The paraoxonase gene family and atherosclerosis

Ng, Carey J.; Shih, Diana M.; Hama, Susan; Villa, Natividad; Navab, Mohamad; Reddy, Srinivasa T.

doi:10.1016/j.freeradbiomed.2004.09.035

Cited by 263 publications

(234 citation statements)

References 98 publications

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“…Paraoxonase-2, a family member of paraoxonase-1, is reported to have antioxidant properties and antiatherogenic capacities as well, although its exact physiological role is still unknown. 31 Our results confirm a relationship between paraoxonase-2 and CVD, and are in concordance with the findings of an earlier study in FH patients, in which homozygotes for the Ser311Cys variant of paraoxonase-2 seem to be protected against CVD. 32 Considering the limitations of association studies, we suggest our results should be replicated in addition to being performed in prospective studies of large and well-defined FH populations, in which genetic and environmental modifiers should be carefully monitored.…”

Section: Discussionsupporting

confidence: 93%

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Genetic Determinants of Cardiovascular Disease Risk in Familial Hypercholesterolemia

Jansen

Cohen

Tanck

et al. 2005

ATVB

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Objective-To investigate the contribution of polymorphisms in multiple candidate genes to cardiovascular disease (CVD) risk in a large cohort of patients with heterozygous familial hypercholesterolemia (FH). (FH) is a common hereditary disease, characterized by elevated levels of plasma low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease (CVD). 1 Characteristically, the mean age of onset of CVD is between 40 and 45 years in male FH patients and in female FH patients 10 years later. 1,2 Nevertheless, the phenotypic expression of this disorder, in terms of onset and severity of atherosclerotic vascular disease, varies considerably. 3 Unfortunately, a paucity of solid data exists on factors that contribute to these phenotypic differences. Previous studies have mostly focused on classical CVD risk factors and the functional variety among LDL receptor mutations. 4 -6 Although both influence the occurrence of CVD, they can only partially explain the observed large differences. We recently studied the contribution of classical risk factors to CVD in a large cohort of FH patients and demonstrated that Ͻ20% of the variation in CVD occurrence could be explained by these risk factors alone. 7 Therefore, other still unknown and possibly genetic factors play an undeniable role in the development of CVD in these patients. Genetic differences affect susceptibility to disease and whereas premature atherosclerosis can be linked in rare cases to single-gene disorders, most individuals do not carry such DNA defects. The "common disorder, common variant" theory predicts that the majority of population-attributable variation in susceptibility to prevalent disease is caused by variants that occur in high frequency in multiple genes. 8 Such genetic variation may also play an important role in the development of CVD in FH. This is substantiated by the fact that clustering of CVD occurs in FH kindred. 9 Unfortunately, large-scale association studies involving multiple polymorphisms are lacking in FH. Our objective, therefore, was to investigate the contribution of polymorphisms in multiple candidate genes to CVD risk in a large cohort of patients with heterozygous FH. Methods and Results-We Methods Study Design and Study PopulationThe present investigation was a retrospective, multicenter, cohort study. The study design and study population have been described elsewhere. 7 Briefly, lipid clinics in the Netherlands submit DNA samples from clinically suspected FH patients to a central laboratory for LDL receptor mutation analysis. 10 We randomly selected hypercholesterolemic patients from this DNA bank database with the aid of a computer program (Microsoft Excel). These patients had been referred from 27 lipid clinics throughout the Netherlands ( Figure I, available online at http://atvb.ahajournals.org).Phenotypic data (including detailed information on CVD) were acquired by reviewing patient's medical records by a trained team of data collectors. 7 Guidelines for data collection from medical records were ...

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Section: Discussionsupporting

confidence: 93%

“…31 The protective effect is generally considered to be caused by the ability of paraoxonase-1 to attenuate oxidative modification of lipoprotein particles. Paraoxonase-2, a family member of paraoxonase-1, is reported to have antioxidant properties and antiatherogenic capacities as well, although its exact physiological role is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Genetic Determinants of Cardiovascular Disease Risk in Familial Hypercholesterolemia

Jansen

Cohen

Tanck

et al. 2005

ATVB

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“…PON1 has been shown to metabolise lipid soluble radicals. 18 As PON1 activity as well as arylesterase activity of PON1 is inversely associated with oxidative stress, this findings strongly support the role of PON1 in modulating free radical injury. Our findings are consistent with the observations of Kao et al (1998), which demonstrated that PON1 levels are low in diabetics with microvascular complications.…”

Section: Discussionsupporting

confidence: 64%

“…17 PON1 has the ability to hydrolyse specific oxidised phospholipids and hydroperoxides in oxidised low density lipoproteins (LDL) and destroying the proinflammatory molecules involved in the initiation and progression of microvascular complications in diabetes. 18 Serum PON1 activity, based on the ability of the enzyme to hydrolyse the substrate paraoxon, found to possess interindividual variability. 19 The molecular basis of these variations is the single nucleotide polymorphism in the PON1 gene (7q21-22).…”

Section: Introductionmentioning

confidence: 99%

“…19 The molecular basis of these variations is the single nucleotide polymorphism in the PON1 gene (7q21-22). 20 An amino acid substitution at position 192 (Q192R polymorphism) give rise to two alleles PON Q and PON R and three phenotypes PON1 QQ, PON1 QR and PON1 RR . The amino acid arginine at position 192 of the protein specifies Q allele which is more abundant in the population and is responsible for protective effects of PON, while glutamine at that position denotes R allele which is proposed to be related with oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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