Paraoxonase Gene Research Articles

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population.

BACKGROUNDFamilial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients.OBJECTIVETo investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients.DESIGNCase-control study.SETTINGTertiary care center, Riyadh.METHODSTwo hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis.MAIN OUTCOME MEASUREThe strength of association between the Q192R polymorphism and FH in the Saudi population.RESULTSWe confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05–3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13–3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09–2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population.CONCLUSIONIn conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH.LIMITATIONOnly a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

The genetic association between PON1 polymorphisms and osteonecrosis of femoral head: A case-control study.

The purpose of this study was to investigate the relationship between Paraoxonase-1 (PON1) gene rs662, rs854555 polymorphisms and osteonecrosis of the femoral head (ONFH) in Han population, northern China.Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of PON1 polymorphisms in 84 patients with ONFH and 96 healthy persons. χ2 test was used to compare distribution differences of genotype, allele, and haplotype between the case and control groups. The odds ratio (OR) and 95% confidence interval (CI) were calculated to reveal the effects of PON1 polymorphisms on risk of ONFH, and the results were adjusted using logistic regression analysis. The linkage disequilibrium and haplotype analysis were performed with haploview software.That people carrying AA genotype of rs662 were easier to be attacked by ONFH than GG genotype carriers (OR = 2.53, 95% CI = 1.05–6.07, P = .038). Meanwhile, the frequency of A allele in the case group was significantly higher than the controls and it was a risk factor for ONFH (OR = 1.56, 95% CI = 1.03–2.38, P = .038). The A-A haplotype frequency of rs854555-rs662 in PON1 was significantly correlated to the increased susceptibility to ONFH (OR = 2.74, 95% CI = 1.28–5.84).The rs662 polymorphism in PON1 may be associated with ONFH susceptibility, but not rs854555 in Han population, northern China. Additionally, haplotype is also a nonignorable risk factor.

A Meta-Analysis on the Relationship of the PON Genes and Alzheimer Disease.

This study aimed to evaluate the association of the paraoxonase (PON) gene variants and Alzheimer disease (AD) using meta-analysis. Relevant studies were identified by searching English and Chinese databases extensively. Allele and genotype frequencies for each included study were extracted. Newcastle-Ottawa Scale (NOS) was employed to assess the quality of included studies. The odds ratio (OR) with 95% confidence interval (95% CI) was calculated using a random-effects or fixed-effects model. A Q statistic was used to evaluate homogeneity, and Egger test and funnel plot were used to assess publication bias. A total of 15 studies (involving 5 polymorphisms) were included and identified for the current meta-analysis. The NOS scores ranged from 7 to 8, meaning good quality of studies. It was found that the SS genotype of PON2 S311C polymorphism had an significant association with AD in the studied population (OR = 0.82, 95% CI: 0.68-0.99, P = .04), and the A allele of PON1 rs705379 polymorphism was positively related to AD in Caucasian population (OR = 1.21, 95% CI: 1.05-1.39, P = .009) as well as the GG genotype decreased AD risk significantly in Caucasians (OR = 0.7, 95% CI: 0.56-0.88, P = .002). However, there was no significant relationship between other 3 genetic variants of PON genes (L55 M, Q192 R, and -161C/T of PON1 gene) and AD. Existing evidence indicates that the S311C polymorphism (SS genotype) and the rs705379 (the A allele and GG genotype) are associated with risk of AD in studied population. Future studies with larger sample sizes will be necessary to confirm the present results.

Effects of PON1 Gene Promoter DNA Methylation and Genetic Variations on the Clinical Outcomes of Dual Antiplatelet Therapy for PatientsUndergoing Percutaneous Coronary Intervention.

The relationship between either paraoxonase 1 (PON1) gene promoter DNA methylation or geneticvariations and bleeding or major adverse cardiac events after dual antiplatelet therapy has been incompletely characterized.We aimed to systematically investigate the role of geneticvariations and DNA methylation of the PON1 CpG island promoter on the clinical outcomes of dual antiplatelet therapy for patients with coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI). This study included 653 patients with CAD undergoing PCI and receiving dual antiplatelet therapy. Genomic DNAs were isolated from whole blood and were genotyped for the three single nucleotide polymorphisms (SNPs) of the PON1gene. The DNA methylation levels in the PON1 promoter region were determined by bisulfite sequencing or pyrosequencing at five CpG sites (positions -142, -161, -163, -170, and -184 from the transcription start site). Clopidogrel and its metabolites in plasma were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and platelet function analysis was performed using the VerifyNow assay. Statistically significant associations between methylation levels at five PON1 CpG sites and bleeding were observed: -184 [odds ratio (OR) 0.98, 95% confidence interval (CI) 0.96-1.00, p=0.028]; -170 (OR 0.99, 95% CI 0.97-1.00, p=0.048); -163 (OR 0.98, 95% CI 0.96-1.00, p=0.029); -161 (OR 0.98, 95% CI 0.97-1.00, p=0.026); and -142 (OR 0.98, 95% CI 0.97-1.00, p=0.042) at a false discovery rate of <5%. Statistical analysis also revealed that aspirin reaction units (ARUs) were significantly associated with PON1 methylation level at CpG site -163 (p=0.0342). The ARUs of patients with the PON1 126 CC genotype was 527±94, which was higher than the ARUs (473±89) of patients with the 126 CG genotype (p=0.0163). Multivariate logistic regression analysis indicated that the PON1 methylation level at CpG site -161 (OR 0.95, 95% CI 0.92-0.98, p=0.002) and the use of angiotensin-converting enzyme inhibitors (OR 0.48, 95% CI 0.26-0.89, p=0.021) were associated with a decreased risk of bleeding events. Hypomethylation of CpGs in the PON1 promoter may be a weak, albeit statistically significant, risk factor of bleeding after dual antiplatelet therapy. Further large-scale studies are needed to verify our results.

Association between promoter polymorphism (− 108C > T) of paraoxonase1 gene and it's paraoxonase activity in patients with Type2 diabetes in northern Iran

Type 2 diabetes mellitus (T2DM) is one of the diseases which depend on the obesity associated with insulin resistance. Various factors, such as a reduction in the activity of paraoxonase-1 enzyme (PON1), could affect T2DM. PON1 is a multifunctional enzyme with paraoxonase and arylesterase activities. The Activity of PON1 is influenced by various SNPs. The aim of presence study is to investigate the association between promoter polymorphism (−108C>T) of PON1 gene and its paraoxonase activity in patients suffering from Type 2 diabetes in Golestan Province, north of Iran. To this end, genomic DNA was extracted from whole blood then genotyping was carried out using PCR-RFLP and enzymatic activity of paraoxonase was measured in the serum of 90 healthy subjects and 90 diabetic patients. Data was analyzed using SPSS version 16. The relationship between the level of paraoxonase activity with polymorphisms of CC, CT, and TT was statistically significant in patients with T2DM. There was a significant association between polymorphism C-108>T of PON1 and type2 diabetes mellitus, with 24.4% of control group subjects and 15.5% of patients having CC genotype; p<0.05. The ratio for CT genotype in target and control groups was 51.1% and 61.1% respectively; p<0.05. TT genotype was 33.3% in patients and 14.4% in the control group; p<0.05. In the present study, the highest frequency belonged to CT genotype in both the control and the target groups, followed by CC genotype in control group and TT genotype in target group. Our findings revealed that paraoxonase activity of PON1 in the control group was significantly higher in comparison with diabetic patients.

Evaluation of Genetic and Biochemical Factors in Patients with Acute Coronary Syndrome

Introduction: The cardiovascular diseases are the principal cause of death worldwide and a public health problem in Colombia. From the cardiac related illnesses, the most frequent is the Acute Coronary Syndrome (ACS). One of its risk factor is high plasma levels of homocysteine. The enzyme Paraoxonase 1 (PON1) hydrolyzes Homocysteine-thiolactone, producing homocysteine, avoiding damage to endothelium related to Homocysteine-thiolactone. Two genetic variants in PON1 gene have been associated with levels of homocysteine and acute coronary syndrome. Objective: to determine the relationship between the polymorphisms Q192R and L55M from gene PON1 and the levels of homocysteine, HDL, apo A-1 and the enzymatic activity of Paraoxonase I in patients who suffered acute coronary syndrome. Methods: sixteen unrelated patients with Acute Coronary Syndrome (ACS) and sixteen healthy controls were enrolled. The paraoxonase activity, levels of homocysteine, HDL and apo A-1 were assessed. The DNA polymorphism analysis was performed using Polymerase Chain Reaction (PCR) and digestion with restriction enzymes. Results: levels of homocysteine are higher in cases (p&amp;lt;0.0001) and the genotypes 192RR and QR are associated with higher levels of homocysteine (p=0.0234). Conclusion: polymorphisms in &lt;em&gt;PON1&lt;/em&gt; gene could be related to homocysteine levels in Acute Coronary Syndrome patients.

A pilot study assessing the association between paraoxonase 1 gene polymorphism and prostate cancer.

We aimed to show the relationship between paraoxonase 1 (PON1) gene polymorphism and the development of prostate cancer (PCa). We investigated the association of single nuclotide polymorphisms of PON1 enzyme with the development of PCa risk. A total of 147 male patients were divided into PCa, and control groups. The control group was also divided into two subgroups according to serum prostate specific antigen (PSA) levels as non PCa-high PSA (>4 ng/mL) and non PCa-low PSA (≤4 ng/mL) groups. The mean ages of the patients were 64.81 years, 63.27 years and 64.22 years in PCa group, non PCa-low PSA and non PCa -high PSA groups, respectively. The mean PSA levels were 10.9 ng/mL, 1.16 ng/mL and 6.63 ng/mL for PCa group, non PCa -low PSA and non PCa -high PSA groups, respectively. In terms of PON1 polymorphisms and allele frequencies, there were no statistically significant differences between PCa and control groups. There was not a statistically significant difference between PCa and non PCa-high PSA groups as for genotypic and allelic frequencies. As a result of this small sample sized hypothetical study of polymorphism, a relationship could not be detected between PCa development and PON1 gene polymorphism. According to the results of this preliminary study, it is thought that more comprehensive future studies are necessary to clarify the possible role of PON1 gene polymorphism in the etiology of PCa.

AB096. Paraoxonase 1 (PON1) Q192R gene polymorphism and cancer risk: a meta-analysis based on 30 publications

BackgroundTo elucidate the association of genetic variation Q192R in the PON1 gene and tumor development.MethodsWe performed a meta-analysis for 8,112 cases and 10,037 controls from 32 published case-control studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association by STATA 12.0 software.ResultsThe results showed that PON1-192R allele was associated with a decreased risk in breast cancer, and prostate cancer in homozygote and recessive models.ConclusionsPON1 Q192R polymorphism was associated with a reduced risk of the overall cancers, nevertheless, it might increase cancer susceptibility of prostate and lymphoma risk.

A non-synonymous single nucleotide polymorphism in the paraoxonase 3 gene regulates meat quality in Berkshire pigs

The paraoxonase (Pon) gene family contains three members: Pon1, Pon2, and Pon3. Pon3 modulates superoxide production and prevents apoptosis. The role of Pon3 has not been fully elucidated in the pig. This study is the first to investigate the association between Pon3 and meat quality in the Berkshire pig. We identified a single nucleotide polymorphism in the Pon3 gene (c.227A &gt; G) that resulted in a change in histidine to arginine at position 76. To elucidate the role of this non-synonymous single nucleotide polymorphism in the Pon3 gene, we analysed the Pon3 genotype and meat quality traits in 434 Berkshire pigs. The results of a codominant model show that carcass weight, meat colour (lightness), cooking loss, and the Warner–Bratzler shear force were significantly associated with the Pon3 genotype. Furthermore, the 24-h post-mortem pH had the strongest relationship with the Pon3 genotype. The G allele decreased cooking loss and fat content, whereas the A allele increased the 24-h post-mortem pH and decreased backfat thickness, which contribute to meat storage life and M. longissimus dorsi depth respectively. In conclusion, the non-synonymous single nucleotide polymorphism in the Pon3 gene showed a close correlation with meat quality traits in the Berkshire pig.

Paraoxonases and psoriasis: negative imbalance of antioxidant endogenous mechanisms.

Numerous reports have shown that psoriasis patients are more exposed to lipoprotein peroxidation and to a decrease in the activity of paraoxonase (PON)1, an antioxidant and anti-inflammatory enzyme. Thus, it has been suggested that malfunction of the antioxidant system and an increased production of reactive oxygen species drive immune inflammatory events, that result in progressive skin cell damage in patients with psoriasis. The PON protein family, including PON1, PON2 and PON3, is one of the most important endogenous defense mechanisms against oxidative stress. In the present study, we investigated PON gene expression in psoriasis and in cutaneous oxidative stress. The study population included 10 patients affected by moderate-to-severe plaque psoriasis and 15 healthy donors who have undergone to plastic surgery, were used as control. Skin punch biopsies of lesional and non lesional psoriatic skin were performed for analysis of PON2 and PON3 gene expression. In addition, oxidation assays in ex vivo full-thickness healthy skin organ cultures were performed. No significant differences were observed between PON2 and PON3 gene expression in psoriatic lesional and non lesional skin compared with healthy controls. H2O2 treatment induced a significant decrease of PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures; conversely the pretreatment of samples with the antioxidant reagent N-acetyl-L-cysteine (NAC) induced a significant increase. Interestingly, no significant alterations were reported for PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures stimulated with IL-17. Taken together our findings have revealed that a strong pro-oxidative activity is not effectively countered by antioxidant endogenous mechanisms both in psoriatic skin and in ex vivo experimental model.

Paraoxonase-1 (PON1) induces metastatic potential and apoptosis escape via its antioxidative function in lung cancer cells.

Paraoxonase-1 (PON1) gene polymorphisms have been closely associated with the development of advanced cancers while PON1 secretion to the serum is linked with inhibition of oxidized high-density lipoprotein by its antioxidative function. Our group previously demonstrated that post-translational modification of serum PON1 in form of fucosylated PON1 is a potential biomarker of small cell lung cancer. Here, we interrogated the role of PON1 in the pathobiology of lung cancer (LC) by addressing cell-autonomous mechanisms using gain-of-function and loss-of-function approaches and protein expression profiling of tissue samples in our clinical biobank. PON1 expression in LC patient tissues varied between overexpression in squamous cell carcinoma and minimal loss in adenocarcinoma sub-types. Simultaneous overexpression of PON1 both at the gene and protein stability levels induced pro-oncogenic characteristics in LC cells and xenografts. PON1 overexpression supported metastatic progression of LC by decreasing G1/S ratio and LC cell senescence involving p21Waf1/Cip1. PON1 suppressed drug- and ligand-induced cell death and protected LC cells from genotoxic damages with maintained ATP levels, requiring p53-directed signals. PON1 promoted ROS deregulation protecting the mitochondria from dysregulation. PON1 knockdown resulted in the blockage of its antioxidant function in LC cells through Akt signaling with reduced invasive signature as a consequence of scant expression. Targeted glycolysis stimulated PON1 antioxidant activity regulating phosphorylation of AMPK-α. The functional data imply that exploitation of the antioxidative function of PON1 is consequential in driving LC pathogenesis at the cell-autonomous mechanistic level with consequences on tumor growth.

Study of the relationship between APOA-II −265T>C polymorphism and HDL function in response to weight loss in overweight and obese type 2 diabetic patients

It has been reported that people may respond differently to the same environmental changes because of genome variations. The main purpose of the present study is to determine gene-diet interactions between-265T>C apolipoprotein A-II polymorphisms and evaluate the effect of weight loss on parameters related to HDL function. In the present study, 56 overweight and obese type 2 diabetic patients were chosen from 697 genotype-specified subjects. After matching for gender, age and BMI, an equal number of patients were chosen for each genotype of APOA-II (TT/TC and CC group). After six-week calorie restriction programme, 44 patients completed the study. Serum paraoxonase-1 (PON1), paraoxonase-3 (PON3), pentraxin-3 (PTX3), and PTX3 gene expression in peripheral blood mononuclear cells were compared between two genotypes and also before and after the intervention separated in each genotype. The mean differences of PON enzymes and PTX3 between groups were not significant at the baseline. After weight loss, the mean weight, BMI and serum concentration of PON1 and PON3 decreased significantly and PTX3 increased in total population. Although, the mean differences of PON enzymes and PTX3 between two groups were not significant. However, in comparison of mean differences within the groups, decreased PON3 and increased PTX3 have been observed only in TT group. A comparison of the mean differences in PON3 and PTX3 within two genotype groups showed that T allele carriers are more sensitive to lifestyle modification, and serum PON3 and PTX3 levels significantly changed only in the TT/TC group.

Interaction between prenatal pesticide exposure and a common polymorphism in the PON1 gene on DNA methylation in genes associated with cardio-metabolic disease risk\u2014an exploratory\xa0study

BackgroundPrenatal environmental conditions may influence disease risk in later life. We previously found a gene-environment interaction between the paraoxonase 1 (PON1) Q192R genotype and prenatal pesticide exposure leading to an adverse cardio-metabolic risk profile at school age. However, the molecular mechanisms involved have not yet been resolved. It was hypothesized that epigenetics might be involved. The aim of the present study was therefore to investigate whether DNA methylation patterns in blood cells were related to prenatal pesticide exposure level, PON1 Q192R genotype, and associated metabolic effects observed in the children.MethodsWhole blood DNA methylation patterns in 48 children (6–11 years of age), whose mothers were occupationally unexposed or exposed to pesticides early in pregnancy, were determined by Illumina 450 K methylation arrays.ResultsA specific methylation profile was observed in prenatally pesticide exposed children carrying the PON1 192R-allele. Differentially methylated genes were enriched in several neuroendocrine signaling pathways including dopamine-DARPP32 feedback (appetite, reward pathways), corticotrophin releasing hormone signaling, nNOS, neuregulin signaling, mTOR signaling, and type II diabetes mellitus signaling. Furthermore, we were able to identify possible candidate genes which mediated the associations between pesticide exposure and increased leptin level, body fat percentage, and difference in BMI Z score between birth and school age.ConclusionsDNA methylation may be an underlying mechanism explaining an adverse cardio-metabolic health profile in children carrying the PON1 192R-allele and prenatally exposed to pesticides.

Plasma Metabolome, PON1 Status, Environmental Exposures and Childhood Autism

BackgroundFew studies have examined Autism Spectrum Disorder (ASD) and the interplay between genetics and environmental factors. The paraoxonase 1 (PON1) gene regulates the breakdown of organophosphate (OP) pesticides in the body and serves as an important antioxidant. PON1 levels may be affected by single nucleotide polymorphisms (SNPs), therefore individuals with certain PON1 SNPs plus environmental exposure during pregnancy may be at an increased risk for having a child with autism.ObjectiveThe objective of this study was to examine a possible gene‐environment interaction that focuses on prenatal environmental exposures and child metabolic vulnerability as a consequence of polymorphisms in the PON1 gene.MethodsAll children (n=400) in the present study including children with Autism Spectrum Disorder (ASD; n=200), and typically developed control children (TD; n=200) are part of a large ongoing population based case‐control CHARGE (CHildhood Autism Risk from Genetics and Environment) Study. Blood plasma metabolome profiles were obtained by Nuclear Magnetic Resonance (NMR) spectroscopy. Untargeted metabolomics analysis using Chemomx NMR Suite 8.1 was used to identify and quantify 69 metabolites in each sample including amino acids, organic acids, sugars and other compounds. The concentration of PON1 was determined by ELISA kits (Cloud‐Clone Corp), and paraoxonase activity was measured using commercially available assay kits (Molecular Probes Inc.). SNP data and environmental exposure data were previously collected in the CHARGE Study.ResultsChildren with ASD had higher levels of lactate, a metabolic waste product, and higher levels of the amino acids: alanine, serine, glycine, and tryptophan, consistent with mitochondrial dysfunction, and altered energy metabolism. In addition, ASD was associated with higher levels of uridine, a component of RNA previously reported to be inversely correlated with methylation capacity. Although we did not find a significant difference in the PON1 concentration and paraoxonase activity of children with ASD compared to controls, we did find that PON1 SNPs in coding and non‐coding regions significantly affected its plasma concentrations. Moreover, there were a disproportionate number of children with ASD and specific PON1 SNPs that correlated with maternal organophosphate exposures.ConclusionOur results add to the growing body of literature indicating autism is associated with an altered metabolic state compared to typically developed controls. These results suggest that maternal environmental exposures during pregnancy in combination with genetics may impact a child's metabolic outcome. Further studies are needed to understand how the metabolome affects neurodevelopmental outcome, or conversely if neurodevelopmental outcome affects the metabolome.Support or Funding InformationThis study was funded by the NIH 1P30 ESO23513‐01A1 pilot grant, the Administrative Supplement to the CHARGE Study R01 ES015359, and the USDA National Institute of Food and Agriculture Hatch Project 1005945.

Ocular distribution of antioxidant enzyme paraoxonase & its alteration in cataractous lens & diabetic retina.

Background & objectives:The enzyme paraoxonase (PON), an antioxidant enzyme that has both arylesterase and thiolactonase activity, is well studied in cardiovascular diseases. Although a few studies have shown altered PON activity in ocular diseases such as age-related macular degeneration and diabetic retinopathy, but the tissue-wise expression of PON in its three gene forms has not been studied. This study was conducted to see the ocular distribution of PON for any altered expression in ocular pathologies such as in cataract and diabetes mellitus.Methods:Immunohistochemistry (IHC) of the ocular tissues was done for localizing all three forms of the PON in the human donor eyeballs. The PON arylesterase (PON-AREase) and thiolactonase (PON-HCTLase) activities were determined by spectrophotometry in kinetic mode, and the mRNA expression of the PON genes (PON1-3) was determined by reverse transcription-polymerase chain reaction.Results:IHC showed the presence of both PON1 and 2 in all the ocular tissues and PON3 was seen only in retina. The mRNA expression analysis showed that PON2 and PON3 were present in all the tissues, whereas PON1 was seen only in ciliary and retina. Both the PON-AREase and PON-HCTLase activities were detected in all ocular tissues and was in the order of lens>retina>choroid>ciliary body>iris. The expression and activity were studied in cataractous lens and in diabetic retina of the donor eyes. A significant decrease in PON-AREase activity was seen in cataractous lens (P<0.05) but not in diabetic retina, and there was an increase in PON- HCTLase activity (P<0.05) only in diabetic retina. Bioinformatic studies and in vitro experiments indicated that advanced glycation end products (AGE) such as carboxymethyl -lysine might decrease the PON- AREase activity of the PON.Interpretation & conclusions:Distribution of PON enzyme and its activity in ocular tissues is reported here. The study revealed maximal PON activity in lens and retina, which are prone to higher oxidative stress. Differential activities of PON were observed in the lens and retinal tissues from cataractous and diabetic patients, respectively.

The Q192R polymorphism of the paraoxonase-1 (PON1) gene is associated with susceptibility to gestational diabetes mellitus in the Greek population

A key factor protecting from oxidative stress in gestational diabetes mellitus (GDM) and in type 2 diabetes (T2D) is paraoxonase-1 (PON1). Inconclusive and limited data exist regarding the effect of a coding polymorphism (Q192R) of the PON1 gene in conferring susceptibility to both states. In the present study, we investigated the association between the PON1 gene and the risk for GDM in the Greek population and assessed for the first time its transcriptional efficiency. We studied 185 women with GDM and 104 non-diabetic controls for the PON1 polymorphism. For PON1 mRNA expression, peripheral leucocytes were harvested from 20 GDM and 20 control women, harboring different genotypes for the polymorphism, using real-time quantitative PCR. The RR genotype and the R allele of the PON1 Q192R polymorphism were significantly associated with an increased risk for GDM (p = 0.012 and p < 0.0001, respectively). Furthermore, there was no statistical correlation between the individual metabolic parameters tested and the three genotypes. Finally, the expression levels of PON1 mRNA in GDM patients did not exhibit any statistical difference compared with normal controls (p = 0.138). These data independently document that the Q192R polymorphism is closely associated with GDM susceptibility, while the PON1 gene expression is not impaired in GDM.

Investigation of paraoxonase 1 activity of the workers at the plant, who have long-term contact with organophosphorus compounds

Background. Liver enzyme paraoxonase 1 (PON1) plays an important role in protection the organism from toxic effects of organophosphorus compounds (OPs) via their hydrolysis whose rate and efficiency depend on PON1 serum level activity. PON1 activity is largely determined by the polymorphic variants of the PON1 gene. Effect of long-term work with exposure to the toxic OPs on the PON1 activity is almost unknown. The aim of the present work was to study the effect of long-term work with exposure to the toxic OPs on PON1 serum enzymatic activity depending on polymorphisms Q191R, L54M, C(-108)T PON1 gene. Materials and methods. PON1 serum enzymatic activity and PON1 polymorphisms were determined in men, who were categorized in 2 groups: workers of companies providing storage and disposal of the OPs (68) and control group (37). The PON1 191, PON1 55 and PON1 108 polymorphisms were studied by polymerase chain reaction/restriction fragment length polymorphism. PON1 serum enzymatic activity was measured by a spectrophotometric method using paraoxon. Results. PON1 activity in workers with exposure to the toxic OPs relative was increased compared to the control group (p = 0,027). Differences in serum PON1 activity was shown for the carriers of certain genotypes of the PON1 gene: PON1 serum activity was higher in workers compared to controls only for LL genotype (L54M polymorphism) and C allele (C(-108)T polymorphism) carriers (p 0,001 and p = 0,002, correspondently). Conclusion. We suggest that the increase in serum PON1 activity in workers providing storage and disposal of OPs could be modulated with the polymorphic variants of the PON1 gene.

Paraoxonase: The Universal Factor of Antioxidant Defense in Human Body

The paraoxonase (PON) gene family includes three members: PON1, PON2, and PON3 aligned in tandem on chromosome 7 in humans. All PON proteins share considerable structural homology and have the capacity to protect cells from oxidative stress; therefore, they have been implicated in the pathogenesis of several inflammatory diseases, particularly atherosclerosis. Increased production of reactive oxygen species as a result of decreased activities of mitochondrial electron transport chain complexes plays a role in the development of many inflammatory diseases, including atherosclerosis. PON1 and PON3 proteins can be detected in plasma and reside in the high-density lipoprotein fraction and protect against oxidative stress by hydrolyzing certain oxidized lipids in lipoproteins, macrophages, and atherosclerotic lesions. Paraoxonase 2 (PON2) possesses antiatherogenic properties and is associated with lower ROS levels. PON2 is involved in the antioxidative and anti-inflammatory response in intestinal epithelial cells. In contrast to PON1 and PON3, PON2 is cell-associated and is not found in plasma. It is widely expressed in a variety of tissues, including the kidney, and protects against cellular oxidative stress. Overexpression of PON2 reduces oxidative status, prevents apoptosis in vascular endothelial cells, and inhibits cell-mediated low density lipoprotein oxidation. PON2 also inhibits the development of atherosclerosis, via mechanisms involving the reduction of oxidative stress. In this review we explore the physiological roles of PON in disease development and modulation of PONs by infective (bacterial, viral) agents.

Association between paraoxonase-1 gene Q192R and L55M polymorphisms in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS) in a population from Cairo of Egypt.

Paraoxonase-1 (PON1) is involved in the oxidative stress process that cause tissue damage observed in systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS). The aim of the present study was to investigate the association of PON1 Q192R and L55M polymorphisms with risk of SLE and associated APS among Egyptian sample. The study included 120 SLE patients (45 without APS and 75 with APS) and 120 healthy subjects. PON1 Q192R and L55M polymorphisms were genotyped by real-time PCR. No significant differences in Q192R genotypes or allele frequencies were found between patients and controls (p=0.5 and 0.1, respectively). The frequency of the 55M allele was significantly higher in SLE patients than in controls (66.6 vs. 43.3%), while the 55L allele was more frequent in controls (56.6%) than in patients (33.3%) (p=0.03). The LL genotype was more frequent in controls (21.6%) than in patients (10%) while M allele carrier genotypes (LM+MM) were more frequent among patients (90%) than controls (78.3%), p=0.04. Also, the 55M allele was more frequent in APS patients (73.3%) than in patients without APS (55.6%), p=0.004. M allele carrier genotypes (LM+MM) was significantly higher among APS patients (95.4%) than in non-APS patients (80%), p=0.008. Our results indicated that the PON1 L55M polymorphism associated with SLE and associated APS in a population from Cairo of Egypt, while the Q192R polymorphism plays no role in disease susceptibility. A large scale study to assess PON1 polymorphisms, PON1 activity, and markers of oxidative stress interaction is needed to clarify the role of PON-1 polymorphisms in the pathogenesis of SLE and associated APS.

CYP/PON genetic variations as determinant of organophosphate pesticides toxicity.

In the present scenario of increased accumulation of pesticides in the environment, it is important to understand its impact on human health. The focus is on gene-environment interaction, highlighting the consequences and factors that may halt the biotransformation of some pesticides and change their actual dose response curve due to mixed exposure to pesticides. The paraoxonase and cytochrome P450 gene families are involved in the metabolism of oxon derivate (toxic than its parent compound) of organophosphate pesticides, thus, mutations in these genes may impact the metabolic outcome of pesticides and subsequent health hazards. The complex multi gene-environment interaction and one gene - one risk factor are two different aspects to understand the potential health effect related to environmental exposure studies. The genetic polymorphisms are associated with varying levels of risk within the population, as gene products of varied genotype alter the biotransformation of exogenous/endogenous substrates. This paper is aimed to review the impact of endogenous and exogenous factors on a mechanistic pathway of organophosphate pesticide biotransformation and various risk associated with it among the human population. Understanding the genetic polymorphism of genes involved in pesticide metabolism and highlighting the gene isoform dependent interindividual differences to metabolize particular pesticides may help us to unravel the reasons behind differential toxicity for pesticides exposure than expected.