Paraoxonase Gene Family Research Articles

A Case-Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease.

The paraoxonase (PON) gene family (including PON1, PON2, and PON3), is known for its anti-oxidative and anti-inflammatory properties, protecting against metabolic diseases such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the influence of common and rare PON variants on both conditions was investigated. A total of 507 healthy weight individuals and 744 patients with obesity including 433 with histological liver assessment, were sequenced with single-molecule molecular inversion probes (smMIPs), allowing the identification of genetic contributions to obesity and MASLD-related liver features. Polymorphisms rs705379 and rs854552 in the PON1 gene displayed significant association with MASLD stage and fibrosis, respectively. Additionally, rare PON1 variants were strongly associated with obesity. This study thereby reinforces the genetic foundation of PON1 in obesity and various MASLD-related liver features, by extending previous findings from common variants to include rare variants. Additionally, rare and very rare variants in PON2 were discovered to be associated with MASLD-related hepatic fibrosis. Notably, we are the first to report an association between naturally occurring rare PON2 variants and MASLD-related liver fibrosis. Considering the critical role of liver fibrosis in MASLD outcome, PON2 emerges as a possible candidate for future research endeavors including exploration of biomarker potential.

Paraoxonase 1: evolution of the enzyme and of its role in protecting against atherosclerosis.

To review the discoveries which led to the concept that serum paraoxonase 1 (PON1) is inversely related to atherosclerotic cardiovascular disease (ASCVD) incidence, how this association came to be regarded as causal and how such a role might have evolved. Animal models suggest a causal link between PON1 present on HDL and atherosclerosis. Serum PON1 activity predicts ASCVD with a similar reliability to HDL cholesterol, but at the extremes of high and low HDL cholesterol, there is discordance with PON1 being potentially more accurate. The paraoxonase gene family has its origins in the earliest life forms. Its greatest hydrolytic activity is towards lactones and organophosphates, both of which can be generated in the natural environment. It is active towards a wide range of substrates and thus its conservation may have resulted from improved survival of species facing a variety of evolutionary challenges. Protection against ASCVD is likely to be the consequence of some promiscuous activity of PON1, but nonetheless has the potential for exploitation to improve risk prediction and prevention of ASCVD.

A Brief Review of the Association between Genetic Polymorphisms of the Paraoxonase Family and Atherosclerosis

Atherosclerosis is known as an inflammatory disease that can affect any vessel in the body. The occurrence of atherosclerosis in heart vessels is called coronary artery disease (CAD). CAD is one of the most significant causes of morbidity and mortality in developed countries. Different genetic and environmental factors can cause cardiovascular diseases, such as age, weight, sex, and low high-density lipoproteins (HDL) levels.
 Antioxidant and anti-atherogenic effects of HDL are related to proteins attached, such as Paraoxonase (PON). The Paraoxonase gene family has three members, PON-I, PON-II, and PON-III, located next to each other, on the long arm of chromosome 7, in humans. It seems polymorphisms and genetic variation resulting in several different phenotypes can affect the PON function. Due to its role in the human antioxidant system, changes in paraoxonase activity can increase or even reduce the risk of CAD. In this investigation, we reviewed different studies that showed, in some populations, specific polymorphisms with an effect on enzymatic activity ultimately increase or decrease the risk of disease in individuals. In contrast, no association has been found between disease and polymorphism in some populations. Therefore, further studies and meta-analyses in this field seem to be useful.

Prevalence and mortality of COVID-19 are associated with the L55M functional polymorphism of Paraoxonase 1

IntroductionAccumulating evidence recommends that infectious diseases including coronavirus disease 2019 (COVID-19) are often associated with oxidative stress and inflammation. Paraoxonase 1 (PON1, OMIM: 168,820), a member of the paraoxonase gene family, has antioxidant properties. Enzyme activity of paraoxonase depends on a variety of influencing factors such as polymorphisms of PON1, ethnicity, gender, age, and a number of environmental variables. The PON1 has two common functional polymorphisms, namely, Q192R (rs662) and L55M (rs854560). The R192 and M55 alleles are associated with increase and decrease in enzyme activity, respectively.ObjectiveThe present study was conducted to investigate the possible association of rs662 and rs854560 polymorphisms with morbidity and mortality of COVID-19.MethodsData for the prevalence, mortality, and amount of accomplished diagnostic test (per 106 people) on 25 November 2020 from 48 countries were included in the present study. The Human Development Index (HDI) was used as a potential confounding variable.ResultsThe frequency of M55 was positively correlated with the prevalence (partial r = 0.487, df = 36, p = 0.002) and mortality of COVID-19 (partial r = 0.551, df = 36, p < 0.001), after adjustments for HDI and amount of the accomplished diagnostic test as possible confounders.ConclusionsThis means that countries with higher M55 frequency have higher prevalence and mortality of COVID-19.

Paraoxonases 1 and 2 (PON1 and 2) Polymorphisms in Diffuse Large B-Cell Lymphoma (DLBCL): Correlation with Clinical Outcomes

Background: The paraoxonase gene family (PON1, PON2 and PON3) is located on chromosome 7. Their proteins prevent oxidative stress and show anti-inflammatory properties, being related to a wide variety of human illnesses. Oxidative stress is related to malignant transformation in some tumors, and PON Single Nucleotide Polymorphisms have been associated with increased risk of some types of cancers.Purpose: To investigate the genotypic and allelic frequency of polymorphisms of PON1 (192QR and 55LM) and PON2 (148AG and 311SC) genes in patients with DLBCL in a Brazilian population, and to analyze the correlations of these polymorphisms with clinical outcomes.Methods: Subjects were HIV negative patients diagnosed with DLBCL CD20+ between February 2009 and April 2011. Patients (78) were from the Instituto do Cancer do Estado de Sao Paulo. They were followed for survival and disease progression (cut-off date: April 2017). All histopathology slides and blocks were reviewed by a trained pathologist. The DNA was extracted from peripheral blood leukocytes by salting-out extraction method. PON1 and PON2 polymorphisms were detected by PCR/RFLP. Overall Survival (OS) and Progression Free Survival (PFS) were estimated using Kaplan-Meier analysis, and the log-rank test was used to assess differences between the curves. Univariate Cox regression analysis was used to assess the association between clinical characteristics and the survival endpoints. Univariate logistic regression was used to examine the association between covariates and complete response.Results: Complete information was available for 67 patients. Median age at diagnosis: 40 years (20-65). 64.1% patients had Performance Status PS 0-1 at diagnosis; 53.7% were female; 64.1% had low-intermediate risk International Prognostic Index (IPI); 43.2% had Bulky Lesion. All patients received rituximab-based chemotherapy. Frequency of the polymorphisms: PON1 192 (QR/RR: 47%, QQ: 53%), PON1 55 (LM: 35.8%, MM: 10.4%, LL: 52.2%), PON2 148 (AG: 46.2%, GG: 5.9%, AA: 46.2%), PON2 311 (SC: 35.8%, CC: 7.4%, SS: 52.2%). Twenty-three patients (34.3%) died after 5 years of follow-up, with OS 5 years: 65.1% (95% CI 51.9-75.5). PFS in 5 years: 51.8%. At Univariate Cox Regression, PS 2-4 compared to PS 0-1 at diagnosis was associated with increased risk of death (HR: 3.96, 95% CI: 1.71-9.13, p=0.001). Regarding the polymorphisms, PON1 55 LM was associated with increased risk of disease progression (HR: 2.01, 95% CI: 0.98-4.11, p=0.05) when compared to LL. No correlation was observed between the studied polymorphisms and clinical outcomes.Conclusions: PON1 55LM was associated with an increased risk of disease progression. Nevertheless, the clinical significance of this finding deserves further investigation. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 16835: Targeted Disruption of Paraoxonase 3 in a Dahl Salt-Sensitive Rat Model of Chronic Kidney Disease Increases Renal Cortical Pro-Inflammatory Eicosanoids

Background: Paraoxonase 3 (Pon3), is one of the three isoforms of the paraoxonase gene family. While Pon1 and Pon2 are widely studied, there is a paucity of knowledge regarding Pon3. Pon3 is synthesized in the liver and can circulate bound to high-density lipoproteins. There is significant expression in the kidney also. Pon3 has the ability to metabolize eicosanoids, which can act as signaling molecules and have known roles in the pathophysiology of some renal diseases. Decreased Pon activity is associated with elevated levels of eicosanoid metabolites and adverse clinical outcomes. We tested the hypothesis that targeted disruption of Pon3 results in elevated levels of pro-inflammatory eicosanoids and progression of renal injury. Methods/ Results: Ten week old male Dahl salt-sensitive (SS rats) and Pon3 mutant rats (SS Pon3 KO) were maintained on 8% high salt diet for eight weeks, to initiate salt-sensitive hypertensive renal disease. Previously we observed that SS Pon3 KO rats on eight weeks high salt diet demonstrated significantly increased phenotypic renal injury and mortality. In the current study, we noted that SS Pon3 KO had significantly decreased (p&lt;0.05) glomerular filtration rate compared to SS wild type. Blood pressure (radiotelemetry) as well as plasma angiotensin and aldosterone (LC-MS/MS) were not different between the two groups after high salt diet. We used targeted lipidomic profiling to determine eicosanoid content in renal cortex from SS Pon3 KO and SS wild type rats at the end of eight weeks of high salt diet. We found that hydroxyl fatty acids 5-HEPE and 5-HETE (5-lipoxygenase dependent arachidonic acid metabolites) were significantly (p&lt;0.05) elevated in the renal cortex of SS Pon3 KO compared to SS wild type rats. In addition to being mediators of inflammation, these metabolites are associated with renal cell injury and death. Furthermore, prostaglandin 6-keto-PGF 1α , which has known links to renal inflammation, was significantly (p&lt;0.05) increased in renal cortex of SS- Pon3 KO compared to SS wild type rats. Conclusion: These findings suggest that targeted deletion of Pon3 increases pro-inflammatory eicosanoids (5-HETE and 5-HEPE) and prostaglandins (6-keto-PGF 1α ), as well as increases renal damage independent of blood pressure.

Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview.

Aging is defined as the accumulation of progressive organ dysfunction. There is much evidence linking the involvement of oxidative stress in the pathogenesis of aging. With increasing age, susceptibility to the development of diseases related to lipid peroxidation and tissue injury increases, due to chronic inflammatory processes, and production of reactive oxygen species (ROS) and free radicals. The paraoxonase (PON) gene family is composed of three members (PON1, PON2, PON3) that share considerable structural homology and are located adjacently on chromosome 7 in humans. The most studied member product is PON1, a protein associated with high-density lipoprotein with paraoxonase/esterase activity. Nevertheless, all the three proteins prevent oxidative stress. The major aim of this review is to highlight the importance of the role of PON enzymes in the aging process, and in the development of the main diseases present in the elderly: cardiovascular disease, diabetes mellitus, neurodegenerative diseases, and cancer.

Paraoxonase 1 (PON1)-L55M among common variants in the coding region of the paraoxonase gene family may contribute to the glycemic control in type 2 diabetes

ObjectiveGenome studies have shown that the genes encoding paraoxonase 1 (PON1) and PON2 are associated with glucose metabolism. The goal of this study was to simultaneously evaluate the association between functional variants in PON1 and PON2 genes and susceptibility for type 2 diabetes (T2D) and determine whether they can affect glycemic control. MethodsWe performed a case-control study with 145 newly diagnosed patients with T2D and 148 controls. The common variants including PON1-Q192R, PON1-L55M and PON2-S311C were genotyped by PCR-based RFLP. A mismatch-PCR/RFLP was applied for genotyping the PON2-A148G variant. ResultsThe variant PON1-Q192R in males (OR = 2.55, 95%CI 1.16–5.69, p = 0.023) and PON2-A148G in females (OR = 1.56, 95%CI 1.00–2.44, p = 0.059) were associated with T2D. Compared with the LL genotypes of PON1-L55M, HbA1c levels were significantly lower in the LM genotypes (p = 0.01) and MM genotypes (p = 0.032) in patients. Multiple linear regression analyses showed that among the study variants only the PON1-L55M variant as an independent variable significantly associated with glycemic control. This variant significantly influenced glycemic control in patients with poor glycemic control so that it was better with the following order: LL < LM < MM. Based on gamma correlation, there was a significant inverse association between the number of M alleles of the PON1-L55M and HbA1c levels (r = −0.261, p = 0.001). ConclusionsSex should be considered a confounding variable in association studies on the variants PON1-Q192R and PON2-A148G in T2D. Patients sharing the 55 M allele were prone to having good glycemic control. Our findings provide genetic evidence that the PON1-L55M variant may be a factor contributing to glycemic control.

Effect of certain non-steroidal anti-inflammatory drugs on the paraoxonase 2 (PON2) in human monocytic cell line U937

The paraoxonase gene family in humans consists of three members as PON1, PON2 and PON3. PON2 can be expressed in several tissues; however, it is not released from the cells in those tissues. PON2 is also expressed in macrophages. Firstly, the commonly used NSAIDs diclofenac sodium and tenoxicam were applied on U937 cell line, the in vitro human monocyte cell line. Than PON2 specific Lactonase activity and paraoxonase family specific arylesterase were determined. Use of Diclofenac sodium in 0.845 mM dose during 6–12 h of incubation and Tenoxicam in 0.74 mM dose during 6 h of incubation resulted in a significant decline in the lactonase activity. Diclofenac sodium didn’t make any change in the arylesterase activity. On the other hand, tenoxicam decreased arylesterase activity during the use of 12 h, in 0.74 mM and 1.48 mM dose.

The role of paraoxonase in cancer.

The paraoxonase (PON) gene family includes three proteins, PON1, PON2 and PON3. PON1 and PON3 are both associated with high-density lipoprotein (HDL) particles and exert anti-oxidant and anti-inflammatory properties. PON2 and PON3 are intracellular enzymes which modulate mitochondrial superoxide anion production and endoplasmic reticulum (ER) stress-induced apoptosis. The pleiotropic roles exerted by PONs have been mainly investigated in cardiovascular and neurodegenerative diseases. In recent years, overexpression of PON2 and PON3 has been observed in cancer cells and it has been proposed that both enzymes could be involved in tumor survival and stress resistance. Moreover, a lower activity of serum PON1 has been reported in cancer patients. This review summarizes literature data on the role of PONs in human cancers and their potential role as a target for antitumor drugs.

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.

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.

Human paraoxonase gene cluster overexpression alleviates angiotensin II-induced cardiac hypertrophy in mice.

Cardiac hypertrophy is the strongest predictor of the development of heart failure, and anti-hypertrophic treatment holds the key to improving the clinical syndrome and increasing the survival rates for heart failure. The paraoxonase (PON) gene cluster (PC) protects against atherosclerosis and coronary artery diseases. However, the role of PC in the heart is largely unknown. To evaluate the roles of PC in cardiac hypertrophy, transgenic mice carrying the intact human PON1, PON2, and PON3 genes and their flanking sequences were studied. We demonstrated that the PC transgene (PC-Tg) protected mice from cardiac hypertrophy induced by Ang II; these mice had reduced heart weight/body weight ratios, decreased left ventricular wall thicknesses and increased fractional shortening compared with wild-type (WT) control. The same protective tendency was also observed with an Apoe -/- background. Mechanically, PC-Tg normalized the disequilibrium of matrix metalloproteinases (MMPs)/tissue inhibitors of MMPs (TIMPs) in hypertrophic hearts, which might contribute to the protective role of PC-Tg in cardiac fibrosis and, thus, protect against cardiac remodeling. Taken together, our results identify a novel anti-hypertrophic role for the PON gene cluster, suggesting a possible strategy for the treatment of cardiac hypertrophy through elevating the levels of the PON gene family.

Developmental expression of paraoxonase 2

Paraoxonase 2 (PON2) is a member of the paraoxonase gene family also comprising PON1 and PON3. PON2 functions as a lactonase and exhibits anti-bacterial as well as antioxidant properties. At the cellular level, PON2 localizes to the mitochondrial and endoplasmic reticulum membranes where it scavenges reactive oxygen species. PON2 is of particular interest as it is the only paraoxonase expressed in brain tissue and appears to play a critical role in mitigating oxidative stress in the brain. The aim of this study was to investigate the expression of PON2 at the protein and mRNA level in the brain and liver of mice through development to identify potential age windows of susceptibility to oxidative stress, as well as to compare expression of hepatic PON2 to expression of PON1 and PON3. Overall, PON2 expression in the brain was lower in neonatal mice and increased with age up to postnatal day (PND) 21, with a significant decrease observed at PND 30 and 60. In contrast, the liver showed continuously increasing levels of PON2 with age, similar to the patterns of PON1 and PON3. PON2 protein levels were also investigated in brain samples from non-human primates, with PON2 increasing with age up to the infant stage and decreasing at the juvenile stage, mirroring the results observed in the mouse brain. These variable expression levels of PON2 suggest that neonatal and young adult animals may be more susceptible to neurological insult by oxidants due to lower levels of PON2 in the brain.

Association Between Paraoxonase Gene Polymorphisms and Intracerebral Hemorrhage in a Korean Population.

The human paraoxonase (PON) gene family includes three members: PON1, PON2, and PON3. PON, which prevents the oxidative modification of lipoproteins, has been implicated as a potential risk factor of the cerebrovascular disease. In this study, we investigated associations between coding region single-nucleotide polymorphisms (cSNPs) of PON1, PON2, and PON3 genes and intracerebral hemorrhage (ICH) in a Korean population. Six cSNPs [rs13306698 and rs662 for PON1; rs12026 and rs7493 for PON2; rs13226149 and rs1053275 for PON3] were genotyped using direct sequencing in 145 ICH patients and 372 control subjects. Of the six cSNPs, rs12026 and rs7493, which were in complete linkage disequilibrium, were associated with ICH in log-additive (GC vs. CC vs. GG, p = 0.0008, OR = 0.53, 95 % CI = 0.36-0.78) and dominant models (GC/CC vs. GG, p = 0.0006, OR = 0.47, 95 % CI = 0.30-0.73). In addition, rs13226149 was associated with ICH in log-additive model (GA vs. AA vs. GG, p = 0.0033, OR = 0.58, 95 % CI = 0.39-0.84). In the allele frequency analysis, the C alleles of rs12026 and rs7493 and the A allele of rs13226149 were also shown to contribute to the decreased risk of ICH (p = 0.001, OR = 0.55, 95 % CI = 0.38-0.80 in rs12026 and rs7493; p = 0.003, OR = 0.58, 95 % CI = 0.40-0.83 in rs13226149). These results suggest that PON genes may be involved in the susceptibility of ICH.

Inflammation, infection, cancer and all that…the role of paraoxonases.

The paraoxonase (PON) gene family consists of three members, PON1, PON2 and PON3. All PON proteins possess antioxidant properties and lipo-lactonase activities, and are implicated in the pathogenesis of several inflammatory diseases including atherosclerosis, Alzheimer's, Parkinson's, diabetes and cancer. Despite the role of PON proteins in critical cellular functions and associated pathologies, the physiological substrates and molecular mechanisms by which PON proteins function as anti-inflammatory proteins remain largely unknown. PON1 is found exclusively extracellular and associated solely with high-density lipoprotein (HDL) particles in the circulation, and, in part, confers the anti-oxidant and anti-inflammatory properties associated with HDL. Recent studies demonstrated that the intracellular PON proteins; PON2 and PON3 (i) are associated with mitochondria and mitochondria-associated membranes, (ii) modulate mitochondria-dependent superoxide production, and (iii) prevent apoptosis. Overexpression of PON2 and PON3 genes protected (i) mitochondria from antimycin or oligomycin mediated mitochondrial dysfunction and (ii) ER stress and ER stress mediated mitochondrial dysfunction. These studies illustrate that the anti-inflammatory effects of PON2 and PON3 may, in part, be mediated by their role in mitochondrial and associated organelle function. Since oxidative stress as a result of mitochondrial dysfunction is implicated in the development of inflammatory diseases including atherosclerosis and cancer, these recent studies on PON2 and PON3 proteins may provide a mechanism for the scores of epidemiological studies that show a link between PON genes and numerous inflammatory diseases. Understanding such mechanisms will provide novel routes of intervention in the treatment of diseases associated with pro-inflammatory oxidative stress.

Role of PON2 in innate immune response in an acute infection model

N-(3-oxododecanoyl)-l-homoserine lactone (3OC12-HSL) is a quorum-sensing molecule produced by gram-negative microbial pathogens such as Pseudomonas aeruginosa (PAO1). 3OC12-HSL is involved in the regulation of bacterial virulence factors and also alters the function of the host immune cells. Others and we have previously shown that paraoxonase 2 (PON2), a member of the paraoxonase gene family expressed in immune cells, hydrolyzes 3OC12-HSL. In this study, we examined i) whether macrophage PON2 participates in 3OC12-HSL hydrolysis, ii) the effect of PON2 deficiency in acute PAO1 infection in mice and iii) the effect of 3OC12-HSL on PON2 deficient (PON2-def) macrophages. When compared to wild type macrophages, both intact cells and membrane-enriched protein lysates obtained from PON2-def macrophages show a marked impairment in their ability to hydrolyze 3OC12-HSL. PON2 expression (message and protein) is not altered in response to 3OC12-HSL in macrophages. 3OC12-HSL treated PON2-def macrophages showed i) an increase in ER stress and oxidative stress, ii) defective phosphatidylinositol 3-kinase (PI3 kinase)/AKT activation, and iii) reduced phagocytosis function. Moreover, the nitration to phosphorylation ratio of Tyr458 in p85 protein, the regulatory subunit of PI3-kinase that has been correlated with the phagocytosis function of macrophages, was increased in PON2-def macrophages. Antioxidant treatment reversed the effects of PON2 deficiency in macrophage phagocytosis function. Furthermore, following administration of 1.6×107 CFU of PAO1, bacterial clearance was significantly reduced in the lungs (5.7 fold), liver (2.5 fold), and spleen (14.8 fold) of PON2-def mice when compared to wild type mice. Our results suggest that PON2 plays an important role in innate immune defense against PAO1 infection.

Association between paraoxonase gene and stroke in the Han Chinese population.

BackgroundThe human paraoxonase (PON) gene family has three isoforms: PON1, PON2 and PON3. These genes are implicated as potential risk factors of cerebrovascular disease and can prevent oxidative modification of low-density lipoproteins and atherosclerosis. This study evaluated the association between the genetic variants of all three PON genes and the risks of total stroke, ischemic stroke and hemorrhagic stroke in the Han Chinese population.MethodsA total of 1016 subjects were recruited, including 508 healthy controls and 498 patients (328 with ischemic stroke and 170 with hemorrhagic stroke). A total of 11 single nucleotide polymorphisms (SNPs) covering the PON genes were genotyped for statistical analysis. Two of the 11 SNPs (rs662 and rs854560) were contextualized in a meta-analysis of ischemic stroke.ResultsThe presence of rs705381 (−162) in the promoter region of PON1 was significantly associated with total stroke (Padjusted = 0.0007, OR = 0.57 [95% CI = 0.41-0.79]) and ischemic stroke (Padjusted = 0.0017, OR = 0.54 [95% CI = 0.37-0.79]) when analyzed using a dominant model, but was not associated with hemorrhagic stroke. There was also a nominal association between rs854571 (−824) and total stroke. Meta-analysis demonstrated a significant nominal association between rs662 and ischemic stroke, but there was no evidence of an association between rs662 and ischemic stroke risk in a single site association study.ConclusionsThese findings indicate that polymorphisms of PON1 gene may be a risk factor of stroke.

Association analysis of PON polymorphisms in sporadic ALS in a Chinese population

Single nucleotide polymorphisms (SNPs) of the paraoxonase gene family (ordered PON1, PON2, and PON3) have been associated with the risk of developing sporadic amyotrophic lateral sclerosis (SALS) in Caucasian populations. However, this association has yet to be confirmed in Chinese SALS patients. Nine SNPs across the PON gene cluster (i.e., rs662, rs705381, rs705382, rs854548, rs854560, rs7493, rs11981433, rs757158, and rs10487132) were analyzed in a large cohort consisting of 373 SALS patients and 248 controls from Southwest China. The data from the present study suggest that these SNPs of the PON gene cluster do not contribute to the risk for developing SALS in a Chinese population.

Modulation of paraoxonases during infectious diseases and its potential impact on atherosclerosis

The paraoxonase (PON) gene family includes three members, PON1, PON2 and PON3, aligned in tandem on chromosome 7 in humans and on chromosome 6 in mice. 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. The major goal of this review is to highlight the modulation of each of the PONs by infective (bacterial, viral and parasitic) agents, which may shed a light on the interaction between infectious diseases and PONs activities in order to effectively reduce the risk of developing atherosclerosis.