PON1 effects in moderate CAAD vs control prediction including independence of PON1 from traditional cardiovascular risk factors and 3 evaluate the possible mechanisms of PON1s association with carotid artery disease specifically PON1s relationship with the susceptibility of LDL to oxidation and variation in LDL density
Two paraoxonase PON1 polymorphisms PON1-Q192R and PON1-L55M have been inconsistently associated with vascular disease However plasma PON1 activity phenotypes vary markedly within genotypes Thus activity was expected to add to the informativeness of genotype for predicting vascular disease The case-control study included 212 age and race matched men with mean age 664 yr range 49-82 yr 95 were Caucasian The 106 carotid artery disease CAAD cases had 80 carotid stenosis and the 106 controls had 15 stenosis Two PON1 substrate hydrolysis rates paraoxon POase diazoxon DZOase were significantly lower in cases than in controls and were significant predictors of CAAD using logistic regression POase p0005 25 reduced DZOase p0019 16 reduced POase and DZOase were both significant when included in the same model DZOase predicted vascular disease independently of lipoprotein profile HDL subfractions apoAI and smoking The marginal effects of PON1-192 p075 and PON1-55 p083 genotypes or haplotype 070 did not predict case-control status However when phenotype was included as a predictor both PON1-192 and PON1-55 genotypes or haplotypes were significant predictors at the 005 level The common methodology of examining PON1-192 andor PON1-55 genotypes alone may lead to the erroneous conclusion that there is no PON1 role in CAAD This may have broad implications for the utility of the genotype only approach These results support the benefit of a level crossing approach that includes intervening phenotypes in the study of complexly inherited disease
Study Oversight
Has Oversight DMC:
Is a FDA Regulated Drug?:
Is a FDA Regulated Device?:
Is an Unapproved Device?:
Is a PPSD?:
Is a US Export?:
Is an FDA AA801 Violation?: