Paraoxonase and LDL Oxidation in Carotid Artery Disease
Paraoxonase and LDL Oxidation in Carotid Artery 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.
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 PON1's
 association with carotid artery disease, specifically PON1's 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 66.4 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, p=0.005, 25% reduced; DZOase, p=0.019, 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 (p=0.75) and PON1-55 (p=0.83) genotypes or haplotype (0.70) 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 0.05 level. The common
 methodology of examining PON1-192 and/or 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
Case: Either had a history of surgical carotid endarterectomy or carotid or CT angiogram
 showing greater than or equal to 80% stenosis in one or more internal carotid artery.
 Control: An ultrasound documenting internal carotid artery stenosis less than 15%
 bilaterally.