Paraoxonase1 55 and 192 gene polymorphisms in an Egyptian population with diabetic complications

Type 2 diabetes is a polygenic disease characterized by interaction of environmental and genetic factors. The paraoxonase 1 gene (PON1) 55 and 192 polymorphisms have been reported to be associated with type 2 diabetes and its complications. Our aim is to study the PON1 55, 192 gene polymorphisms and enzyme activity in type 2 diabetic Egyptian population with complications. 100 type 2 diabetic patients with complications (34 with cardiac and 66 with microvascular complications (neuropathy, retinopathy and/or nephropathy)). This was in addition to 100 healthy control subjects of matched age and sex were taken. PON1 55 L?M and 192 Q?R gene polymorphisms and PON1 enzyme activity serum levels were detected. The LL genotype of PON1 55 polymorphism and QR and QQ genotypes of PON1 192 polymorphism were more frequent among the patients with diabetic complications. The PON1 enzyme activity levels were lower among the diabetic patients than in control subjects. PON1 55 and 192 polymorphisms and enzyme activity seems to be related to diabetic complications in this population.     

Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype

The paraoxonase (PON1) PON1-Q192R and PON1-L55M polymorphisms have been inconsistently associated with vascular disease. Plasma PON1 activity phenotypes vary markedly within genotypes and were, therefore, expected to add to the informativeness of genotype for predicting vascular disease. The case-control sample included 212 age- and race-matched men (mean age 66.4 years). The 106 carotid artery disease (CAAD) cases had >80% carotid stenosis, and the 106 controls had <15%. Two PON1 substrate hydrolysis rates (paraoxon [POase] and diazoxon [DZOase]) were significantly lower in cases than in controls and were significant predictors of CAAD by use of logistic regression (POase, P=0.005; DZOase, P=0.019). DZOase predicted vascular disease independently of lipoprotein profile, high density lipoprotein subfractions, apolipoprotein A-I, and smoking. PON1-192 and PON1-55 genotypes or haplotypes did not predict case-control status unless the activity phenotype was also included as a predictor by use of logistic regression. When phenotype was included as a predictor, PON1-192 and PON1-55 genotypes or combined haplotypes were significant predictors (P<0.05). In conclusion, examining PON1-192 and/or PON1-55 genotypes alone may mistakenly lead to the conclusion that there is no role of PON1 in CAAD. These results support the benefit of a "level crossing" approach that includes intervening phenotypes in the study of complexly inherited disease.     

Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians

BACKGROUND AND AIMS: Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for the immune system genes which regulate immune-inflammatory responses, in particular cytokine gene polymorphisms. The frequency of -174C single nucleotide polymorphism (SNP) in the promoter region of the interleukin (IL)-6 gene is increased in Italian male centenarians. Moreover, the frequency of -1082G SNP at the 5' flanking region of the IL-10 gene coding sequence is increased among male centenarians, and that of +874A SNP at the interferon (IFN)-gamma gene was found more frequently in female centenarians. These findings indicate that different alleles at different cytokine gene codings for pro- (IL-6, IFN-gamma) or anti-inflammatory (IL-10) cytokines may affect the individual life-span expectancy, influencing the type and intensity of immune-inflammatory responses against environmental stressors. METHODS: In the present study, we analyzed these IL-6, IL-10 and IFN-gamma gene polymorphisms in 112 (36 male, 76 female) centenarians from the island of Sardinia, whose population shows a genetic background quite different from that of mainland Italy, as well as in 137 sixty-year-old controls from the same geographic area. RESULTS: No significant differences were observed on analyzing IL-6, IL-10 and IFN-gamma polymorphism frequencies among centenarians and controls, either on the whole and when the data were analyzed according to gender. CONCLUSIONS: These data indicate that gene polymorphisms of cytokines playing a major regulatory role in the inflammatory response do not affect life expectancy in the Sardinian population. Thus, cytokine/longevity associations have a population-specific component, being affected by the population-specific gene pool as well as by gene-environment interactions, behaving as survival rather than longevity genes.     

Paraoxonase (PON1) polymorphisms in farmers attributing ill health to sheep dip

Human serum paraoxonase (PON1) hydrolyses diazinonoxon, the active metabolite of diazinon, which is an organophosphate used in sheep dip. In a case-referent study, 175 farmers with ill health that they attributed to sheep dip nominated 234 referent farmers who also dipped sheep and whom they believed to be in good health. We calculated odds ratios for polymorphisms in PON1 at positions 192 and 55, and for PON1 activity with diazinonoxon as substrate. Cases were more likely than referents to have at least one R allele at position 192 (glutamine to arginine aminoacid substitution; odds ratio 1.93, 95% CI 1.24-3.01), both alleles of type LL (1.70, 1.07-2.68) at position 55, and to have diazoxonase activity below normal median (1.77, 1.18-2.67). Our results support the hypothesis that organophosphates contribute to the reported ill health of people who dip sheep.     

Paraoxonase 1 (PON1) attenuates macrophage oxidative status: studies in PON1 transfected cells and in PON1 transgenic mice

OBJECTIVE: High density lipoprotein (HDL)-associated paraoxonase 1 (PON1), hydrolyzes oxidized lipids in oxidized low density lipoprotein (LDL) and thus protects against atherosclerosis development. Increased susceptibility to atherosclerosis observed in PON1 knockout (PON1(0)) mice was associated with increased LDL lipid peroxidation as well as increased macrophage oxidative stress. Thus, the aim of the present study is to characterize the direct effect of PON1 on oxidative status processes in macrophages. METHODS AND RESULTS: We used in vitro and in vivo models of PON1 expression in macrophages, as PON1 is not synthesized by these cells. Peritoneal macrophages (MPM) harvested from PON1(0) mice were transfected with human (hPON1). These cells exhibited reduced total peroxide levels by 47% and decreased capacity to release superoxide anions by 69%, associated with a small but significant increment of the reduced form of glutathione (GSH), a major cellular anti-oxidant, compared to control cells. MPM were also harvested from PON1 transgenic (PON1Tg) mice. Unexpectedly, these cells expressed hPON1 (mRNA and activity). Compared to MPM derived from control C57BL/6J mice, PON1Tg mouse MPM exhibited 35% decreased cellular total peroxide levels, decreased capacity to produce superoxide anions and 47% decreased capacity to oxidize LDL. PON1Tg mouse MPM were also characterized by 51% increased levels of GSH, compared to control MPM. Similarly, MPM harvested from PON1Tg on the genetic background of the atherosclerotic apolipoprotein E knockout (PON1Tg/E(0)) mice also exhibited decreased oxidative stress, compared to E(0) mouse MPM. Aortas obtained from these mice were characterized by decreased lipid peroxide levels, decreased capacity to oxidize LDL, and also increased GSH levels, compared to aortas obtained from E(0) mice. The decreased macrophage and aortic oxidative stress in PON1Tg/E(0) mice was associated with 2.7-fold decreased atherosclerotic lesion size in comparison to E(0) mice. CONCLUSIONS: PON1 directly reduced macrophage and aortic oxidative status, which was associated with decreased superoxide anion production and increased glutathione content. These phenomena could be responsible for the observed attenuated atherosclerosis development in PON1Tg mice in comparison to control mice.     

对氧磷酶1基因Gln192Arg多态性与阿尔茨海默病的相关性分析

目的 探讨中国汉族人群中对氧磷酶1（PON1）基因Gln192Arg单核苷酸多态性（SNP）与阿尔茨海默病（AD）的相互关系。方法采用实时定量PCR技术检测521例AD患者和578例健康老年人PON1基因Gln192Arg位点SN-P的分布,并通过OR做疾病关联分析。结果AD组（Q／R＋R／R）基因型频率较对照组低,统计分析差异有统计学意义（X^2=4．68,P=0．03）;等位基因频率差异也存在统计学意义,AD组R等位基因频率明显低于对照组（X^2=3．85,P=o．05）。logistic回归分析表明,调整年龄和性别的影响后,（Q／R＋R／R）基因型患AD的危险性是Q／Q基因型的0．71倍（P=0．044,95％CI=0．51～0．99）。结论中国汉族人群中PON1基因Gln192Arg位点R等位基因可能是AD的保护因素。     

Association of the insulin-like growth factor binding protein 3 (IGFBP-3) polymorphism with longevity in Chinese nonagenarians and centenarians

Human lifespan is determined greatly by genetic factors and some investigations have identified putative genes implicated in human longevity. Although some genetic loci have been associated with longevity, most of them are difficult to replicate due to ethnic differences. In this study, we analyzed the association of 18 reported gene single nucleotide polymorphisms (SNPs) with longevity in 1075 samples consisting of 567 nonagenarians/centenarians and 508 younger controls using the GenomeLab SNPstream Genotyping System. Our results confirm the association of the forkhead box O3 (FOXO3) variant (rs13217795) and the ATM serine/threonine kinase (ATM) variant (rs189037) genotypes with longevity (p=0.0075 and p=0.026, using the codominant model and recessive model, respectively). Of note is that we first revealed the association of insulin-like growth factor binding protein 3 (IGFBP-3) gene polymorphism rs11977526 with longevity in Chinese nonagenarians/centenarians (p=0.033 using the dominant model and p=0.035 using the overdominant model). The FOXO3 and IGFBP-3 form important parts of the insulin/insulin-like growth factor-1 signaling pathway (IGF-1) implicated in human longevity, and the ATM gene is involved in sensing DNA damage and reducing oxidative stress, therefore our results highlight the important roles of insulin pathway and oxidative stress in the longevity in the Chinese population.     

Paraoxonase 2 (PON2) polymorphisms and development of renal dysfunction in type 2 diabetes: UKPDS 76

Aims/hypothesis Identification of variants predicting development of renal dysfunction would offer substantial clinical benefits. There is evidence that coding non-synonymous variants in the gene encoding paraoxonase 2 (PON2) are associated with nephropathy in both type 1 and type 2 diabetes.Methods We examined the relationship between variation at the C311S and A148G polymorphisms (together with PON2 intronic variant rs12704795) and indices of renal dysfunction (progression to micro- and macroalbuminuria, plasma creatinine increases) in 3,374 newly diagnosed type 2 diabetic subjects from the UK Prospective Diabetes Study followed prospectively (median 14.0 years), using proportional hazards models, adjusted for sex, ethnicity and other known or putative risk factors.Results rs12704795 genotypes were associated with differing rates of development of microalbuminuria (relative risk [RR] for CC vs AA homozygotes 0.68 [95% CI 0.54–0.87], p=0.002) but not other measures of worsening renal function. Heterozygotes for C311S were more likely to develop microalbuminuria (RR=1.31 [95% CI 1.11–1.54], p=0.001) but less likely to double creatinine levels during follow-up (RR=0.49 [95% CI 0.27–0.89], p=0.02). There was no corroboration of this latter association for related outcomes and no prior evidence supports heterosis effects at this locus.Conclusions/interpretation We conclude that the PON2 variants typed in this study have, at best, a small effect on the risk of renal dysfunction in type 2 diabetes.     

Paraoxonase 1 192 Gln/Arg gene polymorphism and cerebrovascular disease: interaction with type 2 diabetes.

Paraoxonase 1 (PON1) is an HDL-associated enzyme which protects HDL and LDL particles from lipid peroxidation. Its enzymatic serum activity varies 10-40-fold between individuals, and its biallelic gene polymorphism at codon 192 (glutamine-->arginine, Gln/Arg) has been associated with coronary artery disease in diabetic patients. To evaluate the role of this PON1 gene polymorphism in cerebrovascular disease, we determined the PON1 192 genotype in 149 patients with hemodynamically relevant extracranial artery stenosis and in 241 controls. The PON1 192 Gln/Arg genotype was determined using polymerase chain reaction followed by Alw I digestion and polyacrylamide gel electrophoresis. Among all subjects, there was no association between the PON1 192 Gln/Arg genotype and cerebrovascular disease (Odds ratio for Arg/Arg and Gln/Arg vs Gln/Gln 0.99, 95%-CI 0.70-1.39). In contrast, in the subgroup of type 2 diabetic patients the PON1 192 Arg allele conferred about twice the risk of cerebrovascular stenosis compared to those homozygous for the Gln allele (Odds ratio 2.00, 95%-CI 0.92-4.38). Our data indicate that in the general population the PON1 192 Gln/Arg gene polymorphism cannot be regarded as a major risk marker for cerebrovascular disease. The observed interaction with type 2 diabetes, however, is supporting the hypothesis that the effect of the PON1 192 Arg allele on atherosclerosis is modulated by other risk factors like diabetes.     

对氧磷脂酶1、2基因多态性与2型糖尿病氧化型低密度脂蛋白水平相关

目的 探讨对氧磷脂酶(PON)1、PON2基因多态性与T2DM患者氧化型低密度脂蛋白(Ox-LDL)水平的相关性.方法 T2DM患者210例为DM组,健康体检者105名为正常对照(NC)组.两组分别检测Ox-LDL,PON1、PON2基因型.结果 DM组Ox-LDL明显高于NC组(P<0.01),PON1基因QQ型Ox-LDL水平明显高于QR及RR基因型(P＜0.05);PON2基因Ox-LDL水平CC>SC>SS(P＜0.05).多元回归分析表明:HbA1c、PON1基因、PON2基因是血浆Ox-LDL增高的独立危险因素.结论 PON1、PON2基因多态性可能影响2型糖尿病患者Ox-LDL水平.     

Associations between paraoxonase 1 (PON1) polymorphisms and susceptibility and PON1 activity in rheumatoid arthritis patients,and comparison of PON1 activity in patients and controls: a meta-analysis

Clinical Rheumatology - We reviewed the associations between paraoxonase 1 (PON1) polymorphisms and susceptibility and PON1 activity in rheumatoid arthritis (RA) patients and compared PON1 activity...     

The influence of PON1 192 polymorphism on endothelial function in diabetic subjects with or without hypertension.

Hypertension and type 2 diabetes mellitus (T2DM) cause endothelial dysfunction probably through increased oxidant stress. Paraoxonase (PON1) is an high-density lipoprotein (HDL)-linked anti-oxidant enzyme whose capacity is influenced by a genetic polymorphism at codon 192. In the present study we have investigated the role of PON1 polymorphism on endothelial function in subjects with T2DM with or without hypertension. Three groups of male subjects were enrolled: 65 healthy control subjects without T2DM or hypertension (CON), 51 with only T2DM (DM), and 67 with both hypertension and T2DM (HYP+DM). The PON1 Gln192Arg polymorphism was determined by polymerase chain reaction (PCR) amplification and restriction analysis. Endothelial function was evaluated as flow-mediated vasodilatation (FMD) of the brachial artery after forearm ischemia. Data were analyzed according to the presence or absence of the Arg allele. Subjects with T2DM had markedly impaired FMD, compared with those of the CON group. In the CON and HYP+DM groups no difference was observed in FMD between subjects homozygous for the Gln allele and those carrying the Arg allele. In the DM group FMD was lower among those carrying the Arg allele compared with Gln/Gln homozygotes (2.1+/-2.4% vs. 6.2+/-5.2%, p=0.002). In conclusion, the present findings demonstrated that FMD was less impaired in normotensive diabetic subjects homozygous for the Gln allele, consistent with the notion that this isoform has a more effective antioxidant action that serves to protect circulating low-density lipoprotein (LDL). Hypertension seems to abolish the protective effect of the Gln isoform. These findings, however, warrant further investigation to clarify their clinical import.     

Quercetin and Ethanol Attenuate the Progression of Atherosclerotic Plaques With Concomitant Up Regulation of Paraoxonase1 (PON1) Gene Expression and PON1 Activity in LDLR−/− Mice

Background: As moderate wine drinking is atheroprotective, it is clinically relevant to elucidate its possible mechanism/s of action/s. Our objective is to demonstrate the potential benefits of the wine components, quercetin and ethanol, on the development of aortic plaques with parallel changes in antiatherogenic factors. Methods and Results: The effects of quercetin and ethanol on the development of aortic atherosclerotic lesions, liver PON1 gene expression, and serum PON1 activity were measured in LDLR^?/? mice on an atherogenic diet for 4 and 8 weeks. Depending on the duration and dosage of these modulators, 12.5 to 25 mg/dl quercetin (12.5Q to 25Q) and 18 to 25% ethanol, the magnitude of decreases in aortic lesions caused by moderate ethanol and quercetin ranged from 20 to 70% (p < 0.05 to p < 0.001) based on ultrasound biomicroscopy (UBM) analyses, and from 18 to 61% (p < 0.05 to p < 0.001) based on morphometric analyses. The composite plot of all the UBM and morphometric data showed significant correlation between these 2 methods (p = 0.0001, Pearson r = 0.79 for 4‐week treatment; p = 0.000004, Pearson r = 0.84 for 8‐week treatment). Concomitantly, 4‐week treatments with 12.5Q and 18% ethanol up regulated liver PON1 mRNA by 41% (p < 0.05) and 37% (p < 0.05), respectively, accompanied by 92% (p < 0.001) and 61% (p < 0.001) increases in serum PON1 activity, respectively. The corresponding values after 8‐week treatment with 12.5Q and 18% ethanol were 23% (p < 0.05) and 40% (p < 0.02) with respect to the up regulation of liver PON1 mRNA expression, while the stimulations of serum PON1 activity were 75% (p < 0.001) and 90% (p < 0.001), respectively. Conclusions: Based on these findings, we conclude that quercetin and moderate ethanol significantly inhibit the progression of atherosclerosis by up regulating the hepatic expression of the antiatherogenic gene, PON1, with concomitant increased serum PON1 activity.     

Apolipoprotein E and Paraoxonase 1 polymorphisms are associated with lower serum thyroid hormones in postmenopausal women

Objective  Autoimmune thyroiditis and overt or subclinical hypothyroidism have been associated with increased prevalence of cardiovascular disease (CVD).
Design  Cross-sectional investigation of the association between gene polymorphisms related to CVD with thyroid function and autoimmunity.
Patients  In total 84 healthy postmenopausal women aged 49–69 years.
Measurements  FT3, FT4, anti-TPO and anti-TG were assessed in the sera of participants. The following polymorphisms were assessed from peripheral lymphocyte DNA: Apolipoprotein E E2/E3/E4, paraoxonase 1 A/B, Glycoprotein IIIa leu33pro, MTHFR ala222val, ApoBarg3500gln, plasminogen activator inhibitor 1 4G/5G, cholesterol 7-α hydroxylase A204C and cholesterol ester transfer protein B1/B2.
Results  A statistically significant correlation was found between Apolipoprotein E and paraoxonase1 polymorphisms and serum thyroid hormones: carriers of the E2 or E4 allele of the ApoE gene had lower levels of FT4 ( P  = 0·0005) than women with the E3/E3 genotype. Carriers of the B allele of paraoxonase 1 gene had lower levels of FT3 compared to women with the wild-type genotype ( P =  0·047). A statistically significant positive association ( P =  0·049) was also observed between anti-TG antibodies and the presence of the E2 allele of the Apolipoprotein E gene.
Conclusions  Polymorphisms of apolipoprotein E and paraoxonase 1 are associated with different levels of thyroid hormone and anti-Tg antibody levels in the study population in this pilot study. The mechanism underlying this association remains to be elucidated.     

Laser lead extraction in octo- and nonagenarians. A subgroup analysis from the GALLERY registry

Introduction

In an aging population with cardiac implantable electronic devices, an increasing number of octo- and even nonagenarians present for lead extraction procedures. Those patients are considered at increased risk for surgical procedures including lead extraction. Here, we investigated safety and efficacy of transvenous lead extraction in a large patient cohort of octo- and nonagenarians.

Methods and Results

A subgroup analysis of all patients aged ≥80 years (n = 499) in the German Laser Lead Extraction Registry (GALLERY) was performed. Outcomes were compared to the nonoctogenarians from the registry. Primary extraction method was Laser lead extraction, with additional use of mechanical rotational sheaths or femoral snares, if necessary. An analysis of patient- and device characteristics, as well as an assessment of predictors for adverse events via multivariate analyses was conducted. Mean patients age was 84.3 ± 3.7 years in the octogenarians group and 64.1 ± 12.4 years in the nonoctogenarians group. The median lead dwell time was 118.0 months (78; 167) and 92.0 months [60; 133], p < .001 in the octogenarians and nonoctogenarians group, respectively. Clinical procedural success rate was achieved in 97.6% of the cases in octogenarians and 97.9% in nonoctogenarians (p = .70). Overall complication rate was 4.4% in octogenarians and 4.3% in nonoctogenarians (0.91). In octogenarians procedure-related mortality was 0.8% and all-cause in-hospital mortality was 5.4%, while in nonoctogenarians, procedure related and all-cause in-hospital mortality were 0.5% and 3.1%, respectively. A body mass index (BMI) <20 kg/m², was the only statistically significant predictor for procedure-related complications in octogenarians, while systemic infection, BMI ≤20 kg/m², procedural complications and chronic kidney disease were predictors for in-hospital mortality.

Conclusions

Laser lead extraction in octo- and nonagenarians is safe and effective. BMI ≤20 kg/m² was the only statistically significant predictor for procedural complications. According to our data, advanced age should not be considered as contraindication for laser lead extraction.     

Paraoxonase (PON1) and the risk for coronary heart disease and myocardial infarction in a general population of Dutch women

There is strong evidence from both animal- and in vitro-models that paraoxonase (PON1) is involved in the onset of cardiovascular disease. In humans there is no consensus on this issue and therefore we investigated the effect of PON1 genotype and activity on the incidence of coronary heart disease (CHD) and acute myocardial infarction (AMI) in a large prospective cohort of 17,357 middle-aged women. We applied a case-cohort design using the CHD (n = 211) and AMI cases (n = 71) and a random sample from the baseline cohort (n = 1527). A weighted Cox proportional hazards model was used to estimate age- and multivariate-adjusted hazard ratios (HR) for the PON1 genetic variants (192Q > R and −107C > T) and tertiles of the PON1 arylesterase- and paraoxonase activities. Neither the PON1 genetic variants, nor the PON1 activities affected the incidence of CHD in general, but, an increased paraoxonase activity was associated with a higher risk of AMI: the second and third tertile HR were 1.31 and 2.07, respectively (P-trend = 0.029, multivariate model). In the subgroup of never-smokers, paraoxonase activity was associated with an increased risk for AMI: the second and third tertile HR were 4.1 and 4.7, respectively (P-trend = 0.009, multivariate model). Additionally, when compared to the lowest paraoxonase tertile in never-smokers, the highest paraoxonase tertile in current-smokers showed a 19.2-fold higher risk for AMI (95%CI: 5.3–69.5, P < 0.0001, multivariate model). In conclusion, this study shows that in middle-aged women paraoxonase activity was associated with an increased risk for AMI and that the risk was modified by the effects of smoking.     

对氧磷酶-1基因55位和192位多态性与冠心病及其病变程度的相关性研究

目的:探讨中国人对氧磷酶-1(PON-1)基因55位、192位多态性与冠心病(CHD)发病的关系及是否影响CHD的病变程度。方法:应用多聚酶链反应限制性片段长度多态性(PCR-RFLP)方法,对经Judkins选择性冠状动脉造影方法证实的151例CHD患者和61例非CHD的对照人群进行检测,分析PON-1基因55、192位多态性,以及其与Gensini积分表示的冠状动脉病变程度的相关性。结果:CHD组55位L等位基因频率为91%,高于对照组的87%(χ2=6.66,P<0.01)。CHD组192位B等位基因频率为65%,高于对照组的29%(χ2=45.07,P<0.01),CHD患者3种基因型间冠状动脉积分存在差异,BB基因型具有更高的冠状动脉积分(H=11.631,P<0.01)。结论:PON-1基因192位多态性与CHD之间有关联;而未发现PON-1基因55位多态性与CHD有关系。PON-1基因55位L等位基因、192位B等位基因与CHD的发病有关,而且PON-1基因192位多态性影响了冠状动脉病变的程度。