Paraoxonase 1 Rs662 Research Articles

The rs662 polymorphism of paraoxonase 1 affects the difference in the inhibition of butyrylcholinesterase activity by organophosphorus pesticides in human blood.

Organophosphorus pesticides (OPs) are a human health hazard. OPs inhibit acetylcholinesterase (AChE) at nerve endings and accumulate acetylcholine (ACh) at these sites. High levels of ACh and long exposure promote cholinergic crisis. The hydrolysis of OPs by serum paraoxonase 1 (PON1) plays a role in cholinergic crisis in humans. Human serum PON1 can break down organophosphate before binding to ChE. We investigated the effect of PON1 polymorphisms on AChE activity after OP treatment. 50 healthy volunteers were randomly recruited with informed consent. We investigated butyrylcholinesterase (BuChE) activity changes in plasma as a biomarker of AChE after OP treatment in human blood samples immediately following blood sampling. After the standardization of BuChE activity in human blood, we correlated changes in BuChE activity with changes in blood pH. We analyzed the PON1 polymorphisms (rs854560 and rs662) of 50 participants to retrospectively investigate the interindividual variability of changes in BuChE activity. Changes in BuChE activity are strongly correlated with pH changes after OP treatment (R2 = 0.913). We used changes in pH as a surrogate marker for BuChE inhibition after OP treatment. OP treatment significantly decreased BuChE activity by 56.4 ± 5.1% (p < 0.001). The degree of BuChE inhibition was significantly different in the PON1 rs662 genotype (56.10 ± 4.74% vs. 57.96 ± 5.67% vs. 52.34 ± 1.51%; GG vs. GA vs. AA, respectively). Changes in pH can be used as a surrogate marker for the detection of BuChE inhibition after OP exposure. The rs662 polymorphism of PON1 may explain the inter-individual variability in BuChE inhibition.

Association of Paraoxonase 1 Gene Polymorphisms With the Risk of Hepatitis B Virus-related Liver Diseases in a Guangxi Population

Paraoxonase 1 (PON1), a liver-induced glycoprotein enzyme responsible for antioxidant defense against reactive oxygen species and anti-inflammatory, has been linked to various cancers. The objective of this study was to explore the association of PON1 rs662 and rs705382 with the risk of chronic hepatitis B (CHB), hepatitis B virus-related liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in patients living in the Guangxi region of southern China.The PON1 rs662 and rs705382 single-nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) in 99 CHB patients, 84 LC patients, 258 HCC patients, and 221 healthy controls.Significant associations with CHB risk were observed for the rs705382 SNP after adjusting for sex, age, ethnicity, smoking, alcohol consumption, and body mass index. When stratified by sex and age, this positive association was significantly strengthened among men and individuals over 40 years old. Moreover, a decreased risk of LC was associated with the rs705382 CG and the combined GG + CG genotypes among women, with borderline statistical significance. In haplotype analyses, the haplotype GA was associated with a 1.68-fold increase in the risk of HCC.Our results showed that the PON1 rs705382 SNP might be a risk factor for CHB in Guangxi populations.

Paraoxonase-1 and oxidized lipoprotein lipids. The Cardiovascular Risk in Young Finns Study.

Paraoxonase-1 (PON1) is suggested to have a role in the antioxidant activity of high-density lipoprotein (HDL). PON1 activity levels are strongly genetically determined by the rs662 polymorphism (PON1 Q192R). To clarify the role of PON1 in lipoprotein oxidation at the population level, we examined the relations between PON1 activity, the rs662 polymorphism and oxidized lipoprotein lipids in young adults. A population-based cross-sectional study of 1895 Finnish adults ages 24-39 years (872 males and 1023 females). PON1 activity was determined with paraoxon as the substrate. Analysis of oxidized lipids in isolated HDL (oxHDLlipids) and low-density lipoprotein (oxLDLlipids) was based on the determination of conjugated dienes. Oxidized LDL was also measured with a method based on antibodies against oxidized Apo-B (oxLDLprot). Serum lipids and apolipoproteins were measured. Genotyping was performed with the Illumina Bead Chip (Human 670K). In multivariable models, PON1 activity associated inversely with oxLDLlipids (p=0.0001, semi-partial R(2)=0.09%), but it was not associated with oxHDLlipids (p=0.93). There was a borderline significant association between PON1 activity and oxLDLprot (p=0.08). PON1 rs662 polymorphism was strongly associated with PON1 activity (P-value<0.0001), but not with oxidized lipoprotein lipids and oxLDLprot. Higher PON1 activity is associated with decreased oxLDLlipids levels, but not with oxHDLlipids in a population of young Finnish adults. These findings support the suggestion that PON1 activity may have a role in the oxidation of LDL lipids. There is a strong association between PON1 rs662 polymorphism and PON1 activity, but PON1 rs662 polymorphism is not associated with oxidized lipoprotein lipids and oxLDLprot.

Interactions between paraoxonase 1 genetic polymorphisms and smoking and their effects on oxidative stress and lung cancer risk in a Korean population.

BackgroundFew studies in epidemiology have evaluated the effects of gene-environment interaction on oxidative stress, even though this interaction is an important etiologic factor in lung carcinogenesis. We investigated the effects of the genetic polymorphisms of paraoxonase 1 (PON1), smoking, and the interaction between the two on lung cancer risk and oxidative stress.MethodsThis study’s subjects consisted of 416 newly diagnosed lung cancer patients and an equal number of matched controls. The GoldenGate assay was used for genotypic analyses of the PON1 gene. Urinary 8-hydroxydeoxyguanosine (8-OHdG) and thiobarbituric acid reactive substances levels were measured as indicators of oxidative stress.ResultsThe PON1 rs662 AA genotype showed a significantly lower risk of lung cancer than the GG genotype (OR = 0.60, 95% CI: 0.36–0.99). The protective effect of the PON1 rs662 AA genotype on lung cancer risk was limited to non-smokers. Lung cancer patients who had the rs662 A allele showed a dose-dependent association between smoking status and oxidative stress markers. Among non-smoking lung cancer patients, urinary 8-OHdG levels were significantly lower in individuals with the rs662 GA and AA genotypes than in those with the GG genotype. Furthermore, we found a significant interaction effect between PON1 rs662 and smoking status on urinary 8-OHdG levels in lung cancer patients.ConclusionsOur results suggest that the protective effect of PON1 rs662 SNP against lung carcinogenesis and the induction of oxidative stress might be modulated by the interaction between PON1 genetic polymorphisms and tobacco smoking.

Association between PON1 rs662 polymorphism and coronary artery disease.

Paraoxonase 1 (PON1) is a plasma enzyme that is capable of inhibiting the progression of atherosclerosis, and is associated with susceptibility of coronary artery disease (CAD). PON protein expression is present in human aortic tissue and it plays an important role in the progression of atherosclerosis. This study aimed to investigate PON1 immunohistochemistry in human coronary arteries, determine its polymorphisms and plasma status, and analyze its association with the risk of CAD. PON1 expression in human coronary artery tissues was detected by immunohistochemical staining. PON1 polymorphisms were determined by polymerase chain reaction direct sequencing in 2456 unrelated Chinese Han individuals. Serum PON1 levels were indirectly reflected by PON1 activity towards paraoxon and phenylacetate by spectrophotometry, and by its concentrations using a human enzyme-linked immunosorbent assay. Immunohistochemical analysis showed that PON1 expression was lower in atherosclerotic arteries than in normal arteries. PON1 Q192R (rs662) had a significant effect on the risk of CAD (P=0.001). In a logistic regression model, after adjusting for conventional risk factors of CAD, 192R allele carriers had a significantly higher risk of CAD than other allele carriers. Serum PON1 activity and concentrations were significantly reduced in CAD patients compared with controls (P<0.05), and highly associated with the R allele. Low PON1 expression in human atherosclerotic coronary arteries is associated with CAD. Moreover, PON1 Q192R polymorphism is significantly associated with susceptibility of CAD in the Chinese Han population, and the 192R allele might be an independent predictor for CAD.

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.