PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients

Leus, F.R.; Zwart, M.J.W.; Kastelein, John J.P.; Voorbij, H. A. M.

doi:10.1016/s0021-9150(00)00440-8

Cited by 73 publications

(65 citation statements)

References 36 publications

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“…15 A role for PON2 in the development of human atherosclerosis is suggested by its relationship with intima-medial thickness in white patients with heterozygous familial hypercholesterolemia. 16 PON2 can also reduce oxidative stress in vascular cells by decreasing stress-induced caspase activation in the endoplasmic reticulum. 17 PON3 is also an HDL-associated enzyme with biological activity similar to PON1.…”

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confidence: 99%

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

She

Zheng

Wei

et al. 2009

Circulation Research

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Abstract-The paraoxonase (PON) gene cluster consists of the PON1, PON2, and PON3 genes, each of which canindividually inhibit atherogenesis. To analyze the functions of the PON gene cluster (PC) in atherogenesis and plaque stability, human PC transgenic (Tg) mice were generated using bacterial artificial chromosome. The high-density lipoprotein from Tg mice exhibited increased paraoxonase activity. When crossed to the ApoE-null background and challenged by high-fat diet, PC Tg/ApoE-null mice formed significantly fewer atherosclerotic lesions. However overexpression of the PC transgene had no additive effect on atherosclerosis compared to the overexpression of the single PON1 or PON3 transgene. Plaques from PC Tg/ApoE-null mice exhibited increased levels of collagen and smooth muscle cells, and reduced levels of macrophages and lipid, compared with those from ApoE-null mice, indicating lesions of PC Tg/ApoE-null mice had characteristics of more stable plaques than those of ApoE-null mice. PC transgene enhanced high-density lipoprotein ability to protect low-density lipoprotein against oxidation in vitro. Serum intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 were also repressed by PC transgene. Proatherogenic reactions of Tg mouse peritoneal macrophages induced by oxidized low-density lipoprotein were inhibited by PC transgene, as indicated by reduced reactive oxygen species generation, inflammation, matrix metalloproteinase-9 expression, and foam cell formation. Our results demonstrate that the PC transgene not only represses atherogenesis but also promotes atherosclerotic plaque stability in vivo. PC may therefore be a useful target for atherosclerosis treatment. Key Words: atherosclerosis Ⅲ plaques stability Ⅲ macrophages Ⅲ paraoxonase cluster A therosclerosis constitutes the single most important contributor to cardiovascular diseases, which are the leading cause of death and illness in developed societies. 1,2 Atherosclerosis-related ischemic symptoms, especially acute cardiovascular events that result in myocardial infarction and stroke, are generally thought to result from plaque rupture and thrombosis other than narrowing of the vessel lumen. 3 New strategies for preventing and treating plaque rupture are very much needed based on understanding of factors that contributed. Oxidized low-density lipoprotein (oxLDL) plays a pivotal role in triggering proinflammatory events that initiate and exacerbate atherogenesis, 1,4 which induces the expression of adhesion molecules, chemokines, and cytokines in vascular endothelial cells, 5 triggering recruitment of monocytes into the subendothelial space of the arterial wall, where they differentiate into macrophages. Recruited macrophages ingest and further oxidize LDL, transforming into foam cell after excessive oxLDL accumulation. These transformed macrophages not only constitute early fatty streak lesions and the core of atherosclerotic plaques but also become active inflammation centers because of secretion of inflammatory molecules and ma...

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confidence: 99%

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

She

Zheng

Wei

et al. 2009

Circulation Research

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“…However, although AE activity is not associated with any known polymorphism, it is possible that HDL2 AE activity could be affected by PON1P in the different PGs. This is possible because it has been reported that linkage disequilibrium with other functional mutations in the PON gene cluster or at another gene on chromosome 7q can cause interactions and that these interactions may produce phenotype differences 16,50) . There-…”

Section: Correlations Among Variablesmentioning

confidence: 99%

Effects of Anaerobic Training on Paraoxonase-1 Enzyme (PON1) Activities of High Density Lipoprotein Subgroups and Its Relationship with PON1-Q192R Phenotype

Turgay

Şişman

Aksu

2015

JAT

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Aim: Paraoxonase-1 (PON1) is an antiatherosclerotic enzyme located on high-density lipoprotein (HDL). The effects of anaerobic exercise on PON1 activity are unknown. Here we investigated the effects of anaerobic judo training on three different activities of same PON1 enzyme (TDPON1), including basal PON1, salt-stimulated PON1 (SPON1), and arylesterase (AE) activities, of serum, HDL, and HDL subgroups (HDLs; HDL and its subgroups) and its relationship with PON1-Q192R phenotype (PON1P). Methods: Our study included 18 Turkish national female judoists (mean age: 17.9 0.8 years). Before and after 5 months of anaerobic training, critical speed (CS), TDPON1 activities, cholesterol levels in the serum and supernatants of HDLs obtained by polyethylene glycol, and other major blood lipids and lipoproteins (BLLPs) including triglycerides were determined using blood samples taken after overnight fasting. PON1P groups (PGs) were categorized as QQ (QG; persons with low activity) and R carriers (QR RR) (RG; persons with high activity) according to SPON1/AE activity ratios. The results were considered statistically significant at P ≤ 0.05. Results: Anaerobic training resulted in significantly increased the cholesterol levels of HDLs (except HDL2-C) in all subjects, but not HDLs-C in PGs. Anaerobic training resulted in significant increases in most TDPON1 activities of serum and HDLs in all subjects and (except AE) in PGs, whereas SPON1 and HDL2 AE activities increased only in the RG, which was related to PON1P. However, PON1P was not related to other measured markers, including basal BLLP profiles. Conclusions: Anaerobic training improved most TDPON1 activities of serum and HDLs and HDLs -C levels (except HDL2-C) in all subjects, but not HDLs-C in PGs. The beneficial effects of anaerobic training on SPON1 and HDL2 AE activities were depend on PON1P. The lack of response of HDL2-C to anaerobic exercise will require further research. J Atheroscler Thromb, 2015; 22: 313-326.

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“…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. The results of this hypothesis-generating study constitute a basis for further research and form a step forward in the unraveling of the underlying mechanisms of CVD in FH.…”

Section: Discussionmentioning

confidence: 85%

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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PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients

Cited by 73 publications

References 36 publications

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

Effects of Anaerobic Training on Paraoxonase-1 Enzyme (PON1) Activities of High Density Lipoprotein Subgroups and Its Relationship with PON1-Q192R Phenotype

Genetic Determinants of Cardiovascular Disease Risk in Familial Hypercholesterolemia

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