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)

Human HDL-associated paraoxonase (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces oxidation of LDLs and HDLs. These properties of PON1 account for its ability to protect against pesticide poisonings and atherosclerosis. PON1 also hydrolyzes a number of lactone and cyclic-carbonate drugs. Among individuals in a population, PON1 levels vary widely. We previously identified three polymorphisms in the PON1 regulatory region that affect expression levels in cultured human hepatocytes. In this study, we determined the genotypes of three regulatory-region polymorphisms for 376 white individuals and examined their effect on plasma-PON1 levels, determined by rates of phenylacetate hydrolysis. The -108 polymorphism had a significant effect on PON1-activity level, whereas the -162 polymorphism had a lesser effect. The -909 polymorphism, which is in linkage disequilibrium with the other sites, appears to have little or no independent effect on PON1-activity level in vivo. Other studies have found that the L55M polymorphism in the PON1-coding region is associated with differences in both PON1-mRNA and PON1-activity levels. The results presented here indicate that the L55M effect of lowered activity is not due to the amino acid change but is, rather, largely due to linkage disequilibrium with the -108 regulatory-region polymorphism. The codon 55 polymorphism marginally appeared to account for 15.3% of the variance in PON1 activity, but this dropped to 5% after adjustments for the effects of the -108 and Q192R polymorphisms were made. The -108C/T polymorphism accounted for 22.8% of the observed variability in PON1-expression levels, which was much greater than that attributable to the other PON1 polymorphisms. We also identified four sequence differences in the 3' UTR of the PON1 mRNA.
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PMID:Effects of 5' regulatory-region polymorphisms on paraoxonase-gene (PON1) expression. 1133 91

Cardiac death from atherosclerosis is common in hemodialysis patients. Human serum paraoxonase (PON1), an esterase, is associated with high-density lipoprotein and inhibits the susceptibility to oxidization of low-density lipoprotein (LDL). The PON1 genetic polymorphisms of 192 Gln/Arg and 55 Leu/Met in the amino acid sequence are partly involved in the PON1 enzyme activity. We investigated the PON1 enzyme activities for paraoxon (paraoxonase) and phenylacetate (arylesterase), and the two polymorphisms in 96 patients undergoing hemodialysis and in 136 normal controls. Both activities were significantly lower in the hemodialysis patients than in the controls (97+/-43 vs 155+/-57 micromol/min/l for paraoxonase, and 71+/-20 vs 92+/-22 mmol/min/l for arylesterase, respectively). There was no difference in the distribution of the two polymorphisms between patients and controls, and in every subgroup classified by the polymorphisms, both paraoxonase and arylesterase activities were lower in patients than in controls. This suggested that the enzyme activities of PON1 decreased in hemodialysis patients, independent of the genetic polymorphism. The decrease in PON1 enzyme activity in hemodialysis patients may modify a susceptibility to oxidization of LDL, which contributes to an acceleration of atherosclerosis.
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PMID:Serum paraoxonase and arylesterase activities in hemodialysis patients. 1148 Apr 56

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 enzyme paraoxonase (PON) can eliminate lipid peroxides and is believed to protect against low-density lipoprotein oxidation. A common polymorphism in the PON gene (PON1) causes an amino acid substitution of methionine (M) for leucine (L) at position 55 in the protein, which changes the activity of PON and can affect the risk of atherosclerosis. Because smoking is associated with increased lipid peroxidation, we studied the relationship between PON M/L55 polymorphism and the carotid artery intima-media thickness (IMT) in smokers or previous smokers (n = 112) and nonsmokers (n = 87). IMT was measured at 3 standardized segments by B-mode ultrasonography, and the overall mean IMT value of 199 randomly selected men (mean age 54.2 +/- 3.0 years) was calculated. Subjects with IMT > 1.7 mm in at least 1 standard site were considered to have carotid artery atherosclerotic disease (CAAD). For analysis, L55 homozygotes were compared with the M55 allele carriers. Nonsmoking L55 homozygotes had an 8.9% (95% confidence interval [CI], 1.6 to 16.8) higher overall mean IMT than M55 allele carriers. In smokers, however, the M55 allele carriers tended to have higher overall mean IMT values than L55 homozygotes. There was also a statistically significant interaction between M/L55 genotype and smoking status on CAAD (P =.009) by logistic regression analysis. Among nonsmokers, the L55 homozygotes had an odds ratio of 4.22 (95% CI, 1.06 to 16.8) for CAAD compared with nonsmoking M55 allele carriers. Contrary to nonsmokers, the smoking M55 allele carriers had an odds ratio of 2.22 (95% CI, 0.82 to 6.01) for CAAD when the L55/L55 genotype of smokers was a reference group. These data suggest that in nonsmoking men, a PON L55/L55 genotype may represent a genetic risk factor for CAAD. The reverse effect in smokers implies that the ability of PON to protect against CAAD is influenced by cigarette smoking. The efficiency of this inhibition probably depends on the PON M/L55 genotype.
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PMID:Relationship between high-density lipoprotein paraoxonase gene M/L55 polymorphism and carotid atherosclerosis differs in smoking and nonsmoking men. 1155 45

Human serum paraoxonase (PON1) hydrolyzes oxidized lipids in low density lipoprotein (LDL) and could therefore retard the development of atherosclerosis. In keeping with this hypothesis, several case-control studies have shown a relationship between the presence of coronary heart disease (CHD) and polymorphisms at amino acid positions 55 and 192 of PON1, which we associated with a decreased capacity of PON1 to protect LDL against the accumulation of lipid peroxides, but some other studies have not. However, the PON1 polymorphisms are only 1 factor in determining the activity and concentration of the enzyme. Only 3 of the previous 18 studies directly determined PON1 activity and concentration. Therefore, we studied PON1 activity, concentration, and gene distribution in 417 subjects with angiographically proven CHD and in 282 control subjects. We found that PON1 activity and concentration were significantly lower in subjects with CHD than in control subjects (activity to paraoxon 122.8 [3.3 to 802.8] versus 214.6 [26.3 to 620.8] nmol. min(-1). mL(-1), P<0.001; concentration 71.6 [11.4 to 489.3] versus 89.1 [16.8 to 527.4] microg/mL, P<0.001). There were no differences in the PON1-55 and -192 polymorphisms or clusterin concentration between patients with CHD and control subjects. These results indicate that lower PON1 activity and concentration and, therefore, the reduced ability to prevent LDL lipid peroxidation may be more important in determining the presence of CHD than paraoxonase genetic polymorphisms.
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PMID:Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? 1155 71

Little is known about the effects of oxidative stress on macrophage lipid peroxidation and on their atherogenic consequences. Therefore, we questioned the causal relationship between cellular lipid peroxides content and macrophage uptake of oxidized low-density lipoprotein (Ox-LDL). Lipid peroxide content in mouse peritoneal macrophages (MPMs) from E-deficient (E(0)) mice increased progressively by up to 4.6 fold during mice aging, and this was accompanied by an age-dependent increase in the cellular uptake of Ox-LDL (90%), and in the expression of the scavenger receptor CD36 mRNA (41%). Inhibition or stimulation of cellular oxidative stress by administration of dietary potent antioxidants (vitamin E or glabridin) or by inducing cellular glutathione depletion (by using buthionine sulfoximine), respectively, resulted in a significant increment or inhibition of macrophage uptake of Ox-LDL and in cellular CD36 mRNA expression, respectively. Intraperitoneal injection of human serum paraoxonase (PON1) into E(0) mice, resulted in a 40-65% decrement in the lipid peroxide content in MPM harvested from E(0) mice at 2-5 months of age, which subsequently resulted in a similar reduced uptake of Ox-LDL and expression of CD36 mRNA (by 30-40%). In conclusion, our results are the first to demonstrate that macrophage lipid peroxidation stimulates CD36 mRNA expression and enhances the cellular uptake of Ox-LDL.
Atherosclerosis 2002 Apr
PMID:Oxidative stress increases the expression of the CD36 scavenger receptor and the cellular uptake of oxidized low-density lipoprotein in macrophages from atherosclerotic mice: protective role of antioxidants and of paraoxonase. 1188 13

Oxidative modification of low-density lipoprotein in the artery wall plays a crucial role in the development of atherosclerosis. This physiopathological mechanism is clearly inhibited by high-density lipoprotein possibly via paraoxonase enzyme activity, present in high-density lipoprotein. In this study, we determined the in vitro susceptibility of low-density lipoprotein to oxidation and the effect of various factors, such as paraoxonase phenotypes, on this process. Low-density lipoprotein from healthy volunteers (n=66) was isolated using the precipitant reagent and the oxidation was evaluated by measuring the malonyl dialdehyde and diene levels. Low-density lipoprotein cholesterol and phospholipid, vitamin E, serum cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol levels, and erythrocyte antioxidant enzymes were also determined. There was no difference among the parameters with regard to gender. Low-density lipoprotein samples obtained from subjects with the AA allele were more prone to oxidation, as observed by their higher stimulated conjugated diene (P=0.041) and thiobarbituric acid-related substance (P=0.042) levels, than samples from subjects with AB or BB alleles. The subjects with the BB allele had higher superoxide dismutase (P=0.021) and catalase (insignificant increase) activities, while their conjugated diene (P=0.000) levels were lower. In conclusion, our results revealed that the high low-density lipoprotein oxidation is related to the high low-density lipoprotein cholesterol content and low phospholipid content. The present study demonstrated an increase in superoxide dismutase and catalase activities, as well as PON1 activities, in subjects with the BB allele. Since these enzymes all show activity against low-density lipoprotein oxidation, we propose that future investigations on atherosclerotic processes should address PON1 polymorphism as well as PON1 and other antioxidant enzymes.
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PMID:Antioxidant enzymes and paraoxonase show a co-activity in preserving low-density lipoprotein from oxidation. 1191 78

Human paraoxonase (PON1) is a calcium-dependent esterase exclusively bound to apolipoprotein A-I and clusterin, containing high-density lipoprotein (HDL) particles that hydrolyzes organophosphates and aryl esters. Several studies have indicated that PON1 can prevent low-density lipoprotein (LDL) oxidation by hydrolyzing lipid peroxides in the lipoprotein, which is the crucial first step for atherogenesis. Therefore it may protect against the development of atherosclerosis. Serum PON1 activity has been shown to be decreased in familiar hypercholesterolemia and in diseases that are associated with accelerated atherogenesis. The PON1 gene has two common coding region polymorphisms, Leu55-->Met and Gln192-->Arg. Both polymorphisms have been identified as independent risk factors for cardiovascular disease in diabetic and non-diabetic patients. We have established high-speed and easy-to-perform genotyping for the two most significant PON1 gene polymorphisms, employing the LightCycler technology and melting curves. This technique eliminates PCR contamination related to sample handling and does not require digestion of PCR products with restriction enzymes and/or fragment separation on gels.
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PMID:High-speed detection of the two common paraoxonase polymorphisms Leu55-->Met and Gln192-->Arg by real-time fluorescence PCR and melting curves. 1205 71

Human serum paraoxonase (PON1) is an HDL-associated enzyme involved in the protection of lipoproteins from oxidation. A polymorphism at position 192 (Gln/Arg) influences its activity in a substrate-dependent manner. The aim of the present study was to evaluate, in vivo, the contribution of the PON1-192 polymorphism to the protective effect of HDLs. Three hundred and forty seven subjects in the upper and lower decile of sex-specific HDL cholesterol distribution were selected from participants in a cardiovascular disease prevention study. PON1 genotypes were determined by PCR amplification and restriction analysis. Blood pressure, height, weight, smoking and alcohol habits, as well as the presence of familial or personal history of CHD were recorded. Plasma lipids and blood glucose were measured by routine enzymatic methods. As a measure of antiatherogenic HDL effect, carotid atherosclerosis was assessed by ultrasonography. Allele and genotype frequencies did not differ significantly between low- and high-HDL groups. Similarly, no significant difference was observed among genotypes in all variables studied. Subjects with Gln/Arg or Arg/Arg had more carotid abnormalities than Gln/Gln with an adjusted odds ratio (OR) of 3.27 (95% CI, 1.61-6.64, P=0.001) for abnormal carotid score. Stepwise logistic regression analysis showed that in the whole population age and presence of low-HDL were the only independent predictors for abnormal carotid score. In low-HDL, age was the only independent predictor entered into the model (OR 1.09/year, P<0.0001); in high-HDL, age entered first (OR, 1.07/year, P=0.001), followed by the presence of Gln/Arg or Arg/Arg (OR, 2.94, 95% CI, 1.47-5.91, P=0.002). In conclusion, in subjects with low levels of HDL cholesterol, carotid atherosclerosis is not related to PON1-192 polymorphism. On the other hand, in subjects with elevated concentration of HDL cholesterol, the presence of carotid atherosclerosis is significantly associated with the arginine variant in position 192 of the PON1 gene.
Atherosclerosis 2002 Oct
PMID:The Arg allele in position 192 of PON1 is associated with carotid atherosclerosis in subjects with elevated HDLs. 1220


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