Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia

Leus, F.R.; Wittekoek, M. E.; Prins, J. A.; Kastelein, John J.P.; Voorbij, H. A. M.

doi:10.1016/s0021-9150(99)00324-x

Cited by 74 publications

(33 citation statements)

References 37 publications

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“…Similar to HDL-C, the contribution of paraoxonase to IMT is debatable. Some studies have reported a significant association between PON1 and IMT in FH patients (9), in middle-aged women (34), and in a subgroup of nonsmokers (35), but there are also a number of reports, including the current one, that did not find an association between PON1 and IMT (30,(36)(37)(38). These differences in outcome suggest that there is only a weak relation between PON1 and IMT that will not be observed in many small studies that lack the power to detect weak effects.…”

Section: Discussionmentioning

confidence: 99%

“…Four polymorphisms in the promoter sequence of the PON1 gene ( Ϫ 107C/T, Ϫ 162A/G, Ϫ 824G/A, Ϫ 907G/C) also contribute to the variability in protein expression. During an earlier study, our group found a relation between the PON1 genotype combination LLQQ and increased intima-media thickness (IMT), a surrogate marker of CVD, in high-risk subjects with familial hypercholesterolemia (FH) (9). However, there is no consensus on the contribution of these genetic variants to the risk of CVD (10).…”

Section: Supplementary Abstract Atherosclerosis • Antioxidants • Polmentioning

confidence: 99%

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Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Himbergen

Roest

Graaf³

et al. 2005

Journal of Lipid Research

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HDL-associated paraoxonase type 1 (PON1) can protect LDL and HDL against oxidative modification in vitro and therefore may protect against cardiovascular disease. We investigated the effects of PON1 levels, activity, and genetic variation on high density lipoprotein-cholesterol (HDL-C) levels, circulating oxidized LDL (OxLDL), subclinical inflammation [high-sensitive C-reactive protein (Hs-CRP)], and carotid atherosclerosis. PON1 genotypes (L55M, Q192R, ؊ 107C/T, ؊ 162A/G, ؊ 824G/A, and ؊ 907G/C) were determined in 302 patients with familial hypercholesterolemia. PON1 activity was monitored by the hydrolysis rate of paraoxon, diazoxon, and phenyl acetate. PON1 levels, OxLDL, and Hs-CRP were determined using an immunoassay. The genetic variants of PON1 that were associated with high levels and activity of the enzyme were associated with higher HDL-C levels ( P values for trend: 0.008, 0.020, 0.042, and 0.037 for L55M, Q192R, ؊ 107C/T, and ؊ 907G/C, respectively). In addition to the PON1 genotype, there was also a positive correlation between PON1 levels and activity and HDL-C (PON1 levels: r ‫؍‬ 0.37, P Ͻ 0.001; paraoxonase activity: r ‫؍‬ 0.23, P ‫؍‬ 0.01; diazoxonase activity: r ‫؍‬ 0.29, P Ͻ 0.001; arylesterase activity: r ‫؍‬ 0.19, P ‫؍‬ 0.03). Our observations support the hypothesis that both PON1 levels and activity preserve HDL-C in plasma.

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Section: Discussionmentioning

confidence: 99%

Section: Supplementary Abstract Atherosclerosis • Antioxidants • Polmentioning

confidence: 99%

Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Himbergen

Roest

Graaf³

et al. 2005

Journal of Lipid Research

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“…25,26 Results of previous studies looking at associations with carotid IMT in white diabetic and hypercholesterolemic subjects have been conflicting. 27,28 Raised homocysteine levels have been associated with an increased risk of stroke in a number of studies 29 and with increased CCA IMT. 30 The MTHFR polymorphism that we studied has been associated with increased homocysteine levels in white populations 31 and with cardiovascular end points in some studies, although a meta-analysis failed to show an association with cardiovascular disease, despite an association with homocysteine levels.…”

Section: Discussionmentioning

confidence: 99%

Increased Common Carotid Intima-Media Thickness in UK African Caribbeans and Its Relation to Chronic Inflammation and Vascular Candidate Gene Polymorphisms

Markus

Kapozsta²,

Ditrich³

et al. 2001

Stroke

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Background and Purpose-Individuals of African Caribbean descent who live in the United Kingdom have an increased risk of stroke. The reasons for this are not fully understood, but differences in genetic predispositions or other novel stroke risk factors could play a role. US blacks have been reported to have increased common carotid artery wall thickness, or intima-media thickness (IMT), measured by ultrasound. We measured carotid IMT in UK African Caribbeans compared with UK whites and determined whether different distributions of polymorphisms in potential candidate vascular genes or differences in measures of chronic inflammation or infection could account for any difference. Methods-In a population study, common carotid artery IMT was measured in 202 white men and 89 African Caribbean men. The distribution of polymorphisms in ACE, paraoxonase 1, paraoxonase 2, and methylenetetrahydrofolate reductase genes was determined. Serum C-reactive protein and Helicobacter pylori seropositivity were determined. Results-Carotid IMT was increased in African Caribbeans even after controlling for cardiovascular risk factors, including homocysteine and social class: ␤ϭ0.113, 95% CI 0.036 to 0.189, Pϭ0.004. There was a significant interaction with smoking and mean IMT (Pϭ0.022), and the difference in both measures of IMT between ethnic groups was largely limited to individuals who had never smoked. There were significant ethnic differences in the distributions of 3 of the 4 candidate genes studied (ACE, paraoxonase 1, and methylenetetrahydrofolate reductase). H pylori seropositivity was increased in African Caribbeans (78.7% versus 53% in UK whites). However, neither the genetic polymorphisms nor H pylori seropositivity was related to IMT, and ethnic differences in their distribution did not account for the increased IMT seen in African Caribbeans. Conclusions-Carotid IMT is increased in UK African Caribbeans even after controlling for conventional risk factors.There are highly significant ethnic differences in the distribution of many potential cerebrovascular candidate genes. Although those we examined did not explain the ethnic differences in IMT, other genetic predispositions or environmental exposures could account for these differences.

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“…In FH, carotid IMT has been found to be associated with family history of early-onset CHD, 10 presence of CHD, 12,13 gender, 9 lipoprotein levels, 9,10,12 the type of LDLR defect, 11,14 and mutations in other genes. 15 However, most of these studies included selected Lipid Clinic patients receiving hypolipidemic treatment, which may variably influence IMT in FH. 16 This might explain why age-adjusted carotid IMT was not associated with CHD in a large cohort of the Utah MEDPED program, 17 in which a larger proportion of patients with than of those without CHD were using lipid-lowering drugs.…”

mentioning

confidence: 99%

Influence of HDL Cholesterol on Preclinical Carotid Atherosclerosis in Familial Hypercholesterolemia

Junyent¹,

Cofán²,

Núñez³

et al. 2006

ATVB

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Objective-The effect of risk factors on carotid atherosclerosis in heterozygous familial hypercholesterolemia (FH) is unclear. We evaluated carotid intima-media thickness (IMT) by sonography in relation to classical and emergent risk factors in a large FH cohort. amilial hypercholesterolemia (FH) is a common inherited disorder of lipid metabolism that is usually caused by defects in the low-density lipoprotein (LDL) receptor (LDLR) gene. FH is characterized by lifelong elevation of LDL cholesterol levels, tendon xanthomas, and early-onset coronary heart disease (CHD). 1 Despite its strong genetic background, FH shows a great variability in phenotypic expression in terms of the lipid profile, frequency of xanthomas, and onset and severity of CHD. 1-3 Specific LDLR mutations with a differential effect on residual receptor function affect both the lipid phenotype and CHD risk. 2,3 However, phenotypic variation also occurs in families or populations sharing the same LDLR defect, 4 -6 suggesting the influence of additional genetic and/or environmental factors. Conventional cardiovascular risk factors are associated with an increased risk for CHD in FH subjects. 3 Thus, a recent report from a large retrospective cohort of 2400 individuals with FH showed male gender, smoking, hypertension, diabetes, low high-density lipoprotein (HDL) cholesterol, and elevated lipoprotein(a) to be independent risk factors for cardiovascular disease, although they explained only 18.7% of the variation in its occurrence. 7 Carotid intima-media thickness (IMT) is a recognized intermediate marker for cardiovascular risk that has also been examined in FH. Previous studies showed that FH subjects have higher IMT than both age-matched and sex-matched normolipidemic 8,9 and hypercholesterolemic 10,11 controls. In FH, carotid IMT has been found to be associated with family history of early-onset CHD, 10 presence of CHD, 12,13 gender, 9 lipoprotein levels, 9,10,12 the type of LDLR defect, 11,14 and mutations in other genes. 15 However, most of these studies included selected Lipid Clinic patients receiving hypolipidemic treatment, which may variably influence IMT in FH. 16 This might explain why age-adjusted carotid IMT was not associated with CHD in a large cohort of the Utah MEDPED program, 17 in which a larger proportion of patients with than of those without CHD were using lipid-lowering drugs. Therefore, we evaluated with carotid sonography at the time of referral to our Lipid Clinic a large sample of well-phenotyped asymptomatic subjects with clinical FH who were either undertreated or treatment-naive. Methods and Results-Risk

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Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia

Cited by 74 publications

References 37 publications

Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Indications that paraoxonase-1 contributes to plasma high density lipoprotein levels in familial hypercholesterolemia

Increased Common Carotid Intima-Media Thickness in UK African Caribbeans and Its Relation to Chronic Inflammation and Vascular Candidate Gene Polymorphisms

Influence of HDL Cholesterol on Preclinical Carotid Atherosclerosis in Familial Hypercholesterolemia

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