Paraoxonase 1 Polymorphisms Research Articles

Paraoxonase 1 gene polymorphisms contribute to coronary artery disease risk among north Indians

Polymorphisms in paraoxonase 1 (PON1) coding for PON1 enzyme have been studied as genetic markers of coronary artery disease (CAD). PON1 Q192R and PON1 L55M polymorphisms have been analyzed extensively, but data on association and role of these polymorphisms in the etiology of CAD are conflicting. In this study, we tested the genetic association between PON1 Q192R and PON1 L55M polymorphisms and CAD among north Indians. Two hundred eighty-five angiographically proven patients with coronary artery disease and 200 sex-matched and ethnically matched controls were genotyped for 2 PON1 polymorphisms by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Genotype/ allele frequencies were compared in patients and controls using the chi-square test. At PON1-192 locus, there were significant differences between patients and controls (P< 0.05), leading to significant odds ratios for RR genotype (OR= 1.92, CI: 1.19-3.10) and *R allele (OR= 1.30, CI: 1.00-1.70). These odds ratios were higher in the sub-sample of smokers (2.84 and 1.45, respectively). Binary logistic regression analysis also confirmed that *R allele carriers (QR and RR) have a higher risk of CAD (OR= 3.54, CI: 1.67-5.53). PON1-55 locus did not show significant differences between patients and controls, but LL genotype and *L allele were significant risk factors in the nonsmoker group. RL haplotype was also significantly associated with CAD risk (OR= 1.44, CI: 1.08-1.93). PON1-192R allele and RR genotype are significantly associated with CAD patients from the north Indian population (Uttar Pradesh). This association was stronger in smokers, supporting the conclusion that an interaction between PON1 activity and smoking augments CAD risk. Further studies with larger sample size are warranted to confirm these associations in different Indian populations.

Paraoxonase activity against nerve gases measured by capillary electrophoresis and characterization of human serum paraoxonase (PON1) polymorphism in the coding region (Q192R)

An analytical method for determining paraoxonase activity against sarin, soman and VX was established. We used capillary electrophoresis to measure directly the hydrolysis products: alkyl methylphosphonates. After enzymatic reaction of human serum paraoxonase (PON1) with nerve gas, substrate was removed with dichloromethane, and alkyl methylphoshphonates were quantified by capillary electrophoresis of reversed osmotic flow using cationic detergent and sorbic acid. This method was applied to the characterization of human serum PON1 polymorphism for nerve gas hydrolytic activity in the coding region (Q192R). PON1-192 and PON1-55 genotypes were determined by their gel electrophoretic fragmentation pattern with restriction enzymes after polymerase chain reaction (PCR) of blood leukocyte genomic DNA. Frequencies of genotypes among 63 members of our institutes with PON1-192 and PON1-55 were 9.5% ( 192QQ), 30.1% ( 192QR) and 44.4% ( 192RR), and 82.5% ( 55LL), 17.5% ( 55LM) and 0% ( 55MM), respectively. 192Q and 192R enzymes were purified from the respective genotype human plasma, using blue agarose affinity chromatography and diethyl amino ethane (DEAE) anion exchange chromatography. V max and K m were measured using Lineweaver–Burk plots for hydrolytic activities against sarin, soman and VX at pH 7.4 and 25 °C. For sarin and soman, the V max for 192Q PON1 were 3.5- and 1.5-fold higher than those for 192R PON1; and k cat/K m for 192Q PON1 were 1.3- and 2.8-fold higher than those for 192R PON1. For VX, there was little difference in V max and k cat/K m between 192Q and 192R PON1, and VX hydrolyzing activity was significantly lower than those for sarin and soman. PON1 hydrolyzed sarin and soman more effectively than paraoxon.

360: Q192R polymorphism and activity of paraoxonase 1 in high cardiovascular risk subjects on hypolipidemic drugs

360: Q192R polymorphism and activity of paraoxonase 1 in high cardiovascular risk subjects on hypolipidemic drugs

EFFECT OF STATIN THERAPY ON PLASMA HIGH‐DENSITY LIPOPROTEIN–CHOLESTEROL LEVELS IS MODIFIED BY PARAOXONASE 1 IN CHINESE PATIENTS WITH CORONARY HEART DISEASE

1. We sought to determine the effects of Q192R polymorphism of paraoxonase 1 (PON1) gene on plasma high-density lipoprotein-cholesterol (HDL-C) levels and the response to statin therapy in Chinese patients with coronary heart disease (CHD). 2. Two hundred and thirty-six patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids were determined before and after 12 weeks of treatment. 3. No significant differences were detected among the PON1 Q192R polymorphism with respect to plasma lipids. In addition, the effects of simvastatin to increase HDL-C levels were significantly greater in patients with the RR genotype compared with patients with the QR or RR genotypes (P < 0.05). 4. We conclude that the Q192R polymorphism of PON1 significantly modulates the HDL-C response to simvastatin in Chinese patients with CHD.

Association Between p.Leu54Met Polymorphism at the Paraoxonase-1 Gene and Plantar Fascia Thickness in Young Subjects With Type 1 Diabetes

OBJECTIVE— In type 1 diabetes, plantar fascia, a collagen-rich tissue, is susceptible to glycation and oxidation. Paraoxonase-1 (PON1) is an HDL-bound antioxidant enzyme. PON1 polymorphisms have been associated with susceptibility to macro- and microvascular complications. We investigated the relationship between plantar fascia thickness (PFT) and PON1 gene variants, p.Leu54Met, p.Gln192Arg, and c.-107C>T, in type 1 diabetes.RESEARCH DESIGN AND METHODS—This was a cross-sectional study of 331 adolescents with type 1 diabetes (162 male and 169 female). PFT was assessed by ultrasound, PON1 was assessed by genotyping with PCR and restriction fragment–length polymorphism, and serum PON1 activity was assessed by rates of hydrolysis of paraoxon and phenylacetate.RESULTS—Median (interquartile range) age was 15.4 (13.5–17.3) years, and diabetes duration was 7.6 (4.9–10.6) years. The distribution of p.Leu54Met genotypes was LL 135 (40.8%), ML 149 (45%), and MM 47 (14.2%). PFT was abnormal (>1.7 mm) in 159 adolescents (48%). In multivariate analysis, predictors of abnormal PFT were ML/LL versus MM p.Leu54Met polymorphism (odds ratio 3.84 [95% CI 1.49–9.82], P = 0.005); BMI (percentile) (1.02 [1.01–1.03], P = 0.007); systolic blood pressure (percentile) (1.01 [1.00–1.02], P = 0.03); and male sex (3.29 [1.98–5.46], P < 0.001).CONCLUSIONS—Thickening of the plantar aponeurosis occurs predominantly in overweight and male adolescents with type 1 diabetes. The MM genotype at PON1 p.Leu54Met is associated with a reduced risk of abnormal PFT.

Relationship of Paraoxonase 1 (PON1) Gene Polymorphisms and Functional Activity With Systemic Oxidative Stress and Cardiovascular Risk

Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. The relationship between PON1 genotypes and functional activity with systemic measures of oxidative stress and cardiovascular disease (CVD) risk in humans has not been systematically investigated. To investigate the relationship of genetic and biochemical determinants of PON1 activity with systemic measures of oxidative stress and CVD risk in humans. The association between systemic PON1 activity measures and a functional polymorphism (Q192R) resulting in high PON1 activity with prevalent CVD and future major adverse cardiac events (myocardial infarction, stroke, or death) was evaluated in 1399 sequential consenting patients undergoing diagnostic coronary angiography between September 2002 and November 2003 at the Cleveland Clinic. Patients were followed up until December 2006. Systemic levels of multiple structurally defined fatty acid oxidation products were also measured by mass spectrometry in 150 age-, sex-, and race-matched patients and compared with regard to PON1 genotype and activity. Relationship between a functional PON1 polymorphism and PON1 activity with global indices of systemic oxidative stress and risk of CVD. The PON1 genotype demonstrated significant dose-dependent associations (QQ192 > QR192 > RR192) with decreased levels of serum PON1 activity and with increased levels of systemic indices of oxidative stress. Compared with participants with either the PON1 RR192 or QR192 genotype, participants with the QQ192 genotype demonstrated an increased risk of all-cause mortality (43/681 deaths [6.75%] in RR192 and QR192 and 62/584 deaths [11.1%] in QQ192; adjusted hazard ratio, 2.05; 95% confidence interval [CI], 1.32-3.18) and of major adverse cardiac events (88/681 events [13.6%] in RR192 and QR192 and 102/584 events [18.0%] in QQ192; adjusted hazard ratio, 1.48; 95% CI, 1.09-2.03; P = .01). The incidence of major adverse cardiac events was significantly lower in participants in the highest PON1 activity quartile (23/315 [7.3%]) and 235/324 [7.7%] for paraoxonase and arylesterase, respectively) compared with those in the lowest activity quartile (78/311 [25.1%] and 75/319 [23.5%]; P < .001 for paraoxonase and arylesterase, respectively). The adjusted hazard ratios for major adverse cardiac events between the highest and lowest PON1 activity quartiles were, for paraoxonase, 3.4 (95% CI, 2.1-5.5; P < .001) and for arylesterase, 2.9 (95% CI, 1.8-4.7; P < .001) and remained independent in multivariate analysis. This study provides direct evidence for a mechanistic link between genetic determinants and activity of PON1 with systemic oxidative stress and prospective cardiovascular risk, indicating a potential mechanism for the atheroprotective function of PON1.

Paraoxonase 1 (PON1) organophosphate hydrolysis is not reduced in ALS

Four recent studies report a genetic association of the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). We tested the hypothesis that this association correlates with functional changes in paraoxonase 1 (PON1, MIM 168820). Sera from 140 ALS participants; 153 age-, race-, and sex-matched controls; and 30 matched CSF samples were tested for paraoxonase, diazoxonase, and arylesterase activities. Participants with ALS were genotyped using tagging single nucleotide polymorphisms across the PON locus. Survival data and enzyme activity were correlated with genotype. There was a trend toward increased paraoxonase activity in ALS compared with controls (mean control paraoxonase 701.9 +/- 469.7 U/L, mean ALS 792.5 +/- 574.1 U/L; p = 0.066 after correction) which correlated with increased frequency of the homozygous arginine (RR) variant of PON1(Q192R) (p = 0.004). There was no significant difference in PON1 protein levels, or arylesterase or diazoxonase activities. Organophosphate hydrolysis rates had no effect on ALS survival. Contrary to expectations, PON1 protein, paraoxonase, diazoxonase, and arylesterase activities were not reduced in amyotrophic lateral sclerosis (ALS). The increase in PON1(R192) frequency in ALS in our study supports previous genetic susceptibility studies. Our findings suggest that the influence of PON1 polymorphisms on ALS susceptibility is not due to reduced organophosphate hydrolysis.

Paraoxonase 1, Oxidative Stress, and Atherosclerosis

Oxidative stress is an important factor in the development of atherosclerosis. Paraoxonase 1 (PON1), an enzyme associated with HDL, has been reported to have important antioxidant, anti-inflammatory, and cardioprotective actions, and the genetic deletion of PON1 is associated with increased atherosclerosis in animal models. Little is understood, however, about the relation between genetic polymorphisms of PON1 …

Study of the Relationship between Gene Polymorphisms of Paraoxonase 2 and Stroke in a Chinese Population

Background and Purpose: The paraoxonase (PON) gene family has been demonstrated to be capable of preventing lipid peroxidation and could consequently exert antiatherosclerotic effects. Alteration of enzyme activity due to polymorphisms in the PON genes may influence the development of atheroma and thus affect stroke risk. PON2, the second member of this family, has twopolymorphisms, C311S and G148A. Our study explores the relationship between the two polymorphisms of PON2 and stroke. Methods: 120 healthy individuals, 150 patients with primary cerebral hemorrhage and 180 patients with cerebral infarction were included in this study. The genotypes of PON2 were detected with polymerase chain reaction and digested by specific restriction enzymes. Results: C311S and G148A polymorphisms of PON2 exist in Chinese people, with the allele frequencies 0.273/0.727 for C/S and 0.567/0.433 for G/A. No significant differences were observed in genotype and allele frequency between stroke patients and controls (p > 0.05). Conclusions: There was no significant correlation between the two tested polymorphisms of PON2 and stroke in the Chinese population. Allele C/S and G/A might not be independent risk factors for stroke.

The paraoxonase gene polymorphism in stroke patients and lipid profile

The paraoxonase (PON) gene can reduce the risk of developing atherosclerosis. We investigated the associations between PON polymorphisms and ischemic stroke. We also investigated the associations between PON polymorphisms and lipid profile in stroke patients. A total of 350 patients with ischemic stroke and 242 control subjects in Korean population were genotyped for the PON1M55 L, PON1Q192R, PON2A148 G and PON2S311C polymorphisms using melting point analysis with LightCycler real-time polymerase chain reaction (PCR) technology. There were no significant differences in genotype and allele distribution of the PON polymorphisms between the ischemic stroke patients and control subjects. The concentration of total homocysteine was significantly different in the PON1M55 L polymorphism (P = 0.047), and the apolipoprotein (Apo)B concentration was significantly different in the PON1Q192R polymorphism (P = 0.02) in stroke patients. The concentrations of low-density lipoprotein (LDL) cholesterol and ApoB were significantly different between the PON2A148 G (P = 0.011, P = 0.000, respectively) and PON2S311C polymorphisms (P = 0.046, P = 0.003, respectively) in stroke patients. This study did not provide association between PON gene polymorphisms and ischemic stroke. However, it confirmed that the PON1L55 L allele is associated with plasma concentration of total homocysteine and that the PON2G148 G and PON2S311S allele is associated with plasma concentrations of LDL cholesterol and ApoB.

Paraoxonase Activity Polymorphism Relationships With Lipid Profiles in a Brazilian Population

ISEE-697 Objective: The purpose of this work was to describe PON1 activity in a group of Brazilian subjects, analyze its phenotype distribution, to compare PON1 activities between groups of subjects with different lipid profiles, to search for associations between these profiles and paraoxonase activity, and to investigate whether diet and lifestyle might affect this activity. Materials and Methods: Subjects groups included a total of 74 volunteers, age range of 18–60. Variables studied included basal and salt-stimulated PON1 activity, arylesterase activity, PON1 ratio (PON1 salt stimulated/arylesterase); serum cholesterol, HDL, LDL, VLDL, and triglycerides. Other variables such as energy consumption and nutrients intakes were assessed from a validated food consumption frequency questionnaire. Lifestyle variables were also assessed. Correlation analysis, T test, and ANOVA were used for statistical analysis. Results: Results showed a phenotype distribution of A (39.5%), AB (41.9%), and B phenotypes (18.6%). Significant associations between higher LDL levels, lower HDL levels, and PON1 B phenotype were observed. Paraoxonase B phenotype is known to have gene alleles that enhance risk to atherogenesis and associated diseases such as coronary heart disease. We also stratified groups setting recommended dietary intakes as cut off points. Using this approach, no associations were observed between PON1 activity and nutrient intakes. When groups were dichotomized using the first quartile of PON1 activity distribution as a cut-off, there were significant associations between higher levels of PON1 and higher intakes of total fat and cholesterol. Conclusions: PON1 activity may be an important biomarker to assess risk of diseases associated with individual lipid status and diet may also affect PON1 activity. Our results also point out the need of more studies concerning paraoxonase polymorphism since little is known about environmental interactions with PON1 gene polymorphism in the multiethnic Brazilian population.

Paraoxonase-1 (PON1) as a Predictor of Biochemical Outcomes in Farmers

Initially characterized for its ability to hydrolyze organophosphorus (OP) compounds, Paraoxonase- 1 (PON1) has been reported to play an important role in modulating the toxicity of some of these agents, which are “in vitro” substrates for this enzyme. The PON1 polymorphism at position 192 confers different enzyme levels and catalytic activity in a substrate-dependent manner, which has been related to the differential sensitivity of individuals to the toxic effects of OPs, supporting a role for the enzyme as a susceptibility biomarker. Several epidemiologic studies have examined the involvement of PON1 in xenobiotic susceptibility in different scenarios, including occupational exposure to pesticides. The major results of our studies performed in plastic greenhouses workers from Southeast Spain are presented herein. Briefly, PON1 is not only an individual marker of susceptibility, but also a biological indicator of exposure to pesticides, since workers spraying these agents, mainly OPs, showed decreased enzyme levels. On the other hand, carriers of the PON1 192R allele had lower levels of erythrocyte cholinesterase, a lower risk of presenting pesticide-related symptomatology, and less risk of reporting a previous episode of pesticide poisoning. Regarding enzymes involved in oxidative stress, carriers of the PON1 R allele had higher glutathione reductase and lower catalase activities. Intriguingly, PON1 R allele was found to be an independent predictor of higher aspartate aminotransferase and lower amino-oxidase and creatine kinase activities in serum. These findings deserve further attention as they highlight the important role of individual biomarkers of susceptibility on pesticideinduced biochemical changes in target organs that may precede the appearance of clinical changes. Keywords: Paraoxonase, cholinesterases, pesticides, biomarkers, occupational diseases

Synergistic Effects between Q192R Polymorphism of Paraoxonase 1 Gene and Some Conventional Risk Factors in Premature Coronary Artery Disease

Genetic susceptibility to coronary artery disease (CAD) may be determined by polymorphic variants of genes encoding isoforms involved in the processes important in the pathogenesis of atherosclerosis, including lipoprotein oxidation. Participation of single polymorphic variants is relatively small; however, its significance may increase in the presence of specific environmental background. The aim of the study was an evaluation of a possible association between R192Q polymorphism of PON1 gene and CAD as well as interactions between polymorphic variants and conventional risk factors of CAD in determining the risk of the disease. We studied 358 subjects: 178 patients with angiographically confirmed CAD and 180 blood donors without history of CAD. Polymorphisms were genotyped using PCR-RFLP method. We observed statistically significant differences in the frequencies of Q allele and Q allele carriers of PON1 gene between CAD and controls. We also found a strong synergistic effect between Q allele carrier state and smoking, as well as Q allele carrier state and elevated level of total cholesterol. The present study revealed an association between carrier state of Q allele of PON1 gene and coronary artery disease as well as synergistic effects between genotype and some conventional risk factors, mainly smoking and elevated level of total cholesterol.

Changes in antioxidant enzymes in humans with long-term exposure to pesticides

Different pesticides, including organophosphates (OPs), have been reported to induce oxidative stress due to generation of free radicals and alteration in antioxidant defence mechanisms. In this study, a cohort of 81 intensive agriculture workers (pesticide sprayers) was assessed twice during the course of a spraying season for changes in erythrocyte antioxidant enzymes. Acetylcholinesterase (AChE) was used as a reference biomarker. Sprayers presented lower levels of superoxide dismutase (SOD) and glutathione reductase (GR) as compared to controls independently of age, BMI, smoking habit or alcohol consumption. A positive correlation between SOD and AChE was observed at the high exposure period. Those individuals with a decrease in AChE greater than 15% exhibited lower SOD and catalase (CAT) activities at the same period. Glutathione peroxidase (GPx) and glucose-6-phosphate dehydrogenase (G6PDH) remained unaffected in the exposed population. Paraoxonase (PON1) polymorphism influenced erythrocyte CAT and GR, as subjects with the R allele presented lower CAT and higher GR levels. Whether or not the decreased enzyme activities found in this study are linked to the adverse health effects related to chronic pesticide toxicity (in which oxidative damage plays a pathophysiological role, such as cancer or neurodegenerative disorders) is an attractive hypothesis that warrants further investigation.

Paraoxonase 1 gene polymorphisms in patients with osteonecrosis of the femoral head with and without cerebral white matter lesions

Cerebral white matter lesions (WML) are present in more than 50% of patients with osteonecrosis of the femoral head (ONFH). Paraoxonase 1 (PON1) gene product is a detoxifying and pesticide metabolizing enzyme. Genetic variants of the PON1 gene have been found to influence the occurrence and progression of WML. We examined whether two PON1 polymorphisms (M55L and R192Q) are associated with ONFH and influence the occurrence of WML. We studied 104 patients with ONFH and 113 healthy age- and sex-matched subjects. We used logistic regression models to examine associations and survival analyses (Cox proportional hazards models) to examine possible influence of alleles on age at onset of ONFH. We found no association of PON1 M55L alleles and genotypes with ONFH. The distribution of PON1 Q192R alleles (p = 0.001) and genotypes (QQ vs. QR/RR) (p = 0.004) were statistically different between controls and patients. Patients with QQ genotype had six times higher risk for WML at brain MRI (adjusted OR 5.95; 95% CI 1.30-27.03; p = 0.02). In Cox models, there was a significant association of allele Q with risk for ONFH indicating a possible dose effect (HR = 1.43; 95%CI = 1.04-1.97; p for trend = 0.03). We conclude that individuals with PON1 192QQ genotype may have increased risk for ONFH and WMLeOn.

Paraoxonase (PON1) polymorphism and activity as the determinants of sensitivity to organophosphates in human subjects

Paraoxonase (PON1) plays an important role in mechanism of organophosphorus compound (OP) toxicity, as seen both in vitro and in vivo studies. Polymorphisms of PON1 gene at coding and promoter regions have also been to affect on the hydrolytic activity and PON1 level. The objectives of this study were to determine PON1 polymorphism and activity in an OP-exposed population and the effects on inhibition of cholinesterase activity. The studied population consisted of control ( n = 30) and exposed groups ( n = 90). All enzyme activities (AChE, BuChE, paraoxonase, arylesterase and diazonase) were measured once for control group and two periods of exposure for exposed group. Three polymorphisms of PON1 (Q192R, L55M and T−108C) were identified only in the exposed subjects. The results demonstrated that AChE activity in both high (345.5 μkat/gHb) and low exposure periods (496.9 μkat/gHb) of the exposed group were significantly different from control group (649.7 μkat/gHb, p < 0.01). For BuChE activity, the exposed group also showed the statistically lower level in both periods (high exposure period: 62.17 μkat/L and low exposure period: 81.84 μkat/L) than those in the control group (93.35 μkat/L). Serum paraoxonase activity was significantly different among individual genotypes, RR > QR > RR, LL > LM and −108CC > −108CT > −108TT, but this was not found for those of arylesterase and diazonase activities. Q192R and L55M as well as Q192R and T−108C also presented substantial linkage disequilibrium. Further analysis was performed with haplotypes and various enzyme activities. AChE activity was not affected by haplotypes. Individuals with “211” haplotype showed significantly higher paraoxonase activity and BuChE activity than other haplotypes but not in diazonase activity. In conclusion, PON1 gene exhibited a wide variation in enzyme activities both within and between genotypes which implied insights of a potentially difference in sensitivity to OP toxicity.

Effect of Paraoxonase 1 Polymorphisms on the Response of Lipids and Lipoprotein-associated Enzymes to Treatment with Fluvastatin

Decreased paraoxonase 1 (PON1) and increased total serum lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activities are suggested to be risk factors for vascular disease. Common PON1 genetic polymorphisms (Q192R and L55M) significantly affect PON1 activity and may also influence high-density lipoprotein (HDL)-associated Lp-PLA(2) activity. However, little is known about the possible effect of PON1 common genetic polymorphisms on the response of lipids as well as PON1 and Lp-PLA(2) activities to treatment with statins. Two hundred two hypercholesterolemic patients were treated with fluvastatin 40 mg/day. Fasting serum lipids, Q192R and L55M PON1 polymorphisms as well as PON1 and Lp-PLA(2) (total serum and HDL-associated) activities were determined before and after 6 months of treatment. Fluvastatin treatment did not affect HDL-cholesterol or apolipoprotein (apo) AI but resulted in significant decreases in total cholesterol, triglycerides, low-density lipoprotein-cholesterol, apo B and apo E, as well as total serum Lp-PLA(2) activity. In contrast, PON1 activity significantly increased. None of these changes was influenced by Q192R or L55M PON1 polymorphisms. Overall, HDL-Lp-PLA(2) did not change but L55M polymorphism significantly influenced its response to fluvastatin. Specifically, LL homozygotes experienced a significant increase, while M carriers (LM or MM) experienced a non-significant decrease in HDL-Lp-PLA(2) activity (p = 0.030 between groups). Q192R and L55M PON1 polymorphisms did not affect the response of lipids, PON1 and total serum Lp-PLA(2) to treatment with a statin. However, L55M PON1 polymorphism significantly modulated the response of HDL-Lp-PLA(2). It should be noted that this is an association study and therefore provides no proof but only indication that PON1 may also exert Lp-PLA(2) activity in HDL.

Effect of fenofibrate therapy on paraoxonase1 status in patients with low HDL-C levels

ObjectivesWe evaluated the effect of micro-coated fenofibrate on lipid parameters, high sensitivity C-reactive protein and paraoxonase1 levels in dyslipidemic patients with low high-density lipoproteins levels. In addition, the effects of the paraoxonase1 polymorphisms on lipid and paraoxonase1 responses to fenofibrate therapy were examined. MethodsA total of 61 dyslipidemic patients with low high-density lipoproteins levels were recruited into this study to receive micro-coated fenofibrate (160mg/day) for 12 weeks. Lipid parameters, C-reactive protein, paraoxonase1 concentration and activity were measured at baseline and after 6 and 12 weeks of fenofibrate treatment. Four polymorphisms in both the coding (L55M and Q192R) and regulatory regions (T-108C and G-909C) of human paraoxonase1 were also quantified. ResultsMicro-coated fenofibrate significantly decreased total cholesterol, triglycerides, non-high-density lipoprotein cholesterol, oxidized low-density lipoprotein and apolipoprotein-B levels after 6 and 12 weeks (all p<0.001). While high-density lipoprotein and apolipoprotein AI levels were significantly increased by 14.7% and 6.9%, respectively, after 6 weeks and by 17.3% and 7.2%, respectively, after 12 weeks (all p<0.01). There were no significant differences in the mean of low-density lipoprotein and C-reactive protein after fenofibrate treatment. There were significant increases in paraoxonase1 concentration and activity by 7.7% and 5.7% after 6 weeks and by 14.6% and 10.1% after 12 weeks, respectively (all p<0.01). After micro-coated fenofibrate therapy, a significantly positive correlation between the change in high-density lipoprotein and the changes in paraoxonase1 concentration and activity was observed (p=0.001). On the other hand, the changes in paraoxonase1 activity were significantly and negatively correlated with the changes in triglycerides (p=0.007). The therapeutic response of lipid parameters to micro-coated fenofibrate was independent of paraoxonase1 polymorphisms. However, paraoxonase1 Q192R and T-108C polymorphisms significantly affected the increase in paraoxonase1 activity (the highest increase in 192QQ and −108TT) and paraoxonase1 concentration (the highest increase in −108TT). ConclusionLipid-modifying therapy with micro-coated fenofibrate in patients with low high-density lipoprotein levels not only reduced atherogenic lipids (total cholesterol, triglycerides, oxidized low-density lipoprotein and apolipoprotein-B) and increased atheroprotective lipids but also increased paraoxonase1 concentration and activity. Increasing paraoxonase1 levels by fenofibrate may play an important role in decreasing low-density lipoprotein oxidation.

GST, CYP and PON1 polymorphisms in farmers attributing ill health to organophosphate-containing sheep dip

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83–2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88–2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74–3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85–2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92–3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72–10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.

A gene–environment study of the paraoxonase 1 gene and pesticides in amyotrophic lateral sclerosis

Sporadic amyotrophic lateral sclerosis (SALS) causes progressive muscle weakness because of the loss of motor neurons. SALS has been associated with exposure to environmental toxins, including pesticides and chemical warfare agents, many of which are organophosphates. The enzyme paraoxonase 1 (PON1) detoxifies organophosphates and the efficacy of this enzyme varies with polymorphisms in the PON1 gene. To determine if an impaired ability to break down organophosphates underlies some cases of SALS, we compared the frequencies of PON1 polymorphisms in SALS patients and controls and investigated gene–environment interactions with self-reported pesticide/herbicide exposure. The PON1 coding polymorphisms L55M, Q192R and I102V, and the promoter polymorphisms −909c > g, −832g > a, −162g > a and −108c > t, were genotyped in 143 SALS patients and 143 matched controls. Statistical comparisons were carried out at allele, genotype and haplotype levels. The PON1 promoter allele −108t, which reduces PON1 expression, was strongly associated with SALS. Overall, promoter haplotypes that decrease PON1 expression were associated with SALS, whereas haplotypes that increase expression were associated with controls. Coding polymorphisms did not correlate with SALS. Gene–environment interactions were identified at the allele level for some promoter SNPs and pesticide/herbicide exposure, but not at the genotype or haplotype level. In conclusion, some PON1 promoter polymorphisms may predispose to SALS, possibly by making motor neurons more susceptible to organophosphate-containing toxins.