Paraoxonase Gene Research Articles

Lactonase activity and status of paraoxonase 1 in Chinese women with polycystic ovarian syndrome.

To study the relationship between the lactonase activities and status of paraoxonase 1 (PON1) and its association with the PON1 genetic polymorphisms in women with polycystic ovarian syndrome (PCOS). A case-control study. A total of 455 PCOS patients and 441 control women were included in this study. The lactonase activities and concentrations of PON1 were assayed using 5-thiobutyl butyrolactone (TBBL) and 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase:DEPCyMCase activity. The PON1 genotypes, serum malondialdehyde (MDA) levels and total antioxidant capacity were analyzed. The lactonase activities and levels of PON1 were higher in PCOS patients than in the control women. However, the NLA did not significantly differ between groups. The -108C→T variation of the PON1 gene showed decreased lactonase activities and levels of PON1 in a genotype-dependent manner (CC>CT>TT); the 192Q→R variation of the PON1 gene showed increased PON1 lactonase activities and NLA; and the 55L→M variation of the PON1 gene showed decreased lactonase activities and levels of PON1 but an increased NLA. A multivariable regression analysis showed that the -108C/T, 192Q/R, and 55L/M variations of the PON1 gene, serum apolipoprotein A1, and MDA levels were significant predictors of PON1 lactonase activity, PON1 level, and NLA. The serum lactonase activities and concentrations of PON1 are increased in PCOS patients. The increased oxidative stress and the -108C/T, 192Q/R, and 55L/M genetic polymorphisms of PON1 may be associated with these changes.

Addressing the link between paraoxonase-1 gene variants and the incidence of early onset myocardial infarction.

IntroductionThe enzyme paraoxonase-1 (PON1) represents an endogenous defense mechanism against vascular oxidative stress, thereby contributing to the prevention of atherosclerosis. Several polymorphisms have been reported in the PON1 gene, including Q192R. PON1 phenotype is commonly expressed as the paraoxonase/arylesterase ratio (PON/ARE). The major aim of this study was to investigate the association between PON1 Q192R polymorphism, PON1 phenotypes and the incidence of early-onset acute myocardial infarction (AMI) in Egyptians.Material and methodsThe study subjects consisted of 102 AMI patients and 72 age-matched healthy controls. Genotyping and enzyme activities were determined using PCR-RFLP and kinetic spectrophotometric assays, respectively.ResultsThe genotype distribution for the PON1 gene was significantly different between AMI patients (QQ = 38.24%, QR = 49.02%, RR = 12.75%) and controls (QQ = 66.67%, QR = 25%, RR = 8.33%). Allele frequencies were also significantly different between patients (Q = 62.75%, R = 37.25%) and controls (Q = 79.17%, R = 20.83%). The genotypes QR and RR showed higher risk for AMI compared to the homozygous QQ (odds ratio (OR) = 3.231, p < 0.001). The average PON/ARE ratio in MI patients (1.187 ±0.1) did not differ significantly from controls (1.118 ±0.26). However, it showed a significant difference among different genotypes in both AMI patients (QQ = 0.91 ±0.11, QR = 1.09 ±0.11 and RR = 2.65 ±0.4) (p = 0.0002) and controls (QQ = 0.68 ±0.1, QR = 1.07 ±0.11 and RR = 4.89 ±2.84) (p < 0.0001).ConclusionsPON1 192R allele represents an independent risk factor for early-onset AMI in Egyptians, and PON1 Q192R polymorphism modulates the paraoxonase phenotype.

Paraoxonase-1 gene in patients with chronic obstructive pulmonary disease investigation Q192R and L55M polymorphisms.

The effect of increased oxidative stress on the development of chronic obstructive pulmonary disease (COPD) is well known. One of the antioxidative systems against oxidative stress in human body is paraoxonase (PON) enzyme that protects low density lipoproteins (LDL) against oxidation. This study aimed to explore the polymorphisms on PON1, Q192R, L55M genes of patients with COPD. DNAs extraction was obtained from blood samples of 50 patients diagnosed with COPD and 50 patients as a control group who were presented to emergency clinic. Genotypes were obtained with polymerase chain reaction (PCR) and AIw I and Hsp92II restriction enzymes were used for Q192R and L55M polymorphisms, respectively. Analysis of data was done with the Chi-square test and Fisher's exact test. A statistically significant difference in Q192R polymorphism was found between the COPD patients and the control group (P=0.05). There was no statistically significant difference in L55M polymorphisms between the patient and control groups (P>0.05). Q192R polymorphism was significantly correlated with the PON1 gene and cigarette smoking; however other risk factors did not show any significant correlation with this polymorphism. Though L55M polymorphism was significantly correlated with family history and tuberculosis, there was no significant correlation with other risk factors. We believe that more studies are needed to study the correlation of L55M polymorphism with other factors.

0501: Association of Cys311Ser polymorphism of paraoxonase-2 gene with myocardial infarction in the Tunisian male population

Paraoxonase 2 (PON2) has antioxidant properties similar to paraoxonase-1 and paraoxonase-3. However, in contrast to paraoxonase-1 and paraoxonase-3, paraoxonase-2 is not associated with high-density lipoproteins and may only exert its antioxidant function at the cellular level. PON2 may also play a role in the pathogenesis of arterial thrombosis and atherosclerosis. The purpose of the present study was to investigate the possible association between the Cys311Ser polymorphism of PON2 gene and myocardial infarction (MI) in the Tunisian male population A total of 700 unrelated Tunisian subjects including 321 patients with MI and 379 healthy controls were included in this study. Genomic DNA was extracted from peripheral blood leukocytes according to standard methods. PON2 genotypes were determined by PCRRFLP method. A significant difference in genotype distribution and allele frequencies was observed between MI patients and controls. Patients with MI had a frequency of 17.1% for CC genotype, 45.8% for the CS genotype and 37.1% for the SS genotype. The controls had a frequency of 26.1% for the CC genotype, 45.6% for the CS genotype and 28.2% for the SS genotype (χ 2 =10.58; p=0.005). The MI patient group showed a significantly higher frequency of the S allele compared to the controls (0.60 vs 0.51; χ 2 =11.16; p<0.001). In multivariate analysis, C311S polymorphism was independently associated with MI (p<0.001). Our results showed a significant and independent association between the PON2 C311S polymorphism (presence of S allele) and MI in the Tunisian male population.

0143: Serum thiolactonase activity and paraoxonase gene polymorphism in coronary artery Tunisian patients with or without diabetes

Serum homocysteine thiolactonase activity is closely related to homocysteine and ox-LDL levels in coronary artery disease patients. Homocysteine thiolactonase activities are the result of environmental factors and genetic polymorphisms of paroxosonase. The relevance of gene polymorphism in coronary patients with or without diabetes was investigated in a case-control study. The population included 140 control subjects, 47 coronary artery disease patient without diabetes and 44 patients with type 2 diabetes. Serum thiolactonase activity decreased significantly in coronary artery disease patients: 318.9±156 U/l those without diabetes and 388.8±180 in the diabetic ones compared with the controls: 568.8±250U/l (p<0.001). These activities were associated with increased plasma homocysteine and ox-LDL levels (p<0.001). The paroxonase allele frequency is significantly higher in controls than coronary artery patients (p<0.001). The frequency of R high activity allele was also higher in diabetic coronary patients (11.3%), than in those without diabetes (4.2%). No significant association was found between paroxonase LN gene polymorphisms and diabetes in coronary patients. The difference in allele frequency for the paroxonase R gene polymorphism may be the cause of the high thiolactonase activity observed in coronary patients with type 2 diabetes mellitus. Further studies are needed to be conducted to elucidate the role of the enzyme in the development of vascular complications in these patients.

Paraoxonase-1 gene Q192R and L55M polymorphisms and risk of cardiovascular disease in Egyptian patients with type 2 diabetes mellitus.

BackgroundIncreased oxidative stress or an impaired antioxidant defense mechanism may play a crucial role in the onset and progression of atherosclerosis. Recently, Paraoxonase −1 (PON1) which accounts for most of the antioxidant effect of high density lipoprotein (HDL) cholesterol has been presented as a potential therapeutic agent against atherosclerosis development. Allele frequencies for PON1 gene that influence enzyme concentration as well as activity differ greatly among ethnic groups and data from several studies showed ethnic variations in the interpretation of cardiovascular disease (CVD) associated with PON1 polymorphisms. In this work, we investigated PON1 Q192R and L55M polymorphisms in Egyptian patients with type 2 diabetes mellitus (T2DM) and its association with CVD.MethodsThe study included 184 subjects classified into 3 groups; T2DM, T2DM + CVD, and healthy controls. PON1 polymorphisms were genotyped by real-time PCR and PON1 concentration was assayed in serum by ELISA (enzyme linked immunesorbent assay).ResultsGenotype and allele frequencies of Q192R were significantly different between controls and diabetic patients. Frequency of QQ genotype was significantly higher in healthy controls, while QR and RR genotypes were significantly higher in diabetic patients (p = 0.02). Frequency of 55LL and LM genotypes were significantly higher in patients than in controls (p = 0.009). Q192R polymorphism associated with CVD in our diabetic patients (p = 0.01) and with low serum PON1 concentration (p = 0.04). Multiple logistic regression analysis revealed significant correlations between 192R and other independent CVD risk factors.ConclusionPON1 192R and 55 L alleles are associated with T2DM. Q192R polymorphism is associated with CVD and lower serum enzyme concentration and might represents a novel risk factor for CVD in Egyptian patients with T2DM.

Exploring the role of paraoxonases in the pathogenesis of coronary artery disease: a systematic review.

Paraoxonases (PON) are three enzymes (PON1, PON2 and PON3) that play a role in the organism’s antioxidant system; alterations in which are associated with diseases involving oxidative stress. In this review, we summarize the evidence of PON related to the pathogenesis of coronary artery disease (CAD) and atherosclerosis. We searched three electronic databases (PubMed, Scopus and Cochrane Database) with no date limit. All of the articles selected investigated PON enzymatic activity and/or PON gene polymorphisms. The selection focused on PON in relation to atherosclerosis, CAD and myocardial infarction. The exclusion criteria were a sample size <100 patients, non-human studies, editorials and systematic reviews without restrictions on the country of origin. With these criteria, we identified thirty-five prospective studies published between 1986 and 2014 with a total of 28,164 participants. The relationship between PON gene polymorphisms and CAD was not conclusive, but most studies support the concept that alterations in PON1 enzymatic activity levels do influence atheroma formation. Conversely, relationships between PON2 and PON3 vs. CAD have not been extensively investigated. Our review of the current data concludes that the bases of paraoxonases involvement in atherosclerosis are poorly understood and that this issue requires future comprehensive, multi-centered studies.

Investigation of the association between paraoxonase-1 gene polymorphisms and response to therapy in chronic hepatitis C patients

Liver-derived paraoxonase-1 (PON1) enzyme that is found in the circulation is bound to high-density lipoproteins and reduces the amount of oxidized lipids with its antioxidant effect. Humans have at least three different PON gene regions which are adjacent to the other on the 7th chromosome. It has been shown that PON1 gene and its polymorphisms are related with various diseases. It is also known that, hepatitis C virus (HCV) is tightly associated with the cell lipoproteins in each step of its replication cycle leading to modulation of the host lipid metabolism. The aim of this study was to investigate the relationship between the response to chronic hepatitis C (CHC) therapy and aminoacid changes in 55' and 192' regions of PON1 enzyme believed to be involved in the pathophysiology of many chronic diseases. A total of 49 CHC patients (27 male, 22 female; mean age: 52.9 ± 12.6 yrs), all infected with HCV genotype 1b and positive for anti-HCV and HCV-RNA were included in the study. Patients who were HCV-RNA negative at the sixth month following at least once pegilated interferon + ribavirin treatment, were considered as therapy-responders, whereas those who were HCV-RNA positive were considered as non-responders. The genomic DNAs were isolated from patients' blood samples in their routine follow-ups and Q/R192 and L/M55 PON1 polymorphism analysis in 55. and 192. regions was performed by T-ARMS-PCR (Tetra-primer amplification refractory mutation system-polymerase chain reaction) method. In our study, the analysis of PON1 polymorphisms yielded 44.1% of LL, 44.1% of LM and 11.8% of MM genotypes at position 55 and 55.9% of QQ, 41.2% of QR, and 2.9% of RR genotypes at position 192 in therapy-responders. In the evaluation of combined genotype analysis of the patients, there was only one case who was responsive to treatment with LL/RR genotype. Of the patients, eight harbored LL/QQ genotypes and seven of them (87.5%) were responsive to treatment. However, statistical analysis indicated that there was no relationship between PON1 L/M55 and PON Q/R192 polymorphisms and response to CHC treatment (chi-square test, p> 0.05). Our data did not support a relationship between PON1 polymorphisms and response to CHC therapy, in contrast to a few studies pointing out of this correlation. This might be attributed to relatively low number of patients included. In conclusion, since antiviral agents used for CHC therapy are limited and costly, it was thought that further investigations with large numbers of patients should be conducted to establish the presence of any relationship between the response to CHC therapy and genotypes of the PON1 enzyme.

Effects of cytochrome P450 2C19 and paraoxonase 1 polymorphisms on antiplatelet response to clopidogrel therapy in patients with coronary artery disease.

Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75–325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65–5.26; p<0.001) and 11.26 (95%CI, 2.47–51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70–1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10−6). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.

Significant interethnic differencies in functional variants of PON1 and P2RY12 genes in Roma and Hungarian population samples.

Antiplatelet therapy with clopidogrel is one of the most common therapies given to patients worldwide. However, the clinical efficacy and toxicity of clopidogrel is not constant in every patient due to interindividual variations. There are several factors that contribute to these interindividual differencies such as SNPs in genes of specific receptors and enzymes. PON1 (paraoxonase 1) plays an important role in the bioactivation of clopidogrel. Single nucleotide polymorphisms of this gene decrease the activity of paraoxonase enzyme and lead to an unefficient clopidogrel effect. P2RY12 (purinergic receptor P2Y, G-protein coupled, 12) gene is coding a receptor, which is situated on the surface of the platelets and plays a role in ADP-induced platelet aggregation. In this study we investigated 2 functional SNPs of PON1 gene (rs662 and rs854560) and 3 variants of the P2RY12 gene (rs2046934, rs6798347, rs6801273) in samples pooled from average Hungarian Roma and Hungarian population samples with PCR-RFLP method. For the PON1 variants we detected that the R allele frequency was significantly lower in the Roma group compared to the Hungarian population. (0.249 vs 0.318 p < 0.001). By contrast, the frequency of the M allele was significantly higher in Roma than in Hungarians (0.332 vs 0.290 p < 0.05). For the 3 P2RY12 variants we could find significant differencies only in rs2046934: the frequency of the CC genotype is 7 times higher in Hungarians than in Romas (1.4 vs 0.2 %, p < 0.05). The data presented here represent a unique genetic profile in Roma people that has not been reported for other populations.

The influence of renal function on the association of rs854560 polymorphism of paraoxonase 1 gene with long-term prognosis in patients after myocardial infarction.

Paraoxonase 1 (PON1) is an enzyme responsible for the antioxidant properties of high density lipoprotein (HDL). The activity of PON1 is decreased in patients with coronary artery disease, myocardial infarction or chronic kidney disease. rs662 and rs854560 are single nucleotide polymorphisms (SNPs) associated with PON1 activity and 10-year cardiovascular mortality of patients with stable coronary artery disease. We investigated the association of rs662 and rs854560 SNPs of the PON1 gene with 5-year mortality in patients with ST-elevation myocardial infarction (STEMI) treated invasively. We analyzed the data of consecutive patients with STEMI treated with primary PCI. Genotyping was performed with the TaqMan method. The analyzed end-point was total 5-year mortality. Additional subgroup analysis was performed for survival of patients depending on their eGFR. The study group comprised 634 patients (mean age 62.3 ± 11.85 years; 25.2 % of women, n = 160; PCI successful in 92.3 %, n = 585). No clinically relevant differences in baseline characteristics were found between the genotypes. No association between either genotype and 5-year mortality was found: p = 0.4 for the rs662 SNP, p = 0.73 for the rs854560 one (log-rank test). However, in a subgroup of patients with eGFR below median value (78.6 ml/min/1.73m2) the rs854560 AA homozygotes had a significantly lower probability of survival (p = 0.047, log-rank test). The AA genotype of the rs854560 SNPs of the PON1 gene is associated with increased mortality in patients after myocardial infarction in the subpopulation of patients with lowered eGFR. This phenomenon may be explained by potentially lower PON1 activity in kidney disease.

Paraoxonase 1 gene polymorphisms in patients with type 2 diabetes mellitus

The article deals with the features of lipid metabolism in patients with type 2 diabetes - the carriers of different genotypes of paraoxonase 1 gene. Known that the enzyme paraoxonase 1 (PON1) plays a key role in the regulation of lipid peroxidation and its activity is genetically determined. The investigation revealed that the PON1 gene's polymorphic variants may determine the formation of atherogenic changes in lipid profile in patients with diabetes mellitus (DM) type 2.

The relation of PON1-L55M gene polymorphism and clinical manifestation of Behcet's disease.

Behçet's disease is a multisystem disease characterized by recurrent oral and genital ulcers, relapsing uveitis, mucocutaneous, articular, gastrointestinal, neurologic, and vascular manifestations. Paraoxonase is believed to play an important role in protection of LDL and HDL particles from oxidation, in antioxidant effect against lipid peroxidation on cellular membranes, and in anti-inflammatory process. Lipid peroxidation and free oxygen radicals have been thought to play a role in pathogenesis of BD. The association of paraoxonase gene polymorphisms with Behçet's Disease in a group of Turkish patients with clinical manifestations and healthy controls has been investigated. Paraoxonase (PON-1-L55M) gene polymorphism was investigated in 50 Behcet patients and 50 healthy individuals with a PCR/RFLP method. There were significant differences between patients and the control group in allele frequencies of the PON1 L55M polymorphism (p=0.04). Also, when patients were compared with the control group according to clinical manifestations, this statistical significance was getting sharper. Compared with the PON55 L allele, the M allele was associated with greater than 3.5 fold (OR 3.5, 95% CI 1.3-8.9) increased risk of ocular (OR 2.4, 95% CI 1.1-5.3), 2.4 fold joint and 3.1 fold (OR 3.1, 95% CI 1.1-8.4) central nervous system manifestations of BD. The PON L55M gene polymorphism seemed to play a role in the pathogenesis of BD.

Arylesterase activity is associated with antioxidant intake and paraoxonase-1 (PON1) gene methylation in metabolic syndrome patients following an energy restricted diet.

The arylesterase (ARE) activity linked to the paraoxonase-1 (PON1) gene is known to protect lipoproteins from oxidation and provide defense against metabolic syndrome (MetS) and cardiovascular diseases. The epigenetic regulation of enzymatic activities is gaining importance nowadays. This research aimed to assess the potential relationships between the ARE activity with the methylation levels of the PON1 gene transcriptional regulatory region, anthropometrics, biochemical markers and antioxidant dietary components. Forty-seven subjects (47 ± 10 y.o; BMI 36.2 ± 3.8 kg/m(2); 46.8 % female) with MetS features, who followed a six-month energy-restricted dietary weight-loss intervention, were included in this study (www.clinicaltrials.gov; NCT01087086). Anthropometric, biochemical, enzymatic and dietary data were assessed using validated procedures. PON1 transcriptional regulatory region methylation was analyzed by a microarray technical approach. Volunteers reduced ARE activity in parallel with body weight (p = 0.005), BMI (p = 0.006), total fat mass (p = 0.020), diastolic blood pressure (p = 0.018), mean blood pressure (p = 0.022) and triglycerides (p = 0.014). Methylation levels of some CpG sites of the PON1 gene correlated negatively with ARE activity (p < 0.05). Interestingly, dietary vitamin C (p = 0.001), tocopherols (p = 0.009) and lycopene (p = 0.038) were positively associated with ARE activity and showed an inverse correlation (p = 0.004, p = 0.029 and p = 0.021, respectively) with the methylation of some selected CpG sites of the PON1 gene. In conclusion, ARE activity decreased in parallel with MetS-related markers associated to the energy restriction, while dietary antioxidants might enhance the ARE activity by lowering the PON1 gene methylation in patients with MetS features.

Dopamine D1 and D5 receptors differentially regulate paraoxonase 2 (1134.6)

We have previously reported that dopamine D1‐like receptors (D1R and D5R) negatively regulate NADPH oxidase isoform expression and activity in renal proximal tubule (RPT) cells from rodents and humans. We tested the hypothesis that D1‐like dopamine receptors (D1R and D5R) differentially regulate the anti‐oxidant enzyme paraoxonase2 (PON2) in HEK‐293 cells heterologously expressing human D1R and D5R. Fenoldopam (1µM, 15 min), an agonist for both D1R and D5R, increased PON2 co‐immunoprecipitation with D1R (160±4% vs. control, 101±1%) and D5R (132±0.1% vs. control, 102±1%) in both cell lines. Short‐term (15, 30, and 60min) stimulation of D1R and D5R with fenoldopam (1µM) did not alter total PON2 protein. However, in D1R cells, at 15min, fenoldopam increased PON2 protein in both lipid rafts (LRs) (144±3% vs. control, 100±3%) and non‐LRs (163±25% vs. control, 100±21%) (P&lt;0.05, n=6/group, ANOVA). In contrast, in D5R cells, fenoldopam increased PON2 protein only in non‐LRs (132±5% vs. control, 100±1.6%, n=3). Long‐term (2, 4, 8, and 24h) fenoldopam (1µM) stimulation increased PON2 protein in a time dependent manner (146% ±7/8h, and 162% ±10/24h vs. control, 100±9%) (P&lt;0.05, n=4, ANOVA) in D5R but not D1R cells. Fenoldopam also increased PON2 mRNA (1.25‐fold) (n=3, P&lt;0.05, t‐test) at 24h in D5R but not D1R cells. Silencing PON2 gene with PON2‐siRNA (10nM/48h) in D5R cells decreased PON2 protein (‐40±4% vs. mock‐siRNA, 100±17%, n=3) and mRNA (‐17±4% vs. mock‐siRNA, 100±2%, P&lt;0.05, n=3, t‐test) and increased basal ROS production by 1.36‐fold, relative to mock‐siRNA. PON2 protein was decreased in D5R‐/‐ mice (‐44±13%) relative to D5R+/+ mice (100±8%, n=4‐6/group). We conclude that short‐term stimulation of either D1R or D5R leads to PON2 protein recruitment to non‐LRs and also to LRs in the case of D1R. However, long‐term stimulation of PON2 and negative ROS regulation are mainly due to D5R.Grant Funding Source: HL023081, HL074940, DK039308

Response to Letter to the Editor: Paraoxonase Genes and the Susceptibility to Ischemic Stroke

Response to Letter to the Editor: Paraoxonase Genes and the Susceptibility to Ischemic Stroke

Can paraoxonase 1 polymorphisms (L55 M and Q192 R) protect children with type 1 diabetes against lipid abnormalities?

Only a few studies have focused on the possible modulatory role of paraoxonase 1 (PON1) polymorphisms in lipid profiles, especially in children and in adolescents with type 1 diabetes (T1D). We propose to study the association between PON1 polymorphisms (PON1-55 and PON1-192) and a lipid profile in a young Tunisian population with T1D. The study compared 122 children and adolescents with T1D with 97 controls. Genomic DNA was collected from 116 patients and 91 controls. Lipid parameters were determined by automated methods. PON1 activity was measured by a spectrophotometric method and genotyping of the PON1 gene was assessed by multiplex polymerase chain reaction followed by restriction fragment-length polymorphism. A significant increase in total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (ApoB), and lipoprotein (a) (Lp(a)) and a significant decrease in apolipoprotein A1 (ApoA1), ApoA1/ApoB ratio, and PON1 activity/HDL-C ratio were observed in children with T1D compared with controls. In the LLQR haplotype, the group with diabetes showed significantly higher values of total cholesterol, LDL-C, apoB, Lp(a), and apoA1/apoB ratio compared with the control group. Those with diabetes with the LLQQ haplotype showed a significant decrease in LDL-C and Lp(a) compared with controls (P < .0001). PON1 polymorphisms (PON1-55 and PON1-192) seem to be involved in the altering the lipid profile in T1D. The LLQR haplotype provided an atherogenic lipid profile in children with T1D compared with controls. LLQQ haplotype seemed to have a protective effect against the increase in LDL-C and Lp(a) that are heavily involved in the development of cardiovascular diseases.

Methylmercury exposure, PON1 gene variants and serum paraoxonase activity in Eastern James Bay Cree adults

There is growing evidence that cardiovascular health can be affected by exposure to methylmercury (MeHg), by a mechanism involving oxidative stress. Paraoxonase 1 (PON1) is a high-density lipoprotein-bound enzyme that hydrolyzes toxic oxidized lipids and protects against cardiovascular diseases. Evidence from in vitro studies indicates that MeHg can inhibit PON1 activity but little is known regarding this effect in humans. We investigated whether increased blood mercury levels are associated with decreased serum PON1 activity in Cree people who are exposed to MeHg by fish consumption. We conducted a multi-community study of 881 Cree adults living in Eastern James Bay communities (Canada). Multivariate analyses considered sociodemographic, anthropometric, clinical, dietary and lifestyle variables and six PON1 gene variants (rs705379 (-108C/T), rs662 (Q192R), rs854560 (L55M), rs854572 (-909C/G), rs854571 (-832C/T) and rs705381 (-162C/T)). In a multiple regression model adjusted for all potential confounding factors and the rs854560 PON1 variant, a statistically significant MeHg*rs705379 interaction was observed. Blood mercury levels were inversely associated with serum PON1 activities in individual homozygous for the -108T allele (P=0.009). Our results suggest a gene-environment interaction between the rs705379 polymorphism and MeHg exposure on PON1 activity levels in this aboriginal population. This finding will need to be replicated in other population studies.

Paraoxonase Gene Expression in Pediatric Inflammatory Bowel Disease

Background: Oxidative stress plays a role in the pathogenesis of inflammatory bowel disease (IBD). The Paraoxonase (PON) genes, expressed in the human intestine, are thought to prevent oxidative stress and modulate inflammation. We investigated the effect of IBD and steroids on PON gene. We hypothesized that PON gene expression is decreased in IBD patients and that steroid treatment would return it to normal.Methods: Pediatric patients diagnosed with IBD, were enrolled and matched to control subjects. For in vitro studies, human epithelial colorectal adenocarcinoma (Caco-2) cells were treated with hydrogen peroxide (H2O2) and dexamethasone. PON genes expression was evaluated by quantitative real-time PCR for both the biopsies and the Caco-2 cells.Results: PON gene expression was decreased in intestinal biopsies from medication naive IBD patients when compared to controls (p<0.05). Biopsies from IBD patients on steroids exhibited up regulation of PON gene expression (p<0.05). Caco-2 cells treated with H2O2 had decreased PON gene expression compared to controls (p<0.05). Dexamethasone increased PON gene expression in Caco-2 cells (p<0.05).Conclusion: Our data suggests that decreased PON expression in IBD patients is a consequence of oxidative stress which plays a role in the pathogenesis of IBD. Further, steroids counteract the effect of oxidative stress by up regulating PON gene expression. PON genes may be targets for the management of intestinal diseases like IBD.

Paraoxonase 2 Gene (Cys&amp;lt;sup&amp;gt;311&amp;lt;/sup&amp;gt;-Ser) Polymorphism and the Risk of Coronary Artery Disease

Background: Human paraoxonase-2(PON2) which is exclusively intracellular possesses unique properities that distinguish it from PON1 and PON3. Recently, it was demonstrated that PON2 protects against atherosclerosis by preventing LDL oxidation. Emerging evidences have proposed that genetic variations in the PON2 gene may be associated with coronary artery disease (CAD). Objectives: To investigate the relationship between a common PON2 gene (Cys311-Ser) polymorphism and the presence and extent of CAD. Methods: The study comprised 112 patients recruited from those undergoing coronary angiography for suspected CAD, who were divided according to the presence or absence of CAD into 2 groups Group I including 62 patients with CAD and Group II including 50 patients proved to have normal coronaries. All the subjects included in the study were genotyped for the (Cys311-Ser) polymorphism of PON2 gene using RCR-RFLP. Results: The frequency of Cys allele was significantly higher in group I compared to Group II (77.4% vs. 56% respectively, P 311 Cys allele [OR 5.67, CI (1.99 - 14.77), P