PON1 Q192R Polymorphism Research Articles

The association of paraoxonase I gene polymorphisms Q192R (rs662) and L55M (rs854560) and its activity with metabolic syndrome components in fars ethnic group.

Metabolic syndrome (MetS) may cause premature development of some diseases. PON1 genes may be involved in the pathogenesis of MetS. The aim of study was to evaluate the association between Q192R and L55M gene polymorphisms and its enzyme activity with the MetS components in subjects with and without MetS. Polymerase Chain Reaction and Restriction Fragment Length Polymorphism analysis were performed to determine polymorphisms of the paraoxonase1 gene in subjects with and without metabolic syndrome. Biochemical parameters were measured by spectrophotometer. The MM, LM, and LL genotype frequencies of the PON1 L55M polymorphism were 10.5, 43.4, and 46.1%, and 22.4, 46.6, and 31% and; the QQ, QR, and RR genotype frequencies of the PON1 Q192R polymorphism were 55.4, 38.6 and 6%; and 56.5, 34.8 and 8.7% in subjects with and without MetS, respectively. The L and M allele frequencies were 68 and 53%; and 32 and 47% for PON1 L55M in subjects with and without MetS, respectively. The Q and R allele frequencies for PON1 Q192R were 74 and 26% in both groups. There were significant differences in HDL-cholesterol level and PON1 activity in the genotypes QQ, QR, and RR of the PON1 Q192R polymorphism in subjects with MetS. The PON1 Q192R genotypes had only effected on PON1 activity and HDL-cholesterol level in subjects with MetS. Different genotypes of the PON1 Q192R seem to be important candidates to make the subjects susceptible to MetS in the Fars ethnic group.

Association Between Paraoxonase1 (Q192R and L55M) Gene Polymorphisms and Risk of Breast Cancer: A Meta-analysis of 12 Studies

Background: The paraoxonase1 gene (PON1) is part of the paraoxonase family of multifactorial antioxidants (EC 3.1.1.2). The functional single-nucleotide polymorphisms L55M and Q192R are located in the coding site of this gene. The association between these polymorphisms and breast cancer risk has been investigated, with contradictory results. Objectives: A meta-analysis was done to find the association between PON1 (L55M and Q192R) gene polymorphisms and breast cancer risk. Methods: We searched Embase, Pubmed, and Web of Science for related articles. Twelve eligible studies before December 2021 were selected. Statistical analysis was done by STATA 14.0. Result: We summarized 12 studies of L55M and Q192R polymorphisms and breast cancer risk, involving 5,769 subjects (2,519 controls and 3,250 patients). In all genetic models, PON1-L55M polymorphisms were significantly associated with breast cancer risk. Besides, PON1-Q192R polymorphisms decreased breast cancer risk. The PON1-Q192R allele reduced the cancer risk, particularly breast cancer (OR (R vs. Q): 0.7932). However, an association was found between the PON1-L55M allele and increased breast cancer risk (OR (M vs. L): 1.6041). Discussion: The results of 11 out of 12 studies were consistent with our results. In a non-conforming study, this was probably due to errors in conducting experiments. Nonetheless, well-designed studies with more samples are needed to confirm our findings at protein levels.

Genetic Attenuation of Paraoxonase 1 Activity Induces Proatherogenic Changes in Plasma Proteomes of Mice and Humans.

High-density lipoprotein (HDL), in addition to promoting reverse cholesterol transport, possesses anti-inflammatory, antioxidative, and antithrombotic activities. Paraoxonase 1 (PON1), carried on HDL in the blood, can contribute to these antiatherogenic activities. The PON1-Q192R polymorphism involves a change from glutamine (Q variant) to arginine (R variant) at position 192 of the PON1 protein and affects its enzymatic activity. The molecular basis of PON1 association with cardiovascular and neurological diseases is not fully understood. To get insight into the function of PON1 in human disease, we examined how genetic attenuation of PON1 levels/activity affect plasma proteomes of mice and humans. Healthy participants (48.9 years old, 50% women) were randomly recruited from the Poznań population. Four-month-old Pon1−/− (n = 17) and Pon1+/+ (n = 8) mice (50% female) were used in these experiments. Plasma proteomes were analyzed using label-free mass spectrometry. Bioinformatics analysis was carried out using the Ingenuity Pathway Analysis (IPA) resources. PON1-Q192R polymorphism and Pon1−/− genotype induced similar changes in plasma proteomes of humans and mice, respectively. The top molecular network, identified by IPA, affected by these changes involved proteins participating in lipoprotein metabolism. Other PON1 genotype-dependent proteomic changes affect different biological networks in humans and mice: “cardiovascular, neurological disease, organismal injury/abnormalities” in PON1-192QQ humans and “humoral immune response, inflammatory response, protein synthesis” and “cell-to-cell signaling/interaction, hematological system development/function, immune cell trafficking” in Pon1−/− mice. Our findings suggest that PON1 interacts with molecular pathways involved in lipoprotein metabolism, acute/inflammatory response, and complement/blood coagulation that are essential for blood homeostasis. Modulation of those interactions by the PON1 genotype can account for its association with cardiovascular and neurological diseases.

Effect of gene-environment interaction (arsenic exposure - PON1 Q192R polymorphism) on cardiovascular disease biomarkers in Mexican population

Cardiovascular diseases (CVDs) are the primary cause of death worldwide. However, little is known about how the interaction between risk factors affects CVDs. Therefore, the aim of this study was to evaluate the effect of the gene-environment interaction (arsenic exposure x PON1 Q192R polymorphism) on serum levels of CVDs biomarkers in Mexican women. Urinary arsenic levels (UAs) ranged from 5.50–145 μg/g creatinine. The allele frequency was 0.38 and 0.62 for the Q and R alleles, respectively. Moreover, significant associations (p<0.05) were detected between UAs and CVDs biomarkers (ADMA, FABP4, and miR-155). Comparable data were found when CVDs biomarkers were evaluated through PON1 genotype, significant (p<0.05) higher serum concentrations of CVDs biomarkers were identified in R allele carriers compared to levels found in Q allele carriers. Besides, a gene-environment interaction was documented. The results of this study we believe should be of significant interest to regulatory authorities worldwide.

PON1 Q192R Gene Polymorphism and Pesticide Exposure Status of Rice Farmers, Suphan Buri, Thailand

PON1 Q192R (rs662) polymorphism in coding region is conveying differential catalytic activity oforganophosphate. Study was aimed to investigate PON1 Q192R gene polymorphisms in rice farmers alongwith pesticide knowledge and practices; and to evaluate the relationship of gene polymorphisms and serumcholinesterase (SChE) levels. Information of pesticide exposure, knowledge and practices were collectedfrom 50 rice farmers and 50 control respondents by questionnaire interviewing. Each blood sample wasobtained by venipuncture and prepared to serum for SChE activity test by paper test and automatic analyzer;to EDTA blood for genotyping by PCR-RFLP. Exposure status, knowledge and practices on pesticide usewere represented as frequency. Chi-square was used to analyze on the different of personal information;and of polymorphism. Independent t-test was used for comparison of SChE levels. Person correlation wasevaluated relationship between SChE level and genotypes. 60% of rice farmers were used pesticide over10 years. Rice farmers were long-term pesticide exposure with good on pesticide knowledge, howeverpoorly practice. Means of SChE level of both groups were within reference value and significantly different(p = 0.033). Polymorphisms were included wild type (QQ), heterozygote (QR) and homozygote (RR);and were significantly different between rice farmers (high frequency of RR genotype) and control (p =0.02). Relationship of polymorphism and SChE level were negative correlated (r = -0.261; p = 0.031). Thispolymorphism may useful biomarker for chronic pesticide exposure in Thai rice farmer and corresponded todecline of serum cholinesterase; and RR genotype was high risk group.

The Role of PON1 Variants in Disease Susceptibility in a Turkish Population

Paraoxonase 1 (PON1) enzyme plays a major role in antioxidant defense and protects the cells against reactive species. The most common PON1 Q192R and L55M polymorphisms are responsible for a wide variation of PON1 activity, which showed an up to 13-fold interindividual variation among the same genotype. PON1 genotypes were evaluated with the development of pancreatitis, colorectal cancer, and hypothyroidism in a hospital-based, case-control study. Individuals with rs662 G allele had a two-fold risk of developing hypothyroidism. A weak association was found between rs854560 T allele and pancreatitis. The results were preliminary. Further studies with a larger number and detailed biochemical parameters are needed.

Prenatal maternal organophosphorus pesticide exposures, paraoxonase 1, and childhood adiposity in the Mount Sinai Children’s Environmental Health Study

BackgroundAnimal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. MethodsWe summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998–2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7–9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 –108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. ResultsThe geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: −0.6, 2.0) and 0.8% (95% CI: −0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: −0.6, 3.0) but not among those whose mothers had the CC genotype (β = −0.4%, 95% CI: −2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. ConclusionsWe observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.

Genetic associations and serum paraoxonase levels with atherosclerosis in western Iranian patients.

The oxidative modification of low-density lipoprotein (LDL) in the arterial wall plays a pivotal role in the initiation and progression of atherosclerosis which is a complex and progressive disorder. Paraoxonase1 (PON1), which is required for lipid metabolism, is believed to protect LDL from oxidation. The relationship between PON1 gene Leusin55Methionin (L55M) and Glutamine192Arginine (Q192R) polymorphisms in western Iranians with atherosclerosis and its association with enzyme activity and oxidized low-density lipoprotein (oxLDL) were examined in the present study. In this study, blood specimens were collected from 145 healthy individuals and 154 patients with atherosclerosis proven by angiography referred to Shahid Madani Hospital, Khorramabad, Iran. Genomic deoxy ribonucleic acid (DNA) was extracted from whole blood. For all the subjects, restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) was carried out for the detection of L55M and Q192R polymorphisms. PON1 enzyme activity and the level of oxLDL were also evaluated. There was a 3.114-fold increase in the risk of developing atherosclerosis in the subjects presenting the PON1L55M, MM genotype compared to those with the LL genotype (OR 3.114; 95% CI 1.412-6.870). PON1Q192R polymorphism in the PON1 gene was not associated with atherosclerosis. Patients with atherosclerosis had significantly higher oxLDL and reduced PON1 enzyme activity (P < 0.05) compared to the controls. There was no association between the type of genotype, enzyme activity, and oxLDL level. It has been concluded that PON1L55M polymorphism and MM genotype are associated with an increased risk of coronary artery disease (CAD) in Iranian patients with atherosclerosis. We did not find any relationship between PON1Q192R polymorphism and atherosclerosis.

The impact of cytochrome 450 and Paraoxonase polymorphisms on clopidogrel resistance and major adverse cardiac events in coronary heart disease patients after percutaneous coronary intervention

BackgroundClopidogrel is an inactive prodrug, it catalyzed into its active form by Cytochrome 450 and Paraoxonase-1(PON-1). polymorphisms of genes encoding these enzymes will affect the efficacy of Clopidogrel. The main objective of our study was to investigate the association of CYP2C19*2, CYP2C19*3 and PON-1Q192R polymorphisms with Clopidogrel resistance and major adverse cardiac events in Jin Hua district in the middle of Zhe Jiang Province in China.MethodsOne hundred sixty coronary heart disease patients with percutaneous coronary intervention, who were followed-up for 1 year, were enrolled in our study. These patients were co-administered aspirin 100 mg/d and clopidogrel 75 mg/d following a loading dose of 300 mg. The ADP-induced platelet aggregation rate was measured by Platelet aggregator. Genotypes of CYP2C19*2, CYP2C19*3, PON-1Q192R were determined using Sanger sequencing in all patients. Various clinical data were collected.ResultsThe frequencies of CYP2C19*2, CYP2C19*3 and PON-1Q192R homozygous mutant genotypes were significantly lower in non-responders than those in responders. After for all variables, CYP2C19*2, CYP2C19*3 and PON-1Q192R independently increased the risk of clopidogrel resistance with adjusted ORs 46.65(95% CI,1.77–25.04; p = 0.005); 22.74(95% CI, 3.11–166.27; p = 0.002); 5.69 (95% CI,1.06–30.47; p = 0.042). Over a follow-up of 12 months, the incidence of major adverse cardiac events (MACE) in CYP2C19*1/*2, *1/*3, *2/*2, *2/*3 was significantly higher than no mutant genotype (18/40vs.2/63,3/9vs.2/63, 11/6vs.2/63, 7/1vs2/63, respectively). There was no significant correlation between PON-1Q192R mutant allele and MACE.ConclusionOur study was first time to report on CYP2C19 and PON-1 polymorphisms in Jin Hua population in the middle of Zhe Jiang province in China. The carriage of CYP2C19*2 or *3 mutant allele significantly reduced the platelet response to clopidogrel and increase the MACE. The carriage of PON-1 mutant allele also significantly reduced the platelet response to clopidogrel, but would not increase the major adverse cardiac events after 1 year follow-up.Trial registrationChiCTR, ChiCTR1800018316. Registered 11 September 2018 – prospective registered, http://www.chictr.org.cn/edit.aspx?pid=30927&htm=4.

Clinical significance of PON1 L55M, Q192R and I102V polymorphisms and their association with prostate cancer risk in Polish men.

We tested the association between PON1 L55M, Q192R and I102V polymorphic variants and PC risk in Polish men. DNA from 110 consecutive, newly diagnosed patients hospitalized because of PC and DNA from 110 men - volunteers, healthy at the time of the study. PCR-RFLP method. In our study the average age at PC diagnosis of 55MM genotype carriers from families fulfilling Hereditary Prostate Criteria (HPC) was statistically significantly lower (by 7 years) than the average age at the disease diagnosis of 55MM carriers from families without HPC (54.6 ±6.7 vs. 61.9 ±5.4, respectively, p = 0.03). The probability of 5-year survival for the 55MM carriers was 81.3%, compared to 95.7% for non-carriers (p = 0.08, tendency). This is the first study in Polish men evaluating the impact of PON1 genetic polymorphisms on prostate cancer development and its clinical course. PON1 55MM variant may be probably associated with younger age at PC onset in men from families with HPC and with a shorter survival. However, more extensive studies on a larger number of PC patients, possibly from various populations, are necessary to confirm, and extend our findings.

Pon1 (Paraoxonase 1) Q192R gene polymorphism in ischemic stroke among North Indian population

PON1 is an HDL-associated esterase, two common polymorphisms in the PON1 gene, the Q192R and L55M substitutions, determine inter-individual variation in PON1 activity. The association of these polymorphisms with the risk of Ischemic stroke remains controversial. Hence, the role of PON1 Q192R gene polymorphism in Ischemic stroke was studied in North Indian Population. In the present study, the PON1 Q192R gene polymorphism was analyzed in Ischemic stroke patients (n-63) and age, sex and geography matched healthy controls (n-63) through PCR-RFLP method. Ethical clearance was obtained from Ethics committee for Human Research, Lady Hardinge Medical College, New Delhi. In the present study, distribution of PON1 Q192R gene polymorphism was not seen to differ between cases and controls. Unadjusted odds ratio analysis showed that RR genotype was found to pose 3.07 fold (CI = 0.30-30.67) increased risk for Ischemic stroke, albeit with no statistical significance (p = 0.34). The R allele was also found to pose 1.077 fold (CI = 0.50-2.29) increased risk for Ischemic stroke, albeit with no statistical significance (p = 0.847). After adjustment for conventional vascular and prothrombotic risk factors, odds ratio analysis revealed that both RR genotype [OR-0.153 (0.012 - 1.898), p = 0.144] and R allele [OR-0.932 (0.349 - 2.492), p = 0.888] posed reduced risk for Ischemic stroke, albeit with no statistical significance. Our study suggests the possible role of R allele of PON1 Q192R polymorphism as genetic risk factor when presented simultaneously with other known traditional risk factors of Ischemic stroke. Further studies are necessary before PON1 Q192R gene polymorphism can be considered as genetic risk factor for Ischemic Stroke.

Paraoxonases (PON) 1, 2, and 3 Polymorphisms and PON-1 Activities in Patients with Sickle Cell Disease.

(1) Background: Oxidative stress, chronic inflammation, vasoocclusion, and free iron are all features present in sickle cell disease. Paraoxonases (PON) are a family (PON-1, PON-2, PON-3) of antioxidant enzymes with anti-inflammatory action. Here, for the first time, we described PON-1 activities and PON-1, PON-2, PON-3 polymorphisms in patients with sickle cell disease, homozygous for HbSS, compared with healthy controls. (2) Methods: The groups were matched for age and gender. PON-1 activities (arylesterase and paraoxonase) were determined by enzymatic hydrolysis of phenylcetate and paraoxon, respectively. Polymorphisms were determined by Restriction Fragment Length Polymorphism- Polymerase Chain Reaction (RFLP-PCR). (3) Results: Plasma cholesterol and fractions, ApoA1 and ApoB levels were all decreased in sickle cell disease patients, while anti-oxidized low-density lipoprotein (LDL) antibodies and C-reactive protein were increased. Serum arylesterase activity was lower in sickle cell disease patients when compared with healthy controls. In patients, paraoxonase activity was higher in those with PON-1 RR Q192R polymorphism. In these patients, the increase of serum iron and ferritin levels and transferrin saturation were less pronounced than those observed in patients with QQ or QR polymorphism. No differences were observed with PON-1 L55M, and PON-2 and PON-3 polymorphisms. Multivariate regression analysis showed that transferrin and ferritin concentrations correlated with arylesterase and paraoxonase activities. (4) Conclusions: Both transferrin and ferritin were the main predictors of decreased arylesterase and paraoxonase activities in patients with sickle cell disease. LDL oxidation increased, and RR PON-1 Q192R polymorphism is likely to be a protective factor against oxidative damage in these patients.

The Association between PON1 (Q192R and L55M) Gene Polymorphisms and Risk of Cancer: A Meta-Analysis Based on 43 Studies.

Q192R and L55M polymorphism were considered to be associated with the development of multiple cancers. Nevertheless, the results of these researches were inconclusive and controversial. Therefore, we conducted a meta-analysis of all eligible case-control studies to assess the association between PON1 (Q192R and L55M) gene polymorphisms and risk of cancer. With the STATA 14.0 software, we evaluated the strength of the association by using the odds ratios (ORs) and 95% confidence intervals (CIs). A total of 43 case-control publications 19887 cases and 23842 controls were employed in our study. In all genetic models, a significant association between PON1-L55M polymorphisms and overall cancer risk was observed. Moreover, in the stratified analyses by cancer type, polymorphism of PON1-L55M played a risk factor in the occurrence of breast cancer, hematologic cancer, and prostate cancer. Similarly, an increased risk was observed in the Caucasian and Asian population as well as hospital-based group and population-based group. For PON1-Q192R polymorphisms, in the stratified analyses by cancer type, PON1-Q192R allele was associated with reduced cancer risks in breast cancer. Furthermore, for racial stratification, there was a reduced risk of cancer in recession model in Caucasian population. Similarly, in the stratification analysis of control source, the overall risk of cancer was reduced in the heterozygote comparison and dominant model in the population-based group. In conclusion, PON1-Q192R allele decreased the cancer risk especially breast cancer; there was an association between PON1-L55M allele and increased overall cancer risk. However, we need a larger sample size, well-designed in future and at protein levels to confirm these findings.

Both CYP2C19 and PON1 Q192R Genotypes Influence Platelet Response to Clopidogrel by Thrombelastography in Patients with Acute Coronary Syndrome.

Objective The objective of this study is to explore the relationships of the effects of CYP2C19 and PON1 Q192R polymorphism on the activity of clopidogrel and the risk of high platelet responsiveness (HPR) by thrombelastography in patients with acute coronary syndrome (ACS). Methods 459 ACS patients with aspirin and clopidogrel were enrolled in this observational case control study from July 13, 2015, to November 11, 2017. The patients with <30% platelet inhibition were defined as HPR group, while the others were defined as normal platelet responsiveness (NPR) group. The genotypes distribution between the groups was assessed, and the clinical impact of genetic variants was investigated by comparing the relationship between the risk of HPR and genotypes including CYP2C19⁎2, CYP2C19⁎3, CYP2C19⁎17, ABCB1, and PON1. Results Compared with CYP2C19⁎1/⁎1 wild type carriers, CYP2C19⁎2 and ⁎3 carriers showed a significant association with the lower platelet inhibition (P=0.048). The platelet inhibition in carriers of at least one CYP2C19 loss-of-function (LOF) alleles was obviously higher than noncarriers (P=0.031). The platelet inhibition of PON1 192R carriers was lower than PON1 192Q carriers (P=0.044). Patients with the CYP2C19⁎2 and ⁎3 alleles had a greater risk of HPR than CYP2C19 wild type carriers (adjusted P=0.018 and adjusted P=0.005). At least one PON1 192R carrier predicted a significantly higher risk of HPR than PON1 192Q carriers (adjusted P=0.021). Individual CYP2C19⁎17 and ABCB1 variants did not differ significantly between the two groups. Conclusions CYP2C19 and PON1 Q192R variants influence ADP-induced platelet inhibition by thrombelastography (TEG) in ACS patients with clopidogrel. In addition, both LOF CYP2C19 and PON1 192R variants are independent risk factors of HPR, which is measured by the relative platelet inhibition.

Relationship between internal and external factors and the activity of PON1

Paraoxonase 1 (PON1) is an A-esterase calcium-dependent enzyme that is associated with high-density lipoprotein (HDL) and capable of hydrolyzing a wide variety of substrates, including organophosphate (OP) pesticides. The PON1 phenotype can be modulated by multiple internal and external factors, thereby affecting the catalytic capacity of the enzyme. The aim of this study was to evaluate factors that could modulate PON1 activity in a sample occupationally exposed to pesticides. A cross-sectional, descriptive, and analytical study was carried out with 240 workers. The participants were stratified according to their level of pesticide exposure as reference, moderate-exposure, and high-exposure groups. PON1 activities (arylesterase/AREase, CMPAase, and ssPONase (salt-stimulated)) were determined by spectrophotometry, and the Q192R and L55MPON1 genotypes by real-time PCR. The most frequent genotypes were heterozygous (QR) and homozygous (LL) for PON1Q192R and PON1L55M polymorphisms, respectively. The internal factors associated with the activity of PON1 were the PON1 genotypes (55 and 192) and biochemical parameters related to the lipid profile, in contrast, various external factors related to diet and harmful habits as well as with exposure to pesticides were associated with the activity of PON1. However, using a multivariate mixed ordinal regression model, we found a significant reduction of ssPONase activity in the high-exposure group compared with the reference group only in haplotypes QQLL and RRLL.

Effects of nanoparticles exposure and PON1 genotype on heart rate variability

ObjectivesThis study was to assess the association between different NPs exposure and PON1 genotype on Heart Rate Variability (HRV) parameters among workers. MethodsThis study included 235 non-CVD subjects handled to nanomaterials (NM) and 185 non-exposed controls without CVD from 14 NM plants. All participants completed short-term HRV measurements, and were collected blood specimens to measure PON1 activities and the genotype of the PON1 Q192R polymorphism. ResultsIn a multivariate regression model, this study observed a positive relationship between nano-Ag exposure and HRV time-domain (RMSSD) and frequency-domain (HF). After adjusting for confounders, the results showed positive associations between RR homozygosity, PON1 paraoxonase/arylesterase activities with HRV, and was particularly noteworthy in RMSSD and HF. ConclusionsThis study shows a significant increment of RMSSD and HF among workers who handled Nano-Ag materials. These results imply that Nano-Ag and PON1 Q192R genotype can trigger ANS reflexes and alter cardiac frequency and function.

Paraoxonase 1 (PON1) Q192R and L55M polymorphisms, lipid profile, lipid peroxidation and lipoprotein-a levels in Turkish patients with pregnancy-related disorders

The aim of this study was to investigate the role of PON1Q192R and L55M single nucleotide polymorphisms(SNPs) and its association with the maternal levels of lipid parameters in gestational diabetes mellitus(GDM) and preeclampsia(PE). Ninety-nine pregnant with GDM, 97 pregnant with PE and 98 healthy pregnant were included in the study. No statistically significant difference was observed in the alleles or in the genotypes frequencies of SNPs between groups. In GDM patients, total cholesterol was higher in MM genotype of L55M gene (p < .05); Lp(a) were lower in LM genotype of the gene compared to their respective control (p < .05). In PE, HDL-C levels were higher in LM genotype (p < .05); LDL-C levels were lower in MM genotype of the gene compared to their respective control (p < .05). In PE patients, malondialdehyde(MDA) were higher in QQ genotype compared to their respective control (p < .05). Triglyceride levels were higher in PE patients with QR genotype compared with GDM patients with QR genotype (p < .05). Our results indicated that lipid profiles, Lp(a) and MDA levels showed significant differences in GDM and PE pregnants. These findings support the importance of the lipid profile, oxidized lipid and Lp(a) in different genotypes of L55M and Q192R in Turkish pregnant women with PE/GDM suggesting their roles in etiopathogenesis in these pregnancy-related disorders.

Serum paraoxonase 1 activity and protein N-homocysteinylation in primary human endometrial cancer.

Paraoxonase 1 plays an important role in protection from oxidative stress and also decomposes homocysteine thiolactone, the toxic metabolite of homocysteine. A limited number of reports evaluated the role of paraoxonase 1 in women affected by female genital tract neoplasms, including endometrial cancer. This study aimed to analyze the paraoxonase activity in the group of endometrial cancer patients (n = 48) who underwent primary surgery and to compare the data available with a well-matched control group (n = 30). Due to the role of paraoxonase 1 in the metabolism of homocysteine (Hcy) thiolactone, the amount of Hcy-thiolactone as well as total serum Hcy concentrations was also measured. Serum paraoxonase 1 activity toward synthetic substrates, paraoxon and phenyl acetate, in the study group was significantly lower compared to the control one. The mean paraoxonase 1 activity toward homocysteine thiolactone tended to be lower in the endometrial cancer group but this difference was not significant. There was no relationship between endometrial cancer and Q192R polymorphism of PON1 assessed by the dual substrate method. No differences in paraoxonase 1 activity between endometrial cancer subgroups according to clinico-pathological features were detected. Total serum homocysteine and protein-bound homocysteine thiolactone did not differ between control and cancer groups. In conclusion, reduced paraoxonase 1 activity suggests diminished important antioxidant mechanisms during the development of primary endometrial cancers in humans. PON1 Q192R polymorphism is not associated with the risk of endometrial cancer. Despite lower paraoxonase 1 activity, homocysteine concentration, and protein N-homocysteinylation in endometrial cancers do not differ from matched controls.

Association between the PON1 Q192R polymorphism and coronary heart disease in Chinese: A meta-analysis.

Background:The relation has not been reported consistently between the PON1 Q192R polymorphism and coronary heart disease (CHD). To clarify the discrepancy, we performed the present meta-analysis to evaluate the association between the PON1 gene Q192R polymorphism and CHD risk in Chinese population.Methods:We conducted a comprehensive search of the PubMed, EMBASE, and China National Knowledge Infrastructure databases for all available case–control studies. Two reviewers independently selected studies. Data were analyzed by STATA software package v 12.0.Results:Thirteen studies investigating the association between the PON1 Q192R polymorphism and risk of CHD were selected in this meta-analysis with 4353 cases and 4882 controls. The association between the PON1 Q192R polymorphism and CHD is statistically significant under the recessive genetic model (R/R vs Q/R + Q/Q, odds ratio [OR] = 1.111, 95% confidence interval [CI] = 1.017–1.214). We observed no statistical association between PON1 Q192R polymorphism and risk of CHD under allele model (R vs Q, OR = 1.087, 95% CI = 0.976–1.209), homozygous model (RR vs QQ, OR = 1.192, 95% CI = 0.949–1.496), and dominant genetic model (Q/R + R/R vs Q/Q, OR = 1.127, 95% CI = 0.938–1.354).Conclusion:This meta-analysis suggests that the PON1 Q192R polymorphism has a weak association with CHD risk in Chinese.

2042 CYP2C19*2 and PON1 Q192R polymorphisms are associated with platelet reactivity to clopidogrel in Puerto Rican Hispanics with cardiovascular disease

OBJECTIVES/SPECIFIC AIMS: High on-treatment platelet reactivity (HTPR) with clopidogrel imparts an increased risk for ischemic events in adults with coronary artery disease. Although more potent antiplatelet agents are available, clopidogrel remains the most commonly used P2Y12 inhibitor in Puerto Rico. Platelet reactivity varies with ethnicity and is influenced by both clinical and genetic variables; however, no clopidogrel pharmacogenetic studies with Puerto Rican patients have been reported. Therefore, we sought to identify clinical and genetic determinants of on-treatment platelet reactivity in a cohort of Puerto Rican patients with cardiovascular disease. METHODS/STUDY POPULATION: We performed a retrospective study of 111 Puerto Rican patients on 75 mg/day maintenance dose of clopidogrel. Patients were allocated into 2 groups: Group I, without HTPR; and Group II, with HTPR. Clinical data was obtained from the medical record. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay and HTPR was defined as P2Y12 reaction units (PRU)≥230. Genotyping of CYP2C19, ABCB1, PON1, PY2R12, B4GALT2, CES1, and PEAR1 was performed using Taqman® Genotyping Assays. RESULTS/ANTICIPATED RESULTS: The mean PRU across the cohort was 203±61 PRU (range, 8–324), and 42 (38%) patients had HTPR. One in four individuals carried at least 1 copy of the CYP2C19*2 variant allele. Hematocrit and PON1 p.Q192R variant were inversely correlated with platelet reactivity (p&lt;0.05). Multiple logistic regression showed that 27% of the total variation in PRU was explained by a history of diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R. Body mass index (OR=1.15; CI: 1.03–1.27), diabetes mellitus (OR=3.46; CI: 1.05–11.43), hematocrit (OR=0.75; CI: 0.65–0.87), and CYP2C19*2 (OR=4.44; CI: 1.21–16.20) were the only independent predictors of HTPR. DISCUSSION/SIGNIFICANCE OF IMPACT: In a representative sample of Puerto Rican patients with cardiovascular disease, diabetes mellitus, hematocrit, CYP2C19*2, and PON1 p.Q192R were associated with on-treatment platelet reactivity. These factors may identify a subset of patients at higher risk for adverse events on clopidogrel in the Hispanic population.