2型糖尿病肾病对氧磷酶基因多态性的研究

目的 探讨对氧磷酶基因2（PON2）多态性与单纯2型糖尿病（T2DM）及2型糖尿病肾病（DN）的关系。方法 选取单纯T2DM患者154例、DN患者145例，并选取97例健康者进行对照所有样本试剂盒提取DNA，进行PCR扩增，PCR扩增产物有限制性内切酶水解，最后通过凝胶成像分析基因多态性。结果 PON2（G148A）各基因型频率三组间差异有显著性（P〈0．001），PON2（C311S）各基因型频率三组间差异有显著性（P〈0．001）。结论 PON2（G148A）和PON2（C311S）基因多态性均可能作为糖尿病肾病的预测指标。     

对氧磷酶2 C311S基因多态性与脑梗死的关系

目的 探讨对氧磷酶2(paraoxonase 2.PON2)基因多态性与湖南地区人群脑梗死的关系.方法 采用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)控查PON2基因C311S多态性在脑梗死组和正常对照组的基因频率.结果 发现湖南地区人群存在PON2 C311S基因多态性,S/C等位基因频率0.727/0.273.脑梗死患者PON2基因C311S的基因型和等位基因频率与正常对照组相比无显著差异(P0.05).脑梗死组CC基因型HDL水平明显低于SS、CS两型(P＜0.05).结论 PON2基因第311位密码子的多态性与湖南地区人群脑梗死的发病无关,而可能与脑梗死患者的高密度脂蛋白水平有关.     

对氧磷脂酶基因多态性与2型糖尿病大血管病变

对氧磷脂酶 (PON)基因家族 ,至少包括PON1 、PON2 、PON33种基因。研究发现 ,PON1 基因在 3个位点出现多态性 ,分别是Q R、M L、C T等位基因 ;PON2 基因在两个位点出现多态性 ,为A G和C S等位基因。其中PON1 的R等位基因和L等位基因均是 2型糖尿病大血管病变的独立危险因素 ,而PON1 的T等位基因与 2型糖尿病大血管病变具有相关性 ,PON2 的C等位基因则对 2型糖尿病大血管病变具有保护作用     

对氧磷脂酶基因多态性与2型糖尿病大血管病变

对氧磷脂酶（PON）基因家族，至少包括PON1，PON2，PON33种基因。研究发现，PON1基因在3个位点出现多态性，分别是Q／R、M／L、C／T等位基因；PON2基因在两个位点出现多态性，为A／G等C／S等位基因。其中PON1的R等位基因和L等位基因均是2型糖尿病大血管病变的独立危险因素，而PON1和T等位基因与2型糖尿病大血管病变具有相关性，PON2的C等位基因则对2型糖尿病大血病变具有保护作用。     

对氧磷酶2基因C311S多态性与脑梗死的相关性研究

目的探讨对氧磷酶2(paraoxonase2,PON2)基因多态性与脑梗死(cerebralinfarction,CI)的关系。方法用聚合酶链反应限制性片段长度多态性分析法探查PON2基因C311S多态性在脑梗死组、无栓对照组和正常对照组的基因频率。结果发现中国广西人存在PON2基因C311S多态性,C/S等位基因频率为0203/0797。脑梗死组患者PON2基因的C等位基因频率显著高于无栓对照组和正常对照组(P<005)。结论中国人脑梗死患者PON2基因第311位密码子的多态性与脑梗死的遗传学基础有关,C等位基因是动脉粥样硬化性脑梗死的易感基因之一。     

对氧磷酸酯酶与糖尿病血管病变关系的研究进展

对氧磷酸酯酶(PON)具有过氧化物酶活性,在体内起抗氧化作用.研究显示,PON1的192RR、54LL、 (-107)TT等位基因是糖尿病大血管病变的独立危险因素;PON1-54L/M基因型与糖尿病视网膜病变、PON2-311C/S、148A/G基因型与糖尿病肾病间可能存在相关关系.合并血管病变的糖尿病患者PON1活性显著低于无并发症者,提示PON1活性下降可能参与了糖尿病血管病变的发生.     

对氧磷酸酯酶与糖尿病血管病变关系的研究进展

对氧磷酸酯酶(PON)具有过氧化物酶活性，在体内起抗氧化作用。研究显示，PONl的192RR、54LL(-107)TT等位基因是糖尿病大血管病变的独立危险因素；PONl—54L/M基因型与糖尿病视网膜病变、PON2—311C／S148A／G基因型与糖尿病肾病间可能存在相关关系。合并血管病变的糖尿病患者PONl活性显著低于无并发症者提示PONl活性下降可能参与了糖尿病血管病变的发生。     

对氧磷酶基因多态性及血浆同型半胱氨酸硫内酯复合物水平与冠心病的关系

目的探讨对氧磷酶(PON)基因多态性(PON1 T-107C、PON2 C311S)及血浆同型半胱氨酸(Hcy)、同型半胱氨酸硫内酯(HTL)复合物水平与冠心病发病的关系。方法对203例经冠状动脉造影证实为冠心病的患者及117例经冠状动脉造影证实无冠状动脉病变的对照者进行研究,采用竞争性 ELISA 法测定血浆 HTL 复合物水平;采用高压液相色谱法测定血浆 Hcy 的水平;采用多聚酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)分析 PON 基因中 PON1 T-107C 和 PON2 C311S基因多态性。结果冠心病组血浆 Hcy 和 HTL 复合物水平明显高于对照组(P<0.01);PON1 T-107C 基因型与等位基因频率分布在冠心病组与对照组间比较差异无统计学意义(P>0.05);而PON2 C311S 的 SS 基因型分布在冠心病组低于对照组(P<0.05),但等位基因频率分布两组间差异无统计学意义(P>0.05);当两位点的等位基因 T、S 同时出现时(即 CT/TF+CS/SS 基因型)血浆 Hcy及 HTL 复合物水平较 CC+CS/CC 或 CT+CC 基因型明显降低[Hcy(11.83±4.76)μmol/L 与(15.32±10.32)μmol/L;HTL(24.36±9.30)U/ml 与(32.05±10.44)U/ml],差异有统计学意义(P<0.05)。冠心病合并2型糖尿病组与冠心病无糖尿病组及对照组相比,PON2基因型分布差异有统计学意义,冠心病合并2型糖尿病患者中 C 等位基因频率明显增高(P<0.05)。结论血浆 Hcy 和 HTL 复合物水平升高可能是冠心病发病的独立危险因素,PON1 T 等位基因和 PON2 S 等位基因同时出现可能在动脉粥样硬化形成过程中起到保护作用,而 PON2 C311S 多态性的 C 等位基因存在可能与冠心病患者合并2型糖尿病的几率增高相关。     

对氧磷酶2基因311Cys/Ser多态性与2型糖尿病合并大血管病变的相关性

目的探讨对氧磷酶2基因311 Cys/Ser多态性与山东青岛地区2型糖尿病患者合并大血管病变的关系。方法通过抽提基因组DNA并应用聚合酶链反应扩增包含对氧磷酶2基因311位点的基因片段,然后应用聚合酶链反应限制片长多态性技术检测对氧磷酶2基因311 Cys/Ser多态性在2型糖尿病合并大血管病变组、单纯2型糖尿病组以及正常对照组的基因频率。结果山东青岛地区人群存在对氧磷酶2基因311 Cys/Ser多态性。2型糖尿病合并大血管病变组对氧磷酶2基因的3种基因型(CC、CS、SS)的构成比与单纯2型糖尿病组和正常对照组比较差异具有显著性(P<0.05或P<0.01),S等位基因频率较单纯2型糖尿病组和正常对照组显著增高(P<0.05或P<0.01);携带S等位基因的个体患糖尿病大血管病变的风险为非携带者的2.932倍;对氧磷酶2基因311 Cys/Ser多态性不同基因型亚组间血脂水平无明显差异。结论在山东青岛地区人群中,对氧磷酶2基因311 Cys/Ser多态性与2型糖尿病合并大血管病变具有相关性,其S等位基因可能是该地区2型糖尿病合并大血管病变的危险因素之一。     

醛固酮合酶CYP11B2(-344C/T)基因多态性与2型糖尿病肾病的相关性

目的探讨醛固酮合酶CYP11B2(-344C/T)基因多态性与2型糖尿病肾病的关系。方法采用聚合酶链反应-限制性酶切片段长度多态性分析(PCR-RFLP)技术检测95例2型糖尿病患者(其中合并肾病患者32例,未发生肾病63例)和175例健康对照组醛固酮合酶CYP11B2(-344C/T)基因多态性。结果糖尿病肾病组、糖尿病非肾病组和健康对照组两两比较,CYP11B2基因型和等位基因分布均无统计学差异(P>0.05)。与健康对照组比较,糖尿病肾病组和糖尿病非肾病组的血浆醛固酮水平均有极明显增高(P<0.01);糖尿病肾病患者CYP11B2(-344C/T)基因多态性的3种基因型间血浆醛固酮水平比较差异有显著性(P<0.05)。结论醛固酮合酶CYP11B2(-344C/T)基因多态性与2型糖尿病肾病的发生无显著相关性,但可能与血浆醛固酮水平有关。     

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.     

The paraoxonase-2-310 polymorphism is associated with the presence of microvascular complications in diabetes mellitus

OBJECTIVE: To investigate the paraoxonase-2 (PON 2)-C/S 310 polymorphism and its relationship to the presence of diabetic complications and glycaemic control. DESIGN: Case-control study. SETTING: One study centre at University hospital. MATERIALS AND METHODS: The subjects were people with type 2 diabetes (n=252), type 1 diabetes (n=152) and healthy controls (n=282). The PON 2-C/S 310 polymorphism was measured by restriction fragment length polymorphism analysis. Lipids and lipoproteins were measured by standard clinical chemistry methods. Diabetes and diabetic complications were defined by World Health Organization criteria. RESULTS: There was an over-representation of the C/C 310 genotype in those with diabetes and microvascular complications (type 2 diabetes P=0.043, type 1 diabetes P=0.052, both populations combined P=0.014). The PON 2-C/S 310 polymorphism was also associated with glycaemic control. C 310/C 310 homozygotes had the highest HbA(1c) concentration (P=0.020 type 2 diabetes, P=0.065 type 1 diabetes, P=0.035 both populations combined). There was no association between the PON 2-310 polymorphism and lipid and lipoprotein concentrations. CONCLUSIONS: PON 2 could be directly involved in protecting critical enzymes or organelles against oxidative damage; PON2 may thus predispose to the development of microvascular complications.     

对氧磷酶2基因多态性与阿尔茨海默病的相关性研究

目的 探讨对氧磷酶2（paraoxonase 2,PON2）基因多态性（148Ala/Gly;311Cys/Ser）与Alzheimer病（AD）之间的关系.方法 用PCR-RFLP分析技术对132例AD患者和186例年龄匹配的健康对照者进行PON2 148Ala/Gly及311Cys/Ser基因多态性的分析.结果 PON2基因148、311位点存在多态性,其基因型频率和等位基因频率在AD患者和正常对照者间差异无显著性.结论 PON2基因多态性与AD未发现显著相关性.     

PON2 gene variants are associated with clinical manifestations of cardiovascular disease in familial hypercholesterolemia patients

Paraoxonase is an enzyme associated with the high-density lipoprotein (HDL) particle. It catalyses the hydrolysis of organophosphates and protects LDL from oxidative modification in vitro by hydrolyzing lipid peroxides, suggestive of a role for paraoxonase in the development of atherosclerosis. Two frequent mutations at the paraoxonase gene locus (PON1) underlie the leucine (Leu allele) --> methionine (Met allele) and the glutamine(Gln allele) --> arginine(Arg allele) aminoacid substitutions at residues 55 and 192, respectively. These polymorphisms have been associated with increased risk for cardiovascular disease (CVD) in several studies, while others have not found this association. Recently, another member of the PON gene family designated PON2 has been identified. While the PON2 gene product is expressed ubiquitously, its physiological role is unknown. A common polymorphism at codon 311 (Cys-->Ser) in the PON2 gene has been described. In our study we assessed the frequency and genotype distribution of the PON1 and PON2 polymorphisms in 197 patients with familial hypercholesterolemia (FH), to determine the possible association between these mutations and susceptibility for CVD. The FH cohort group was divided into subjects with (n=83) and without (n=114) definite clinical manifestations of CVD (FH-Symptomatic and FH-Asymptomatic respectively). The control population consisted of 201 healthy normolipidemic blood donors. All subjects in this study were of Caucasian background. Genotypes were identified by PCR based analysis. With regard to the PON1 polymorphisms 55 and 192, no different distributions of allele frequencies were found between the groups studied. However, we did show an association between the PON2 311 polymorphism and CVD. The frequencies of PON2 Ser311 carriers (Ser/Ser and Cys/Ser) between FH-Symptomatic and both FH-Asymptomatic and controls did show a significant difference (P=0.01 and P=0.02 respectively). In the FH-Symptomatic population, surprisingly, no subjects were homozygous for PON2 Cys311, whereas in the FH-Asymptomatic population nine persons (7.9%) and in the control group 12 persons (6.0%) were homozygous. Our data indicate that the common PON2 polymorphism is associated with clinical manifestations of CVD in FH patients. While PON2 Ser311 carriers seem to be at risk, subjects with the Cys/Cys311 genotype are likely to be protected against the development of premature CVD.     

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.     

PON1 M/L55 mutation protects high-risk patients against coronary artery disease

The paraoxonase (PON) gene family contains at least three members: PON1, PON2, and PON3. The enzyme PON1 has been implicated in the pathogenesis of atherosclerosis. Recently, an association between PON2 and quantitative metabolic phenotypes, such as plasma lipoproteins, plasma glucose, and coronary artery disease (CAD), has been reported. We analyzed two common polymorphisms in PON1 (i.e., M/L55 and R/Q 192 mutations) and PON2 (i.e., G/A148 and C/S311 mutations) in 352 high-risk patients with angiographically defined CAD. These results were compared to those in 380 age- and sex-matched control subjects at high risk for CAD. Polymerase chain reaction with specific primers followed by Hsp92, Alw1, DdeI and Fnu4HI restriction digestion were employed to identify the PON1 M/L55 and R/Q192 and the PON2 G/A148 and C/S311 genotypes, respectively. Univariate analysis showed a higher prevalence of the MM genotype (12% vs. 5%; p=0.004) for the PON1 M/L55 polymorphism and the GG genotype (21% vs. 15%; p=0.047) PON2 G/A148 polymorphism in the control subjects. The PON1 M/L55 mutation (MM genotype) was associated with lower triglyceride levels and the PON2 G/A148 mutation (GG genotype), with higher total and low-density lipoprotein (LDL)-cholesterol levels. No mutation was associated with the number of major coronary artery vessels with a >50% reduction in lumen diameter. Multiple regression analysis disclosed smoking, a family history of CAD, high-density lipoprotein (HDL)-cholesterol and the PON1 M/L55 mutation [OR=0.59 (CI95%: 0.42-0.82); p=0.002] as independent markers for CAD. In contrast to traditional coronary risk factors, the PON1 M/L mutation can be considered predictive of protection against CAD.     

A paraoxonase gene polymorphism,PON 1 (55), as an independent risk factor for increased carotid intima-media thickness in middle-aged women

Paraoxonase (PON) gene polymorphisms have been proposed as genetic markers of risk for cardiovascular disease (CVD). Sporadic results suggest they are correlated with intima-media thickness (IMT), an indicator of preclinical atherosclerotic disease. We have investigated whether polymorphisms PON 1 (M/L) 55, (Q/R) 192, PON 2 (S/C) 311 are related to site-specific carotid plaques in 310 middle-aged women. Subjects were also investigated for physical and biochemical parameters including oxidative markers to evaluate their effect on development of atherosclerotic plaques (IMT>1.2 mm) identified by high resolution B-mode ultrasound. We demonstrate that PON 1 (LL+ML) 55 is associated with plaques both at the bifurcation (OR=2.40; 95% CI 1.00-5.90) and at the common carotid artery (OR=2.75; 95% CI 1.01-7.50), and to the total number of plaques at any site (P<0.05). This polymorphism is an independent parameter with respect to other variables that are significantly associated with plaques, i.e. systolic blood pressure (OR=2.06; 95% CI 1.11-3.81) and oxidized low-density lipoprotein (LDL) antibodies (OR=1.96; 95% CI 1.05-3.69) in cases of common carotid plaques, and lipid peroxides (OR=1.86; 95% CI 1.00-3.50) in cases of bifurcation plaques. In conclusion, PON 1 (LL+ML) 55 but not PON 1 (Q/R) 192 or PON 2 (S/C) 311, appears to be an independent risk factor for increased carotid IMT in middle-aged women.     

Serum arylesterase/diazoxonase activity and genetic polymorphisms in patients with type 2 diabetes

Human serum paraoxonase (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidation of low-density lipoprotein (LDL) in vitro, suggesting that PON1 protects against atherosclerosis. We detected 3 polymorphisms of the PON1 gene and investigated PON1 enzyme activities as paraoxonase (PON), arylesterase (ARYL) and diazoxonase (DIAZ), and serum PON1 concentration in 106 patients with type 2 diabetes and 161 control subjects. All 3 enzyme activities and specific activities of PON1 in diabetic patients were significantly lower than those in controls, while there was no difference in serum PON1 concentration between the patient and control groups. The specific activities of PON, ARYL, and DIAZ in patients were 6.82 +/- 3.14 nmol x min(-1) x U(-1) (mean +/- SD, U; unit for serum PON1 concentration), 4.77 +/- 0.17 micromol x min(-1) x U(-1), and 193 +/- 92 nmol x min(-1) x U(-1), respectively, whereas those in controls were 9.33 +/- 3.92 nmol x min(-1) x U(-1), 5.36 +/- 0.14 micromol x min(-1) x U(-1), and 242 +/- 103 nmol x min(-1) x U(-1), respectively. There was no significant difference in the allelic frequencies of -108C/T, 55L/M, or 192Q/R between the patient and control groups. When each enzyme activity was compared between the patient and control groups in each genotype subgroup, all activities were lower in the patient group. The PON and ARYL activities were lower in patients with retinopathy or nephropathy than in those without such complications, and the ARYL activity was also lower in patients with neuropathy. In conclusion, all specific enzyme activities of PON1 were lower in patients with type 2 diabetes independent of the -108C/T, 55L/M, or 192Q/R polymorphism, and this impaired PON1 function may be involved in development of diabetic microangiopathy.     

Paraoxonase (PON)1 192R Allele Carriage is Associated with Reduced Risk of Inflammatory Bowel Disease

The paraoxonase (PON) genes family maps to chromosome 7q21-q22, within a loci that also showed evidence of susceptibility genes for both Crohn’s disease (CD) and ulcerative colitis (UC). In this case-control study we investigated the possible relationship between PON1 and PON2 polymorphisms and the risk of inflammatory bowel disease (IBD). PON1 192Q/R, PON1 55L/M, and PON2 311S/C polymorphisms were investigated by RFLP analysis in DNA samples from 224 patients with CD, 58 patients with UC, and 311 healthy controls. The PON1 192R allele was significantly less common among IBD Ashkenazi patients (allelic OR = 0.61, P = 0.004, 95% CI = 0.44–0.85). In agreement with the individual SNP analysis, Ashkenazi IBD patients had a higher frequency of haplotype PON1 192Q/PON1 55L/PON2 311S (26.3% vs 17.3%; P=0.003) and a lower frequency of haplotype PON1 192R/PON1 55L/PON2 311S (18.9% vs 27.7%; P=0.008). Our results suggest that in this Ashkenazi Jewish population, carriage of PON1 R192 allele may confer protection against the development of IBD.