Variation at the paraoxonase gene locus contributes to carotid arterial wall thickness in subjects with familial hypercholesterolemia

Roest, Mark; Jansen, Angelique C.M.; Barendrecht, Arjan D.; Leus, F.R.; Kastelein, John J.P.; Voorbij, H. A. M.

doi:10.1016/j.clinbiochem.2004.10.005

Cited by 26 publications

(19 citation statements)

References 15 publications

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“…Several studies have investigated genetic polymorphisms in candidate pathways implicated in the pathogenesis of atherosclerosis [43][44][45][46][47][48][49][50][51][52][53]. For instance, functional variants in the genes APO A-E [44,45,50], eNOS [47], PCK1 [48], PON1 [49], OPG [53], PPARG [52], and GPx-1 [51] are associated with carotid IMT or its risk factors. However, association studies of genetic polymorphisms with carotid IMT are inconsistent.…”

Section: Discussionmentioning

confidence: 99%

Heritability of carotid intima-media thickness: A twin study

Zhao¹,

Cheema²,

Bremner³

et al. 2008

Atherosclerosis

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Objective-To estimate the heritability of carotid intima-media thickness (IMT), a surrogate marker for atherosclerosis, independent of traditional coronary risk factors.Methods and Results-We performed a classical twin study of carotid IMT using 98 middleaged male twin pairs, 58 monozygotic (MZ) and 40 dizygotic (DZ) pairs, from the Vietnam Era Twin Registry. All twins were free of overt cardiovascular disease. Carotid IMT was measured by ultrasound. Bivariate and multivariate analyses were used to determine the association between traditional cardiovascular risk factors and carotid IMT. Intraclass correlation coefficients and genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in carotid IMT. In our sample, the mean of the maximum carotid IMT was 0.75 ± 0.11. Age, systolic blood pressure and HDL were significantly associated with carotid IMT. The intraclass correlation coefficient for carotid IMT was larger in MZ (0.66; 95% confidence interval [CI], 0.62-0.69) than in DZ twins (0.37; 95% CI, 0.29-0.44), and the unadjusted heritability was 0.69 (95% CI, 0.54-0.79). After adjusting for traditional coronary risk factors, the heritability of carotid IMT was slightly reduced but still of considerable magnitude (0.59; 95% CI, 0.39-0.73).Conclusion-Genetic factors have a substantial influence on the variation of carotid IMT. Most of this genetic effect occurs through pathways independent of traditional coronary risk factors.

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Section: Discussionmentioning

confidence: 99%

Heritability of carotid intima-media thickness: A twin study

Zhao¹,

Cheema²,

Bremner³

et al. 2008

Atherosclerosis

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“…Several studies have examined PON1 gene variants with respect to IMT, with some showing an association [11, 14, 16, 17, 29], and others failing to find an effect of different alleles on IMT [10, 12, 13, 15, 30, 31]. Because of the conflicting results the role of the PON1 gene in carotid artery disease is currently unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Most of them [10,11,12,13,15,16,17,18], but not all [14, 19] could exclude the association between PON1-192 polymorphism and carotid IMT. Jarvik et al [20 ]studied the PON1-192 and 55 polymorphisms and PON1 activity toward paraoxon and diazoxon as predictors of carotid artery atherosclerotic disease (CAAD) in 212 men (mean age was 66.4 years).…”

Section: Introductionmentioning

confidence: 99%

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Association between Human Paraoxonase 1 Activity and Intima-Media Thickness in Subjects under 55 Years of Age with Carotid Artery Disease

et al. 2007

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Background: Human serum paraoxonase (PON1) protects lipoproteins against oxidation by hydrolyzing lipid peroxides in oxidized low-density lipoprotein (oxLDL); therefore, it may protect against atherosclerosis. PON1 activity and polymorphisms have been inconsistently associated with carotid artery disease. The goal of this study was to clarify the role of PON1 activity and phenotype on carotid artery disease and its correlation with some inflammatory and immune markers in subjects under 55 years with early-onset carotid atherosclerosis. Methods: Sixty patients with occlusive carotid artery disease and 30 healthy controls were enrolled. Intima-media thickness (IMT) was measured by high-resolution ultrasound of both common carotid arteries. Anti-oxLDL antibody levels were determined by ELISA. Results: In the whole study population we found a negative correlation between PON1 activity and IMT (r = –0.27, p = 0.011), and between salt-stimulated PON1 activity and IMT (r = –0.24, p = 0.02). Both PON1 activity and salt-stimulated PON1 activity negatively correlated with anti-oxLDL levels (r = –0.28, p = 0.008; r = –0.26, p = 0.01). PON1 activity was lower in patients compared to controls; however, the difference was not significant.PON1 phenotype distribution of patients and controls did not differ significantly. Conclusion: The importance of PON1 activity as a predictive risk factor for early-onset occlusive carotid artery disease should be assessed in future studies.

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“…The mutations causing the enzyme de¢ciency generally do not confer an increased risk of CHD, but when occurring in the presence of FH, there are reports of increased cardiovascular risk, although in another report LDL levels were quite low. 92,93 The e¡ect of other genetic factors such as cholesteryl ester transfer protein (CETP), 94,95 microsomal triglyceride transfer protein (MTP), 96 hepatic lipase, fatty acid-binding protein, 97 methylene tetrahydrofolate reductase (MTHFR), 98 ATP-binding cassette A1 (ABCA1), 99 renin--angiotensin 100 and paraoxonase 101,102 have been described, but it would seem that it is rare for them to exert a major in£uence on the FH phenotype. Gender does seem to have a major in£uence on the FH phenotype, 77 with women demonstrating clinical features of CHD later than men, but earlier than women without FH.…”

Section: Factors Influencing the Fh Phenotype Geneticmentioning

confidence: 99%

Diagnosis and screening for familial hypercholesterolaemia: finding the patients, finding the genes

Bhatnagar

2006

Ann Clin Biochem

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Familial hypercholesterolaemia (FH) is a genetic disorder in which the concentration of serum cholesterol is elevated from birth and leads to premature coronary heart disease. FH is commonly caused by a mutation in the LDL receptor, but mutations in other genes can lead to a phenotype similar to FH. FH exhibits marked phenotypic variability due to genetic, metabolic and environmental factors. The presence of tendon xanthomata is the characteristic clinical sign seen in many patients with FH, but they may also have other non-specific signs of lipid disorders such as corneal arcus and xanthelasmata. Premature vascular disease is apparent in many patients. The wide variety of mutations and phenotypic variability have made it difficult to establish definite diagnostic criteria, but three sets of clinical criteria commonly used are the Simon Broome criteria, the Dutch Lipid Clinic criteria and the American criteria. FH screening fits the Wilson and Jungner recommendations for validity of a screening programme. Screening could be carried out on a population basis, in a clinical setting or by application to relatives of probands. This latter approach, termed cascade testing, appears to be the more cost-effective compared with population screening and can be carried out using clinical criteria or genetic testing, or by a combination of both methods. Clinicians need to be made more aware of the clinical features of FH and how to diagnose it in order to increase the index of suspicion and instigate appropriate treatment early, with the aim of preventing premature coronary heart disease.

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Variation at the paraoxonase gene locus contributes to carotid arterial wall thickness in subjects with familial hypercholesterolemia

Cited by 26 publications

References 15 publications

Heritability of carotid intima-media thickness: A twin study

Heritability of carotid intima-media thickness: A twin study

Association between Human Paraoxonase 1 Activity and Intima-Media Thickness in Subjects under 55 Years of Age with Carotid Artery Disease

Diagnosis and screening for familial hypercholesterolaemia: finding the patients, finding the genes

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