Paraoxonase Gene Research Articles

The Effects of PON1 (Q192R, rs662) Gene Polymorphism, Heavy metals and Oxidative Stress on Risk of Recurrent Spontaneous Abortion in Samples of Iraqi Women

Recurrent spontaneous abortion (RSA) is defined as the occurrence of two or more spontaneous pregnancy losses before reaching the midpoint of gestation. Oxidative stress plays a pivotal role in the pathogenesis of RSA, serving as a key factor in its underlying causes. This research aims to investigate the connection between the Q192R polymorphisms identified in the PON1 gene, responsible for encoding an antioxidant enzyme and the vulnerability to RSA. Paraoxonase 1 (PON1) is a critical enzyme in the body's antioxidant defence system, safeguarding cells against damage caused by reactive oxygen species and heavy metal concentrations that affect pregnancy. The most prevalent PON1 polymorphism is Q192R (rs662), known to influence the antioxidant activity and power of the PON1 enzyme. In this research, blood samples were collected from two groups: 50 women with RSA and 50 women who were apparently in good health. Following DNA extraction, high-resolution melting (HRM) analysis was used to identify the studied SNP; Elisa was used to determine DNA damage and MDA concentrations in serum and heavy metals were determined by a Graphite Furnace-Atomic Absorption Spectrophotometer (GFAAS). The results of this study showed significantly higher levels of 8-OHdG, MDA, arsenic and lead in serum in RSA patients than in apparently healthy women. The genotype findings indicated that the prevalence of the QR (AG) genotype in women experiencing recurrent spontaneous abortion was notably greater than that in seemingly healthy women (74% compared to 16%, respectively, with an odds ratio of 27.2). The values of allele frequency for the A allele were 0.76 and 0.51 for apparently healthy women and women with recurrent spontaneous abortion respectively. The G allele frequency was 0.24 and 0.49 for apparently healthy women and women with recurrent spontaneous abortion respectively. The heterozygous QR genotype is related to the risk of RSA and the minor allele (G allele) is increased in women with RSA.

Effect of hydroalcoholic extract of Tanacetum parthenium on gene expression and paraoxonase 1 enzyme activity: An experimental and molecular dynamic study

Background and aims: Cardiovascular diseases are among the most common causes of death worldwide. The paraoxonase 1 (PON1) enzyme is a main factor in preventing these diseases. This study investigated the effect of hydroalcoholic extract of Tanacetum parthenium plant on the activity and gene expression of PON1. Methods: Forty male rats were divided into 4 groups: a control group, a hyperlipidemic group, and two hyperlipidemic groups that were treated with 400 and 800 mg/kg of hydroalcoholic extract. Arylesterase activity of PON1 and serum triglyceride and cholesterol levels were measured. Moreover, the gene expression of PON1 in the liver tissue samples was measured using real-time PCR. Finally, molecular dynamics studies of apigenin as a main compound in the plant were performed to investigate the activity of PON1 in the simulated environment. Results: Hydroalcoholic extract of T. parthenium decreased serum triglyceride (from 105.8±10.1 to 60.5±21.5 and 50.9±11.2 mg/dL) and total cholesterol (from 97.5±16.8 to 59.6±8.5 and 52.0±9.6 mg/dL) levels, while it increased the activity of arylesterase paraoxonase1 significantly (P<0.001). It also showed a significant (P<0.001) effect on PON1 gene expression. However, the dose of 800 mg/kg was more effective. The results of simulation and molecular dynamics showed that apigenin binds to PON1 with a high affinity and induces changes in the molecular dynamics parameters. Conclusion: The 800 mg/kg of hydroalcoholic extract of T. parthenium can increase the activity of PON1 and its gene expression. It seems that apigenin as one of the most important antioxidant compounds of this plant can increase the activity of this enzyme by direct binding to PON1.

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.

A comprehensive insight from molecular docking and dynamics with clinical investigation on the impact of direct oral anticoagulants on atheroprotective protein in atrial fibrillation

BackgroundDirect oral anticoagulants (DOACs) have high potency against their therapeutic target and are widely used in the treatment of atrial fibrillation (AF). Most DOACs are often claimed to have adverse effects due to off-target inhibition of essential proteins. Human serum paraoxonase 1 (PON1), one of the essential proteins, known for its anti-inflammatory and antioxidant properties, could be affected by DOACs. Thus, a comparative evaluation of DOACs and their effect on PON1 protein will aid in recommending the most effective DOACs for AF treatment. This study aimed to assess the impact of DOACs on PON1 through a combination of computational and experimental analyses.MethodsWe focus on apixaban, dabigatran, and rivaroxaban, the most recommended DOACs in AF treatment, for their impact on PON1 through molecular docking and molecular dynamics (MD) simulation to elucidate the binding affinity and drug-protein structural stability. This investigation revealed the most influential DOACs on the PON1 protein. Then experimental validation was performed in DOAC-treated AF participants (n = 42; 19 treated with dabigatran and 23 treated with rivaroxaban) compared to a healthy control group (n = 22) through gene expression analysis in peripheral blood mononuclear cells (PBMC) and serum enzyme concentration.ResultsOur computational investigation showed rivaroxaban (−4.24 kcal/mol) exhibited a lower affinity against the PON1 protein compared to apixaban (−5.97 kcal/mol) and dabigatran (−9.03 kcal/mol) through molecular docking. Dabigatran holds complex interactions with PON1 at GLU53, TYR197, SER193, and ASP269 by forming hydrogen bonds. Additionally, MD simulation revealed that dabigatran disrupts PON1 stability, which may contribute functional changes. Further experimental validation revealed a significant down-regulation (p < 0.05) of PON1 gene expression in PBMC and decreased serum PON1 enzyme concentration on DOAC treatment. Rivaroxaban as about 48% has inhibitory percentage and dabigatran as about 75% of inhibitory percentage compared to healthy control.ConclusionOverall, our computational and experimental results clearly show the higher inhibitory effect of dabigatran than rivaroxaban. Hence, rivaroxaban will be a better drug candidate for improving the outcome of AF.

Association of paraoxonase-1 (Q192R) gene polymorphism with coronary artery spasm during cardiac catheterisation in Egyptians

Background Coronary artery spasm is among the etiology of myocardial infarction. Oxidative stress is involved in the pathogenesis of coronary artery spasm (CAS). Paraoxonase-1 (PON1) is an HDL-bound antioxidant enzyme that protects LDL from oxidative modification. Oxidative-stress-related genetic factors and certain polymorphisms in the paraoxonase 1 gene might influence the pathogenesis of CAS. We aimed to investigate the association between PON1 gene polymorphism and its enzymatic activity and coronary artery spasm during cardiac catheterization. Methods and results The study population was 150 patients who underwent elective coronary angiography. Subjects were genotyped to the Q192R polymorphism (rs662) on the PON1 gene by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and PON1 activity was quantitatively analyzed by enzyme linked immunosorbent assay. Results showed that the subjects carrying the RR genotype and R allele were significantly more likely to develop coronary artery spasm (OR=4.2, 2.03, P< 0.006, P˂0.02, respectively). Moreover, serum PON1 levels were significantly decreased (P˂0.001) in the CAS group. RR genotype of PON1 Q192R polymorphism, Tc, LDLc, TG, catheter size, and paroxonase-1 serum level are independent predictors of coronary spasm. Conclusion We conclude that the PON1 (rs662) gene polymorphism is associated with CAS during cardiac catheterization in Egyptians. The PON1-192R allele and lower serum enzyme concentration may play an important role in coronary spasm.

Association between paraoxonase 1 -108C/T polymorphism and coronary heart disease: an updated meta-analysis.

At present, no consensus is reached among articles that investigate the relationship of paraoxonase 1(PON1) -108C/T polymorphism with susceptibility of coronary heart disease (CHD) so far. In this regard, the present meta-analysis was conducted to comprehensively review existing articles related to the relationship of PON1 -108C/T polymorphism with CHD susceptibility. It was preregistered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY)-INPLASY202430117. Articles that explored the relationship between PON1 -108C/T polymorphism and CHD incidence were searched from electronic databases according to our preset study selection criteria. Thereafter, we adopted stata 12.0 software to analyze our screened studies. At the same time, odds ratios (ORs) and related 95% confidence intervals (95% CIs) were determined for evaluating association strength. At last, this meta-analysis selected altogether 13 case-control studies that involved 2,979 cases and 2,887 control subjects. We found that the PON1 -108C/T polymorphism displayed marked relationship with CHD susceptibility (T vs. C: OR = 1.24, 95% CI 1.07-1.45; CT vs. CC: OR = 1.33, 95% CI 1.17-1.52; TT vs. CC: OR = 1.51, 95% CI 1.09-2.09; Recessive model: OR = 1.16, 95% CI 0.93-1.45; Dominant model: OR = 1.45, 95% CI 1.16-1.81). Moreover, subgroup analysis showed that race and sample size had no impact on the results. Bioinformatics analysis showed that -108C>T polymorphism was relation to PON1 gene expression (https://gtexportal.org/home/). The PON1 -108T allele is identified as the possible low-penetrant risk factor of CHD, as suggested by our present meta-analysis.Systematic Review Registration: https://inplasy.com/inplasy-2024-3-0117/, Identifier INPLASY202430117.

Pon1 and Sult1a1 Polymorphisms and Breast Cancer Among Young Women in Brazil.

Purpose: To investigate the association of genetic polymorphisms Gln192Arg and Leu55Met of Paraoxonase 1 (PON1) gene, and Arg213His of Sulfotransferase 1A1 (SUT1A1) gene with occurrence of breast cancer among young women living in Rio de Janeiro city. Methods: This is a hospital-based case-control study including 265 women aged 18-35 years, diagnosed with breast cancer at National Cancer Institute; and 277 controls in the same age group selected among women patients and companions of three general hospitals from Rio de Janeiro public health network. Polymorphisms genotyping was performed using the PCR-RFLP technique. Results: For PON1 gene, breast cancer women had a greater chance of being homozygote for Leu55Met polymorphism (ORadjusted = 1.42, 95% CI= 0.67-3.00, recessive model) and a lower chance of having at least one allele of Gln192Arg polymorphism (ORadjusted = 0.75, 95% CI = 0.50-1.13, dominant model), but without statistical significance. Accordingly, frequency of the haplotype Met55/Arg192 was lower among breast cancer women, but no statistically significant association was observed (ORadjusted = 0.85; 95% CI = 0.48-1.51). SULT1A1 His/His genotype was significantly associated with a protective effect for breast cancer (OR adjusted = 0.51, 95% CI = 0.28-0.91, recessive model). Conclusion: Arg213His polymorphism of SUT1A1 gene showed a protective effect against breast cancer among Brazilian young women. More studies with different designs are needed to understand the role of PON1 and SULT1A1 polymorphisms in breast cancer development in young Brazilian women.

Association of the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene with preeclampsia among Chinese women

To assess the association of -c.108C>T and c.192Q>R polymorphisms of paraoxonase 1 (PON1) gene with preeclampsia (PE) and the influence of genotypes on the metabolic and oxidative stress indexes among Chinese women. This case-control study has included 334 patients with PE and 1337 healthy pregnant women. The -c.108C>T and c.192Q>R genotypes were determined by PCR and restriction fragment length polymorphism method. Metabolic and oxidative stress parameters were also analyzed. No statistical difference in the genotypic and allelic frequencies for the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene was found between the PE patients and the healthy controls (P > 0.05). Nevertheless, the 192Q-108T haplotype of these polymorphisms was associated with an increased risk of PE (P = 0.007). Total antioxidant capacity (TAC) and atherosderosis index were higher in patients with the -108TT genotype compared with those with a CT genotype (P < 0.05); whilst total oxidant status was lower in patients with a CT genotype compared with those with a CC genotype (P = 0.036). Malondialdehyde level was higher in patients with a 192RR genotype compared with those with a QQ genotype (P = 0.019). TAC level was higher in patients with a RR genotype compared with those with a QR genotype (P = 0.015). The 192Q-108T haplotype of the PON1 gene is associated with the risk for PE. These polymorphisms may be associated with abnormal lipid metabolism and oxidative stress among Chinese PE patients.

Bioinformatic Investigation of Genetic Changes in Paraoxonase Genes in Breast Cancer and Breast Cancer Subtypes.

Among women, breast cancer (BC) is the most prevalent form of cancer. Many molecular targets have been discovered for BC prognosis and treatment. However, new markers still need to be identified, as cancer pathogenesis is triggered by different mechanisms. The aim of this study was to examine the changes in the paraoxonase genes (PON1, PON2, and PON 3) involved in the pathogenesis of BC. The characteristics of the mutations were evaluated with the Cbioportal database. Kaplan-Meier Plot evaluated recurrence-free survival (RFS). The UALCAN database determined the promoter methylation. Gene expression was evaluated by GEPIA2.0 database. PON1 harbored the most mutations. There was a significant decrease in PON3 expression levels in BC samples compared with healthy samples. PON1 and PON2 expression levels did not differ between BC tissue and normal adjacent tissue. Elevated expression levels of PON1 and PON2 genes were correlated with longer RFS, whereas reduced expression of the PON2 gene showed an association with longer RFS. Moreover, the promoter regions of PON1 and PON 3 were found to be hypermethylated, while the promoter region of PON 2 was found to be hypomethylated. The PON3 promoter region was significantly hypermethylated in luminal and human epidermal growth factor receptor 2 (HER2) + BC subtypes. However, the PON3 promoter region was significantly hypomethylated in the triple negative breast cancer (TNBC) subtype. These results suggest that methylation and expression status of PON3 in BC and BC subtypes (TNBC, luminal and HER2) may indicate a poor prognosis. The PON3 gene could be a negative prognostic marker in BC. However, the results should be supported by prospective studies.

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.

PON1, APOE and SDF-1 Gene Polymorphisms and Risk of Retinal Vein Occlusion: A Case-Control Study.

Numerous studies have tried to evaluate the potential role of thrombophilia-related genes in retinal vein occlusion (RVO); however, there is limited research on genes related to different pathophysiological mechanisms involved in RVO. In view of the strong contribution of oxidative stress and inflammation to the pathogenesis of RVO, the purpose of the present study was to investigate the association of inflammation- and oxidative-stress-related polymorphisms from three different genes [apolipoprotein E (APOE), paraoxonase 1 (PON1) and stromal cell-derived factor 1 (SDF-1)] and the risk of RVO in a Greek population. Participants in this case-control study were 50 RVO patients (RVO group) and 50 healthy volunteers (control group). Blood samples were collected on EDTA tubes and genomic DNA was extracted. Genotyping of rs854560 (L55M) and rs662 (Q192R) for the PON1 gene, rs429358 and rs7412 for the APOE gene and rs1801157 [SDF1-3'G(801)A] for SDF-1 gene was performed using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Multiple genetic models (codominant, dominant, recessive, overdominant and log-additive) and haplotype analyses were performed using the SNPStats web tool to assess the correlation between the genetic polymorphisms and the risk of RVO. Binary logistic regression analysis was used for the association analysis between APOE gene variants and RVO. Given the multifactorial nature of the disease, our statistical analysis was adjusted for the most important systemic risk factors (age, hypertension and diabetes mellitus). The dominant genetic model for the PON1 Q192R single nucleotide polymorphism (SNP) of the association analysis revealed that there was a statistically significant difference between the RVO group and the control group. Specifically, after adjusting for age and hypertension, the PON1 192 R allele (QR + RR) was found to be associated with a statistically significantly higher risk of RVO compared to the QQ genotype (OR = 2.51; 95% CI = 1.02-6.14, p = 0.04). The statistically significant results were maintained after including diabetes in the multivariate model in addition to age and hypertension (OR = 2.83; 95% CI = 1.01-7.97, p = 0.042). No statistically significant association was revealed between the other studied polymorphisms and the risk of RVO. Haplotype analysis for PON1 SNPs, L55M and Q192R, revealed no statistically significant correlation. In conclusion, PON1 192 R allele carriers (QR + RR) were associated with a statistically significantly increased risk of RVO compared to the QQ homozygotes. These findings suggest that the R allele of the PON1 Q192R is likely to play a role as a risk factor for retinal vein occlusion.

Investigation of the effects of Terminalia chebula seed hydroalcoholic extract on Paraoxonase1 enzyme activity in rats

Background and aims: Paraoxonase 1 (PON1) is related to high-density lipoprotein (HDL) in serum and protects against low-density lipoprotein (LDL) oxidation. This study aimed to investigate the effects of Terminalia chebula on PON1 in hyperlipidemic rats and the molecular docking effects of some compounds of this medical plant on PON1 activity. Methods: Overall, 40 male rats (200–250 gr) were randomly divided into four groups, including the control group, the hyperlipid group, the hyperlipid group receiving 400 mg/kg of the hydroalcoholic extract of T. chebula seeds, and the hyperlipid group receiving 800 mg/kg of the hydroalcoholic extract of T. chebula seeds. The PON1 arylesterase activity in serum and the PON1 gene expression in the liver tissue underwent investigation. Then, the molecular docking effects of its compounds were studied on PON1 through in-silico studies using the AutoDock software (version 4.2.0). Results: T. chebula decreased (P&lt;0.001) the serum triglycerides from 105.88±10.15 mg/dL in the hyperlipidemic group to 66.88±14.90 and 74.25±9.51 mg/dL in hyperlipidemic groups receiving 400 and 800 mg/kg of the hydroalcoholic extract of T. chebula seeds, respectively. In addition, the PON1 serum aryl esterase activity increased from 202.12±6058 in hyperlipidemic rats to 224.34±58.74 (P=0.83) and 235.80±37.05 (P=0.6) in hyperlipidemic groups receiving 400 mg/kg and 800 mg/kg of the hydroalcoholic extract of T. chebula seeds, respectively. It also demonstrated a significant effect on PON1 gene expression (P&lt;0.001). In addition, the in-silico and docking results revealed that the main antioxidant compounds of T. chebula, such as catechin, kaempferol, and quercetin, could bind to the PON1 enzyme directly and influence the enzyme activity. Conclusion: T. chebula increased PON1 activity and PON1 gene expression. However, among the plant’s compounds, catechin, kaempferol, and quercetin played the most substantial role in the PON1 activity. It seems that these compounds can be useful as co-treatments in hyperlipidemia therapies.

Ассоциации полиморфизма гена параоксаназы 1 с поражением коронарного русла у больных хронической ишемической болезнью сердца и сахарным диабетом 2-го типа

Aim. To determine the features of coronary lesions in patients with chronic coronary heart disease (CHD) and type 2 diabetes mellitus (DM), to analyze their relationship with polymorphic variants of the paraoxonase gene (PON) 1. Design. A cross-sectional retrospective observational study. Materials and methods. The study included 200 patients with a stable form of IHD, divided into two groups: the main group included 112 people with IHD in combination with type 2 diabetes, the comparison group included 88 patients without carbohydrate metabolism disorders. All patients underwent selective coronary angiography (CAG) using a General Electric INNOVA 3100IQ angiographic unit (GE, USA) according to the M. Judkins method. Real-time polymerase chain reaction (PCR) was used to determine the rs622 polymorphism of the PON1 gene. Statistical processing of the obtained results was carried out using the IBM SPSS Statistics Version 25.0 software package (International Business Machines Corporation, USA). Results. In patients with coronary artery disease on the background of type 2 diabetes, coronary lesions were more often of a multivessel nature (p = 0.015) with the development of hemodynamically significant stenoses (p = 0.027); compared with patients with coronary artery disease without diabetes, they had more cases of lesions in the middle and distal parts of the arteries (p = 0.005 and p = 0.038, respectively). Multivascular coronary disease in patients was associated with the presence of the GG genotype rs622 of the PON1 gene (in the main group p = 0.010, odds ratio (OR) = 5.098, confidence interval (95% CI) — 1.337–19.433, in the comparison group p = 0, 02, OR = 7.143, 95% CI — 1.287–39.630). The AG genotype of the rs622 polymorphism of the PON1 gene has a protective effect against widespread lesions of the coronary arteries in patients with coronary artery disease and type 2 diabetes (p = 0.019, OR = 0.377, 95% CI — 0.165–0.860) and the development of hemodynamically significant stenoses of the coronary arteries in patients with IHD without diabetes (p = 0.005, OR = 0.255, 95% CI — 0.966–0.676). Conclusion. In patients with coronary heart disease and type 2 diabetes, coronary angiography demonstrated pronounced atherosclerotic changes in the coronary arteries. Multivessel coronary lesion is associated with the GG genotype of the rs622 polymorphism of the PON1 gene, which determines the possibility of predicting and further preventing the development of coronary heart. Key words: coronary heart disease, coronary atherosclerosis, type 2 diabetes mellitus, multivessel lesion, gene polymorphism, paraoxanase 1

The Regulatory Variant -108C/T in the Promoter of Paraoxonase 1 (PON1) Gene has a More Important Role in Regulating PON1 Activity Compared to rs3735590 in 3'-UTR in Patients with Coronary Artery Disease.

This study aimed to assess the serum activity of paraoxonase 1 (PON1) in patients with coronary artery disease (CAD) based on two genetic variants including the -108C/T variant in the promoter region and the rs3735590 variant in the binding site of miR-616 at the 3'-UTR of the PON1 gene. A total of 140 subjects who exhibited clinical symptoms of CAD underwent diagnostic coronary angiography. The patients with CAD were further categorized into two groups: single-vessel disease (SVD) and multi-vessel disease (MVD). The study variants were genotyped using the restriction fragment length polymorphism (RFLP) technique after polymerase chain reaction amplification. After adjusting for age, gender, body mass index, metformin, and statin usage, a significant association was observed between the -108C/T variant and PON1 activity (P < 0.001). In the sub-groups of both SVD and MVD, individuals with the TC+CC genotypes exhibited significantly higher PON1 activity compared to TT homozygotes (P = 0.001 for SVD and P = 0.01 for MVD). As for the rs3735590 variant, individuals with the A allele (GA+AA genotypes) had higher PON1 activity compared to those with the GG genotype in both the SVD and MVD groups, although the results did not reach statistical significance. Our study findings indicate a significant decrease in PON1 activity among patients with obstructive CAD. Notably, our results suggest that the -108C/T variant exerts a greater influence on PON1 activity compared to the rs3735590 variant. These findings highlight the crucial role of the -108C/T variant in modulating PON1 activity within the context of atherosclerosis.

Methylprednisolone Does Not Enhance Paraoxonase 1 Activity During Cardiopulmonary Bypass Surgery—A Randomized, Controlled Clinical Trial

ObjectivesCardiopulmonary bypass (CPB) is linked to systemic inflammatory responses and oxidative stress. Paraoxonase 1 (PON1) is an antioxidant enzyme with a cardioprotective role, whose activity is decreased in systemic inflammation, and in patients with acute myocardial and global ischemia. Glucocorticoids counteract the effect of oxidative stress by up-regulating PON1 gene expression. We aimed to determine the effect of methylprednisolone on PON1 activity during cardiac surgery on CPB. DesignProspective, randomized, controlled clinical trial. SettingThe study was conducted at the University Medical Centre Ljubljana, Slovenia. Participants40 adult patients, who underwent complex cardiac surgery on CPB between February 2016 and December 2017, were randomized into methylprednisolone and control group (n=20 each). InterventionsPatients in the methylprednisolone group received 1g of methylprednisolone in the CPB priming solution, while patients in the control group were not given methylprednisolone during CPB. Measurements and Main ResultsWe compared the effect of methylprednisolone from CPB priming solution with standard care during CPB on PON1 activity until the 5. postoperative day. Correlations of PON1 activity with lipid status, mediators of inflammation, and hemodynamics were analyzed as well. No significant differences existed between study groups for PON1 activity, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) in any of the measurement intervals (p>0.016). Methylprednisolone group had significantly lower TNF-a (p<0.001), IL-6 (p<0.001), as well as CRP and procalcitonin (p<0.016) after surgery. No significant difference was found between groups for hemodynamic parameters. A positive correlation existed between PON1 and lipid status, whereas a negative correlation was found between PON1 activity and TNF-a, IL-6, as well as CPB duration. ConclusionsMethylprednisolone doesn't influence PON1 activity during cardiac surgery on CPB.

The effect of rs662 genetic polymorphism of the paraoxonase-1 gene on the level of adipokines and myokines in the blood of obese children

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CDKN2B-AS (rs2891168), SOD2 (rs4880), and PON1 (rs662) polymorphisms and susceptibility to coronary artery disease and type 2 diabetes mellitus in Iranian patients: A case-control study.

Coronary artery disease (CAD) is a devastating illness and primary cause of death worldwide that arises from a combination of genetic and environmental factors. Several large-scale studies found that 9p21.3, superoxide dismutase 2 (SOD2), and paraoxonase 1 (PON1) polymorphisms increase type 2 diabetes mellitus (T2DM) and/or coronary artery disease (CAD) risk. Our research aimed to investigate whether the SNPs of the 9p21.3 locus (rs28911698), SOD2 (rs4880), and PON1 (rs662) genes were associated with the risk of T2DM and/or CAD in the Iranian population. In this case-control study four group subjects including patients with CAD non-T2DM, with CAD and T2DM, non-CAD with T2DM, and non-CAD non-T2DM were recruited to the study from 2019 to 2020. Molecular analysis was carried out by allele specific-polymerase chain reaction (AS-PCR) technique for rs4880, Taqman genotyping assay for rs2891168, and PCR followed by restriction fragment length polymorphism (PCR-RFLP) technique for rs662. The rs2891168 polymorphism presented an elevated risk of CAD in non-T2DM with CAD and with T2DM CAD groups compared to the non-T2DM non-CAD group with GG genotype and dominant model after adjustment (p < 0.05). G-allele in PON1 rs662 polymorphism associated with increased risk of T2DM in T2DM non-CAD, and T2DM CAD groups compared to non-T2DM non-CAD group with dominant model, GG and AG genotypes (p < 0.05). However, SOD2 rs4880 polymorphism presented no significant association with the development of diabetes or CAD. These results provide a prime witness that rs2891168 and rs662 gene variants might have a possible increased risk of CAD and T2DM occurrence, respectively. To obtain more definitive and accurate results in this area, further research is required.

The content of adipokines and myokines in the blood of children and adolescents with different genotypes according to the polymorphism rs662 of the paraoxonase-1 gene

BACKGROUND. Among the many causes of obesity, genetic factors occupy a special place. An obvious role among them belongs to the genetic polymorphism of lipid metabolism enzymes, including paraoxonase-1 (PON-1). Until now, the character of the relationship between PON-1 polymorphism and the state of the endocrine function of mesenchymal tissues remains unclear. Its study will clarify the subtle mechanisms of the development of obesity in childhood and adolescence.AIM. The aim of the study was to investigate the relationship between PON-1 polymorphism (rs662) and changes in the content of adipokines, myokines, and blood lipid metabolism in children and adolescents of different sexes with obesity.MATERIALS AND METHODS. In 100 healthy children and adolescents of different sexes and 89 of their peers with obesity, a genetic study was conducted to assess the single nucleotide polymorphism of the PAO-1 (rs662) genes. In blood serum, total cholesterol, HDL cholesterol, LDL cholesterol, VLDL cholesterol, triacylglycerols, glucose and aminotransferase activity (alanine aminotransferase and aspartate aminotransferase) were determined by photometric methods, as well as leptin, adiponectin, resistin, apelin, irisin, adipsin, myostatin, FGF21, osteocrine, oncostatin and insulin — by multiplex ELISA, and asprosin — by ELISA ones.RESULTS. The patients with the homozygous Arg192/Arg allele, the development of complications of obesity in boys is limited and their occurrence in girls is prevented. In other variants of PON-1 polymorphism (Gln192/Gln and Gln192/Arg genotypes), protective mechanisms are formed in the body of girls aimed at preventing complications in obesity. In boys with the Gln192/Gln genotype, obesity reveals more pronounced shifts in lipid metabolism, manifestations of alteration and an increase in the mass of adipose tissue, and in boys-carriers of the heterozygous Gln192/Arg allele, atherogenesis processes increase.CONCLUSION. Polymorphism of the paraoxonase-1 gene (rs662) contributes to the appearance of gender differences in changes in the content of adipokines and myokines in the blood during obesity in childhood and adolescence.

Misclassification Bias in the Assessment of Gene-by-Environment Interactions.

Misclassification bias is a common concern in epidemiologic studies. Despite strong bias on main effects, gene-environment interactions have been shown to be biased towards the null under gene-environment independence. In the context of a recent article examining the interaction between nerve agent exposure and paraoxonase-1 gene on Gulf War Illness, we aimed to assess the impact of recall bias-a common misclassfication bias-on the identification of gene-environment interactions when the independence assumption is violated. We derive equations to quantify the bias of the interaction, and numerically illustrate these results by simulating a case-control study of 1000 cases and 1000 controls. Simulation input parameters included exposure prevalence, strength of gene-environment dependence, strength of the main effect, exposure specificity among cases, and strength of the gene-environment interaction. We show that, even if gene-environment independence is violated, we can bound possible gene-environment interactions by knowing the strength and direction of the gene-environment dependence ( ) and the observed gene-environment interaction ( )-thus often still allowing for the identification of such interactions. Depending on whether is larger or smaller than the inverse of , is a lower (if ) or upper (if ) bound for the true interaction. In addition, the bias magnitude is somewhat predictable by examining other characteristics such as exposure prevalence, the strength of the exposure main effect, and directions of the recall bias and gene-environment dependence. Even if gene-environment dependence exists, we may still be able to identify gene-environment interactions even when misclassification bias is present.

Ailesel Koroner Arter Hastalığına Yatkınlıkta Güçlü Adaylar PON1, ITGB3 ve CYP3A4 Genlerinin Hastalıkla İlişkisi ve Haplotip Analizi

Objective: Genetic predisposition is very common among the patients with coronary artery disease (CAD), a complex and multifactorial disease. Our objective was to determine the possible association between the most remarkable functional variants in the paraoxonase 1(PON1), cytochrome P450 3A4 (CYP3A4), integrin subunit beta 3 (ITGB3) genes and familial CAD. Materials and Methods: We included 117 patients diagnosed with familial CAD and 99 healthy subjects with no family history of CAD. PON1 Q192R, PON1 L55M, CYP3A4*1G and ITGB3 L33P single nucleotide polymorphisms were genotyped using the Sequenom MassARRAY system. Results: Comparison of genotype and allele frequencies in inheritance models of polymorphisms between the patient and control groups did not reveal any significant findings related to CAD. Stratified analysis by gender did also not display any association both in females and males. There was no significant difference in the frequencies of the haplotypes of the PON1 Q192R and L55M polymorphisms between the groups. Conclusions: Our findings confirmed previous studies that did not consider PON1, CYP3A4 and ITGB3 genes as risk loci. The fact that our study was conducted only in patients with familial CAD shows the originality and importance of our results.