Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a sample taken from the genetically isolated Alberta Hutterites, we previously found that PON1 variation was associated with variation in plasma lipoprotein traits, including LDL and HDL cholesterol. With the recent cloning of the PON1-related gene PON2, we undertook studies of the association between genetic variation in PON2 and variation in plasma quantitative traits variation in a sample of 745 Alberta Hutterites. We found novel genetic associations between PON2 variation and variation in fasting plasma concentrations of total cholesterol and apolipoprotein AI. We confirmed our previously observed significant associations in this study sample between PON1 genetic variation and variation in plasma apo B-related traits, such as LDL, non-HDL and HDL cholesterol and apo B itself. Furthermore, there was almost complete linkage disequilibrium between PON2 alleles G148 and C311. We found no association between PON2 variation and plasma glucose or insulin. Taken together, our results suggest that common genetic variation on chromosome 7q21.3-22.1 in both PON1 and PON2 that affects the amino acid sequence of the respective gene products is associated with significant variation in intermediate traits in plasma lipoprotein metabolism.
Atherosclerosis 1998 Jul
PMID:Genetic variation in paraoxonase-1 and paraoxonase-2 is associated with variation in plasma lipoproteins in Alberta Hutterites. 969

The paraoxonase gene family contains at least three members, including PON1, PON2 and PON3, which are located on chromosome 7q21.3-22.1. Until recently, there has been little insight into the role of the respective gene products in human physiology and pathology. However, emerging evidence from biochemical and genetic experiments is providing clues about the role(s) of the products of these genes. For example, the PON1 gene product is serum paraoxonase, which is expressed mainly in the liver and which hydrolyzes organophosphates. Serum paraoxonase circulates on a subfraction of high-density lipoproteins and appears to use phospholipids on both low and high-density lipoprotein particles as a physiological substrate. This functional relationship could explain the reported associations between common variation in the PON1 gene and phenotypes related to atherosclerosis and lipoprotein metabolism. In contrast, the PON2 mRNA is expressed ubiquitously, and to date there are no mechanistic experiments that yield insights into its physiological role. However, there have been reports of association between common variation in PON2 and some metabolic quantitative phenotypes, such as plasma lipoproteins, plasma glucose, birthweight and atherosclerosis. Such genetic associations could point to the possible physiological role(s) of PON2. At present, the role of the PON3 gene product is very poorly understood. Complementary lines of research should soon clarify whether there might be merit in clinical testing for genetic variation in the paraoxonase gene family or whether the gene products might be good candidates for therapeutic interventions.
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PMID:Paraoxonase genes and disease. 1044 77

Paraoxonase 1 (PON1) is proposed to have an anti-atherogenic action. Two polymorphisms at the PON1 (M/L55 and Q/R192) have been shown to be associated with coronary artery disease (CAD). This conclusion is not drawn universally, however, and specific ethnic characteristics may be important determinants in this association. Recently two homologues of PON1 - PON2 and PON3 - were identified and Sanghera et al. demonstrated C/S311 polymorphism at PON2 was associated with the risk of CAD. Within that context, we investigated the association between the aforementioned three polymorphisms and CAD and ischemic stroke in a Japanese population. The study population included 431 control subjects, 210 CAD patients, and 235 ischemic stroke patients. Genotype distributions and allele frequencies of M/L55 and C/S311 were similar among the control and patient groups, whereas the R192 allele frequency was significantly higher (P<0.001) in CAD (75%) and ischemic stroke (76%) patients than in control subjects (65%). When confounding influences of other risk factors were controlled for by multivariate analysis, R192 remained an independent risk determinant (additive model: OR (95% CI), P value CAD: 2.01 (1.45-2.79), 0.0001; ischemic stroke: 1.84 (1.34-2.52), 0.0002 (three genotypes into calculation)). Taken together, our data indicate that the Q/R192 is principally associated with both CAD and ischemic stroke in Japanese.
Atherosclerosis 2000 Apr
PMID:Evidence for association between paraoxonase gene polymorphisms and atherosclerotic diseases. 1072 95

Serum paraoxonase circulates on a subfraction of high density lipoproteins and appears to use phospholipids on both low and high density lipoprotein particles as a physiological substrate. This functional relationship could explain the reported associations between common variation in the PON1 gene--at codons 55 and 192--and phenotypes related to atherosclerosis and lipoprotein metabolism. We evaluated associations between plasma lipoproteins and PON1 L/M55, PON1 Q/R192 and PON2 A/G148 polymorphisms in samples from two Canadian aboriginal populations, namely the Oji-Cree and the Inuit. In diabetic Oji-Cree, we found that carriers of PON1 M55 had a higher mean plasma triglyceride concentration than non-carriers. In non-diabetic Oji-Cree, we found that carriers of PON1 M55 had higher mean plasma concentrations of total and low density lipoporetein cholesterol and apo B than non-carriers. In Inuit, we found that carriers of PON1 M55 had higher mean plasma concentrations of total and low density lipoprotein cholesterol than non-carriers. The other polymorphic markers were not associated with variation in any plasma lipoprotein trait. Thus, the PON1 M55 allele appeared to be associated with deleterious changes in the plasma lipoprotein profile from two independent Canadian aboriginal samples. These results suggest that common variation in PON1 codon 55 is associated with variation of intermediate traits in plasma lipoprotein metabolism in aboriginal Canadians.
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PMID:Association between PON1 L/M55 polymorphism and plasma lipoproteins in two Canadian aboriginal populations. 1095 24

Paraoxonase is an enzyme associated with the high-density lipoprotein (HDL) particle. It catalyses the hydrolysis of organophosphates and protects LDL from oxidative modification in vitro by hydrolyzing lipid peroxides, suggestive of a role for paraoxonase in the development of atherosclerosis. Two frequent mutations at the paraoxonase gene locus (PON1) underlie the leucine (Leu allele) --> methionine (Met allele) and the glutamine(Gln allele) --> arginine(Arg allele) aminoacid substitutions at residues 55 and 192, respectively. These polymorphisms have been associated with increased risk for cardiovascular disease (CVD) in several studies, while others have not found this association. Recently, another member of the PON gene family designated PON2 has been identified. While the PON2 gene product is expressed ubiquitously, its physiological role is unknown. A common polymorphism at codon 311 (Cys-->Ser) in the PON2 gene has been described. In our study we assessed the frequency and genotype distribution of the PON1 and PON2 polymorphisms in 197 patients with familial hypercholesterolemia (FH), to determine the possible association between these mutations and susceptibility for CVD. The FH cohort group was divided into subjects with (n=83) and without (n=114) definite clinical manifestations of CVD (FH-Symptomatic and FH-Asymptomatic respectively). The control population consisted of 201 healthy normolipidemic blood donors. All subjects in this study were of Caucasian background. Genotypes were identified by PCR based analysis. With regard to the PON1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied. However, we did show an association between the PON2 311 polymorphism and CVD. The frequencies of PON2 Ser311 carriers (Ser/Ser and Cys/Ser) between FH-Symptomatic and both FH-Asymptomatic and controls did show a significant difference (P=0.01 and P=0.02 respectively). In the FH-Symptomatic population, surprisingly, no subjects were homozygous for PON2 Cys311, whereas in the FH-Asymptomatic population nine persons (7.9%) and in the control group 12 persons (6.0%) were homozygous. Our data indicate that the common PON2 polymorphism is associated with clinical manifestations of CVD in FH patients. While PON2 Ser311 carriers seem to be at risk, subjects with the Cys/Cys311 genotype are likely to be protected against the development of premature CVD.
Atherosclerosis 2001 Feb 15
PMID:PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients. 1125 65

Paraoxonase (PON) is a high-density lipoprotein (HDL) associated protein which is supposed to protect low-density lipoprotein (LDL) against oxidation and to play a role in the development of atherosclerosis. Interindividual variability in serum PON activity is attributable to common variants in components of the PON gene cluster on chromosome 7. We describe experimental conditions that permit the simultaneous determination of three common PON polymorphisms (PON1-192, PON1-55 and PON2-311) that are tightly associated with an increased risk of atherosclerosis. We used a multiplex PCR-based DNA assay using mismatch primers that introduce a unique recognition site for the endonuclease HinfI in the PCR products in case of presence of the R allele of PON 1-192, of the L allele of PON1-55 and of the S allele of PON2-311. The restriction analysis with HinfI allows to identify an electrophoretic band pattern which is specific for the combination of the three polymorphisms. This technique could be applied in the association studies aimed at assessing the role of PON and their polymorphisms in many clinical settings. In a preliminary study on a small population sample from south Italy about 10% of chromosomes exhibited the presumed risk-related haplotype R(192)/L(55)/S(311).
Atherosclerosis 2001 Sep
PMID:A multiplex PCR-based DNA assay for the detection of paraoxonase gene cluster polymorphisms. 1150 Jan 72

Trinidadians of South Asian origin have a high prevalence of cardiovascular disease and diabetes compared to Trinidadians of African origin. The degree to which these differences are related to genetic and/or environmental factors is unclear. To determine whether there might be a genetic basis for this difference in prevalence of deleterious phenotypes we examined allele frequencies for candidate genes in atherosclerosis and diabetes. We genotyped 81 consecutive neonates of African origin and 103 consecutive neonates of South Asian origin. We evaluated common polymorphisms in 11 candidate genes for atherosclerosis and diabetes. We found differences between the two subpopulations in the allele frequencies of several candidate genes, including APOE, LIPC, APOC3, PON1, PON2, and PPP1R3. However, the differences in the allele frequencies were not all consistent with the pattern of CHD expression between these two ethnic groups in adulthood. Thus, differences in genetic architecture alone may not explain the wide disparities in disease prevalence between these two subpopulations. It is very likely that environmental factors, or unmeasured genetic factors, influence the genetic susceptibility to disease in these subpopulations.
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PMID:Allele frequencies for candidate genes in atherosclerosis and diabetes among Trinidadian neonates. 1151 79

The antioxidant activity of HDL is largely due to the paraoxonase (PON1) located on it. Experiments with transgenic PON1 knock-out mice indicate the potential for PON1 to protect against atherogenesis. This effect of HDL in decreasing LDL lipid peroxidation is maintained for longer than that of antioxidant vitamins and could thus be more protective. Several important advances in the field of PON research have occurred recently, not least the discovery that two other members of the PON gene family PON2 and PON3 may also have important antioxidant properties. Significant advances have been made in understanding the basic biochemical function of PON1 and the discovery of possible modulators of its activity. Decreased coronary heart disease (CHD) risk associated with polymorphisms of PON1 which are most active in lipid peroxide hydrolysis revealed by meta-analysis is likely to be an underestimate of the true contribution of PON1 to CHD because these polymorphisms explain only a small component of the variation in PON1 activity. However, it is a very important observation because genetic influences are not likely to be confounded by other factors linked with both CHD and diminished PON1 activity. PON1 is extensively researched and strategies will hopefully emerge to increase its activity and provide a more satisfactory test of the antioxidant hypothesis of atherosclerosis than antioxidant vitamins have done.
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PMID:Paraoxonase and coronary heart disease. 1257 63

Human serum paraoxonase (PON1), an HDL-associated esterase, protects lipoproteins against oxidation, probably by hydrolyzing specific lipid peroxides. As arterial macrophages play a key role in oxidative stress in early atherogenesis, the aim of the present study was to examine the effect of PON1 on macrophage oxidative stress. For this purpose we used mouse arterial and peritoneal macrophages (MPM) that were harvested from two populations of PON1 knockout (KO) mice: one on the genetic background of C57BL/6J (PON1(0)) and the other one on the genetic background of apolipoproteinE KO (PON1(0)/E(0)). Serum and LDL, but not HDL, lipids peroxidation was increased in PON1(0), compared to C57BL/6J mice, by 84% and by 220%, respectively. Increased oxidative stress was shown in peritoneal and in arterial macrophages derived from either PON1(0) or PON1(0)/E(0) mice, compared to their appropriate controls. Macrophage oxidative stress was expressed by increased lipid peroxides content in MPM from PON1(0) and from PON1(0)/E(0) mice by 48% and by 80%, respectively, and by decreased reduced glutathione (GSH) content, compared to the appropriate controls. Furthermore, increased capacity of MPM from PON1(0) and PON1(0)/E(0) mice to oxidize LDL (by 40% and by 19%, respectively) and to release superoxide anions was observed. In accordance with these results, PON1(0) mice MPM exhibited 130% increased translocation of the cytosolic p47phox component of NADPH-oxidase to the macrophage plasma membrane, suggesting increased activation of macrophage NADPH-oxidase in PON1(0) mice, compared to control mice MPM. The increase in oxidative stress in PON1-deficient mice was observed despite the presence of the two other members of the PON gene family. PON2 and PON3 activities and mRNA expression were both found to be present in PON1-deficient mice MPM. Upon incubation of PON1(0)/E(0) derived macrophages with human PON1 (7.5 arylesterase units/ml), cellular peroxides content was decreased by 18%, macrophage superoxide anion release was decreased by 33%, and macrophage-mediated oxidation of LDL was reduced by 22%. Finally, a 42% increase in the atherosclerotic lesion area was observed in PON1(0)/E(0) mice, in comparison to E(0) mice under regular chow diet. We thus concluded that PON1 can directly reduce oxidative stress in macrophages and in serum, and that PON1-deficiency results in increased oxidative stress not only in serum, but also in macrophages, a phenomenon that can contribute to the accelerated atherosclerosis shown in PON1-deficient mice.
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PMID:Paraoxonase (PON1) deficiency is associated with increased macrophage oxidative stress: studies in PON1-knockout mice. 1263 54

The human paraoxonase (PON) gene family consists of three members, PON1, PON2, and PON3, aligned next to each other on chromosome 7. By far the most-studied member of the family is the serum paraoxonase 1 (PON1), a high-density lipoprotein-associated esterase/lactonase. Early research focused on its capability to hydrolyze toxic organophosphates, and its name derives from one of its most commonly used in vitro substrates, paraoxon. Studies in the last 2 decades have demonstrated PON1's ability to protect against atherosclerosis by hydrolyzing specific derivatives of oxidized cholesterol and/or phospholipids in oxidized low-density lipoprotein and in atherosclerotic lesions. Levels and genetic variability of PON1 influence sensitivity to specific insecticides and nerve agents, as well as the risk of cardiovascular disease. More recently, the other two members of the PON family, PON2 and PON3, have also been shown to have antioxidant properties. A major goal in present research on the paraoxonases is to identify their natural substrates and to elucidate the mechanism(s) of their catalytic activities.
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PMID:Pharmacogenetics of paraoxonases: a brief review. 1457 13


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