多药耐药多态性对环孢素急性肝毒性作用的影响

目的 探讨多药耐药(MDR)多态性对环孢素急性肝毒性作用的影响.方法 采用聚合酶链反应(PCR)和限制性内切片段多态性(RFLP)方法 对187例肾移植患者进行MDR外显子26(exon 26)基因分型;并以外显子26基因型分组,观察不同MDR基因型患者环孢素急性肝毒性的发生率.结果 187例,MDR exon26基因型分为CC、CT和TT.各基因型所占的比例分别为29.4%(55/187),40.1%(75/187)和30.5%(57/187).在环孢素使用剂量相同的情况下,CT/TT基因型的患者肝毒性的发生率明显高于CC基因型(35.9%/31.6%∶18.3%,P＜0.05);不同基因型分组之间,发生环孢素肝毒性的平均血药浓度也有较大的差别(CC:CT/TT:432.5±30.0∶338.6±26.8/315.3±25.6,P＜0.05).结论 MDR多态性是影响环孢素急性肝毒性作用的重要因素之一.

Abstract：

Objective To investigate the influence of MDR polymorphism on CsA-associated hepatotoxicity. Methods PCR/RFLP was used to analyze the genotypes of MDR exon26 in 187 recipients. CsA-associated hepatotoxicity was evaluated among groups being classified according to the genotypes. Results MDR exon26 takes 3 genotypes:CC,CT and TT, in the following ratio: 29.4%(55/187), 40.1%(75/187), 30. 5%(57/187). Among the same range of whole blood CsA concentration, incidence of CsA-associated hepatotoxicity is markedly higher in the CT/TT group than that in in patients with CsA-associated hepatotoxicity between the CC group and the CT/TT group is signifiimportant role in the development of CsA-associated hepatotoxicity.     

肾移植患者的多药耐药基因外显子26基因型与术后他克莫司用量的关系

目的研究肾移植患者的多药耐药基因(MDR1)外显子26(exon26)的基因型与术后他克莫司(FK506)用量的关系。方法回顾106例肾移植术后常规使用FK506患者的临床资料。肾移植患者MDR1 exon26基因分型的方法为:提取患者的DNA,采用聚合酶链反应(PCR)扩增MDR1基因,检测限制性内切酶片段的多态性(RFLP)。根据MDR1 exon26基因分型将患者分为CC、CT和TT 3组。检测各组患者肾移植后第3、6和12个月的FK506血药浓度,比较各组患者FK506血药浓度／FK506用量(μg·L-1／mg·kg-1·d-1)的比值及术后1个月内的急性排斥反应发生率。结果受者经MDR1 exon26基因分型示:CC型32例(30．2％),TT型30例(28．3％),CT型44例(41．5％)。CC型患者FK506血药浓度／FK506用量的比值明显低于CT型和TT型(P<0．01),而CT型患者又低于TT型(P<0．05)。CC型患者的排斥反应发生率明显高于CT和TT型(P<0．05),CT与TT型比较,差异无统计学意义(P>0．05)。结论MDR1 exon26 CC型的患者与CT或TT型比较,需服用更高剂量的FK506才能取得与CT或TT型相似的血药浓度。因此,了解患者的MDR1 exon26基因型有利于指导患者肾移植术后个体化用药。     

多药耐药基因多态性与免疫抑制剂应用关系的研究

目的探讨多药耐药基因(MDR1)外显子21(exon21)的基因多态性对肾移植术后患者免疫抑制剂应用的影响. 方法选择同种异体肾移植术后患者168例.采用聚合酶链反应(PCR)扩增MDR1基因,限制性内切片段多态性(RFLP)方法对MDR1基因进行分型.根据分型将患者分为GG、GT和TT 3组,对肾移植术后第1、3、6、12个月中每月每2组患者间的CsA浓度与每天每公斤体重的CsA剂量比值进行比较. 结果168例患者中GG型46例(27.4%),GT型76例(45.2%),TT型46例(27.4%).GG型患者CsA浓度剂量比值明显低于GT型和TT型患者,差异均有统计学意义(P＜0.01),而GT型患者CsA浓度剂量比值又低于TT型患者,差异有统计学意义(P＜0.05).结论同种异体肾移植患者MDR1exon21基因型和CsA血药浓度与每天每公斤体重CsA剂量的比值有明显关系.GG型患者的比值明显低于GT或TT型患者,GG型患者达到相似的血药浓度需服用更高剂量的CsA.     

供、受者细胞因子基因多态性预测肾移植效果的意义

目的 评价供受者细胞因子基因多态性预测移植肾急性排斥反应的意义。方法 采用序列特异引物聚合酶链反应(PCR-SSP)方法,对144例肾移植受者和65例供者进行细胞因子INF-α,IL-10,IL-6,TGF-β及IFN-γ基因型检测。结果 受者TNF-α或IL-10为高分泌型时移植肾急性排斥反应发生率与受者为低分泌型者相比有极显著性差异(P<0.01)。供者TNF-α或IL-1O为高分泌型时移植肾急性排斥反应发生率与供者为低分泌型者相比无显著性差异(P>0.05))。受者高分泌/供者高分泌TNF-α基因型组合的受者急性排斥反应发生率比所有其它基因型组合者高(P<0.01),而受者低分泌/供者低分泌TNF-α基因型组合的受者急性排斥反应发生率比所有其它基因型组合者低(P<0.01)。结论 同时检测供受者TNF-α基因型能为我们更加合理地选择肾移植供受者提供一种有效手段。     

乳腺癌MDR1基因多态性与其表达及化疗血液毒性的关系

目的：探讨乳腺癌多药耐药基因MDR1基因多态性与其表达及与化疗血液毒性之间的关系。 方法：提取92例乳腺癌患者外周静脉血DNA,利用限制性片段长度多态性（PCR-RFLP）技术检测MDR1外显子（exon）26（C3435T）位点的多态性,并用RT-qPCR方法检测该92例患者癌组织及其中26例配对癌旁组织MDR1 mRNA的表达。根据患者的临床资料,分析C3435T位点多态性与化疗血液学毒性的关系。 结果：92例乳腺癌中, C3435T位点CC,CT,TT 3种基因型分别占21.7%（20/92）,62.0%（57/92）和16.3%（15/92）,所有乳癌组织中均有不同程度的MDR1 mRNA表达,但各基因型间MDR1 mRNA表达水平差异无统计学意义（F=0.173,P=0.841）;癌组织MDR1 mRNA表达水平明显高于其对应的癌旁组织[（3.83±5.27） vs. (1.81±4.42),t=2.522,P=0.018]。C3435T各基因型患者中性粒细胞减少反应差异有统计学意义,CC型中性粒细胞减少（III~IV度）的发生频率（5.0%）明显低于CT和TT型（26.3%和46.7%;χ2=8.075,P=0.018,95%CI=0.017~0.022）,而白细胞减少、贫血、血小板减少等方面各基因型间无统计学差异（均P>0.05）。 结论：乳腺癌患者MDR1基因C3435T位点多态性与MDR1基因表达水平无明显关系,CT和TT型患者化疗后发生中性粒细胞减少症的风险较大。     

霉酚酸酯药代动力学与多重耐药基因1多态性的相关性研究

目的 研究肾移植受者术后早期霉酚酸酯(MMF)的药代动力学与人类多重耐药基因1(MDRI)多态性的相关性.方法 选择初次肾移植的汉族受者28例,肾移植术后2周时,于口服MMF之前及服药后0.5、1、1.5、2、4、6、8、10、12 h共10个时间点分别采集外周血,以高效液相色谱(HPLC)法测定全血霉酚酸酯(MMF)的活性成分霉酚酸(MPA)的浓度,直接观察其峰值浓度(Cmax)和达峰时间(Tmax).应用Winnolin 3.1软件计算MPA 0～12 h药物时间一浓度曲线下面积(AUC)和平均滞留时间(MRT).同时从外周血提取基因组DNA,应用多聚酶链反应-限制性片断长度多态性(PCR-RFLP)测定MDR1第12、21、26号外显子C1236 T、G2677 T/A、C3435 T单核苷酸多态性(SNP).比较3个SNP位点的不同基因型、单倍型间MMF药代动力学参数的差异;比较MPA高暴露组(MPA AUC≥60 mg·h-1·L-1)与MPA低暴露组(MPA AUC＜60 mg·h-1·L-1)间MDR1多态性差异.结果 MDR1第12、21、26号外显子SNP位点突变型纯合子基因型(1236 TT、2677 TT/AA、3435 TT)频率分别为0.368、0.184和0.211.1236 TT基因型受者MPA AUC水平显著高于1236 cc/CT受者,分别为(65.36±11.51)mg·h-1·L-1和(53.33±13.77)mg·h-1·L-1(P=0.032).MPA高暴露组第12号外显子SNP位点上,TT基因型频率显著高于低暴露组,分别为66.7%和15.8%(P=0.013,OR=2.526);T等位基因频率有高于低暴露组的趋势,分别为83.3%和53.3%(P=0.072).结论 具有MDR1第12号外显子TT等位基因的受者,肾移植早期MPA AUC显著高于同一位点其他基因型受者,是MPA高暴露的危险个体.     

细胞因子基因多态性与移植肾慢性排斥反应的关系

目的探讨供、受者细胞因子基因多态性与移植肾慢性排斥反应的关系。方法用序列特异引物聚合酶链反应（PCR-SSP）方法，对144例肾移植受者和65例部分供者进行5种细胞因子[肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）、白细胞介素10（IL-10）、转化生长因子β1（TGF-βt）、干扰素7（IFN-7）]基因型检测。结果TGF-β1。高分泌型的受者与中低分泌型受者相比，移植肾慢性排斥反应发生率明显升高，差异有统计学意义（P〈0．01）。TGF-β1高分泌型的供者与中低分泌型供者相比，移植肾慢性排斥反应发生率差异无统计学意义（P〉0．05）。TGF-β1，基因型为供者高分泌／受者高分泌组合时，移植肾慢性排斥反应发生率比所有其它基因型组合者高（P〈0．01）；而TGF-β1。基因型为供者中低分泌／受者中低分泌组合时，移植肾慢性排斥反应发生率比所有其它基因型组合者低（P〈0．01）。TNF-α、IL6、IL-10及IFN-γ的基因型与移植肾慢性排斥反应发生率的关系不明显。结论同时检测供、受者TGF-β1，基因多态性对预测移植肾慢性排斥反应发生率有指导意义。     

多药耐药基因表达与肾移植急性排斥机制的初步探讨

目的：研究多药耐药基因（MDR1）与肾移植受者急性排斥的关系。方法：用定量RT-PCR技术分别检测14全我急性排斥受者和28例肾功能稳定受者MDR1表达水平，并与36例尿毒症患者比较；14例健康人作为对照组。结果：MDR1阳性表达率急性排斥受者为85.7%。肾功能稳定受者为71.4%。尿毒症患者为44.4%，前二者表达率均高于尿毒症患者，而且急性排斥受者MDR1含量大于肾功能稳定的受者。结论：在肾移植受者中表达增加可能是肾移植受者获得对CsA耐受从而在CsA治疗浓度下发生排斥的机制之一。     

肾移植术后常规免疫抑制方案下发生他克莫司肾毒性的影响因素

目的 探讨在常规免疫抑制方案下和正常血药浓度范围内肾移植受者发生他克莫司(Tac)肾毒性的影响因素及其对个体化治疗的指导意义。方法 回顾分析132例肾移植术后2年内按照Tac常规剂量(0.15～0.3 mg·kg-1·d-1)和血Tac浓度维持在8～11 μg/L,并坚持随访的首次肾移植受者的资料。Tac肾毒性经移植肾活检和临床实验室检测结果诊断。根据是否发生Tac肾毒性,分为肾毒性组和对照组。对可能的影响因素,包括受者的年龄、性别、是否发生过移植肾功能延迟恢复、药物暴露量、用药时间、肝功能异常、血清白蛋白水平、红细胞比容以及多药耐药基因(MDR1)和细胞色素P450酶3A5(CYP3A5)基因等共10项指标进行多因素回归分析。结果 在常规免疫抑制剂方案下和正常血药浓度范围内,Tac肾毒性发生率为18.9％(25/132)。经单因素和多因素分析,肝功能异常(RR=3.05,95％可信区间为0.879～11.533,P=0.024)、血清白蛋白水平(RR=0.966,95％可信区间为0.994～1.006,P=0.018)、红细胞比容(RR=0.999,95％可信区间为0.998～1.000,P= 0.032)、CYP3A5基因多态性（RR= 0.777,95％可信区间为0.023～6.798,P=0.032）及MDR1基因多态性(RR=0.654,95％可信区间为0.053～7.109,P=0.017)是导致Tac肾毒性的独立危险因素。结论 肾移植后在常规免疫抑制方案下及正常血药浓度内,肝功能异常是导致Tac肾毒性最主要的危险因素,白蛋白水平低下、红细胞比容降低也是导致Tac肾毒性的影响因素,此外还应考虑受者CYP3A5及MDR1的基因多态性,以实现个体化免疫抑制治疗。     

他克莫司与环孢素A在高致敏肾移植受者中的应用比较

目的 观察和比较高致敏肾移植受者应用他克莫司(FK506)与环孢素A(CsA)的有效性和安全性.方法 根据术后免疫抑制方案的不同,将147例高致敏肾移植受者(其中术前群体反应性抗体＞50%的首次肾移植受者59例,2次肾移植受者88例)分为FK506组(53例)和CsA组(94例),两组的免疫抑制方案分别为FK506(或CsA)+霉酚酸酯+泼尼松.观察并分析两组受者术后移植肾存活率、血肌酐水平以及并发症的发生率.结果 FK506组术后1、3和5年的移植肾存活率(86.8%、82.3%和75.3%)略高于CsA组(81.9%、75.4%和66.9%),但差异无统计学意义(P＞0.05);FK506组术后1年时血肌酐水平为(100.72±15.88)μmol/L,CsA组为(117.29±11.77)μmol/L,两组比较,差异有统计学意义(P＜0.01);FK506组与CsA组相比,术后急性排斥反应、慢性排斥反应、肝功能损害、高血压和高血脂的发生率显著降低(P＜0.05),而高血糖的发生率明显升高(P＜0.01),两组移植肾功能延迟恢复和感染的发生率无明显差异(P＞0.05).结论 FK506与CsA相比,能有效降低高致敏受者肾移植术后急、慢性排斥反应的发生率,减少术后并发症的发生,提高移植肾的长期存活率,对高致敏肾移植受者是非常有效和安全的.     

MDR-1 C3435T polymorphism influences cyclosporine a dose requirement in liver-transplant recipients

BACKGROUND: Cyclosporine A (CsA) is characterized by high interindividual variations in oral bioavailability and a narrow therapeutic index. CsA is a substrate for P-glycoprotein, a member of the ABC transporter family encoded by the multiple drug-resistant gene MDR1. METHODS: Because MDR1 gene exon 26 C3435T polymorphism influences intestinal P-glycoprotein expression, we investigated whether this polymorphism was correlated with variation in CsA dose requirement and concentration/dose ratio in 44 liver-transplant recipients during 1 month after transplantation. CsA concentration was measured 2 hours after administration (C2), according to international recommendations. RESULTS: The MDR-1 wild-type genotype (3435CC) was observed in 15 patients (34%), whereas 21 (48%) patients were heterozygous (3435CT), and 8 (18%) patients were homozygous for the mutation (3435TT). There was no significant difference between the three groups regarding corticosteroids treatment or renal function during this period. One to 3 days after liver transplantation, when every patient received a similar CsA weight-adjusted dose, the concentration/dose ratio was correlated with exon 26 single nucleotide polymorphism and was significantly higher in subjects homozygous for the mutation (P=0.012). This was confirmed 1 month after transplantation (P=0.049), when the dose was adjusted to maintain the C2 target level of 1,000 microg/L and we observed that TT patients required approximately 50% lower weight-adjusted CsA dose than wild-type patients (P=0,033). CONCLUSIONS: These findings demonstrate that the MDR1 exon 26 C3435T polymorphism is a major determinant of CsA concentration/dose ratio in liver-transplant recipients and is predictive of the dose of CsA to be administered to achieve the target C(2) concentration.     

Association between ABCB1 (MDR1) gene 3435 C>T polymorphism and colchicine unresponsiveness of FMF patients

The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene activity and effluxes many chemically diverse compounds across the plasma membrane. We studied the association between C3435T polymorphisms (single nucleotide polymorphism) of MDR1 gene and colchicine-resistant familial Mediterranean fever (FMF) patients. Total genomic DNA samples from 52 FMF patients of colchicine unresponsiveness were used for FMF (MEFV) and MDR1 genes profile analyses. Target genes were genotyped by multiplex PCR-based reverse-hybridization Strip Assay method. The preliminary current results showed increased T allele frequency (0.596) in colchicine unresponsiveness of FMF patients. The distributions of the CC, CT, and TT genotypes in colchicine nonresponder FMF patients were 17%, 46%, and 37%, respectively. Our results indicate that C3435T polymorphism in exon 26 of MDR1 gene is associated with colchicine resistance in nonresponder FMF patients during the common therapy protocol.     

Association between ABCB1 (MDR1) Gene 3435 C>T Polymorphism and Colchicine Unresponsiveness of FMF Patients

The multidrug resistance gene-1 (MDR1, adenosine triphosphate-binding cassette transporter: ABCB1, P-glycoprotein) encodes membrane proteins that play a crucial role in protecting cells from xenobiotics, chemicals, and drugs. The TT genotype of 3435 codon in exon 26 of MDR1 gene causes overexpression of gene activity and effluxes many chemically diverse compounds across the plasma membrane. We studied the association between C3435T polymorphisms (single nucleotide polymorphism) of MDR1 gene and colchicine-resistant familial Mediterranean fever (FMF) patients. Total genomic DNA samples from 52 FMF patients of colchicine unresponsiveness were used for FMF (MEFV) and MDR1 genes profile analyses. Target genes were genotyped by multiplex PCR-based reverse-hybridization Strip Assay method. The preliminary current results showed increased T allele frequency (0.596) in colchicine unresponsiveness of FMF patients. The distributions of the CC, CT, and TT genotypes in colchicine nonresponder FMF patients were 17%, 46%, and 37%, respectively. Our results indicate that C3435T polymorphism in exon 26 of MDR1 gene is associated with colchicine resistance in nonresponder FMF patients during the common therapy protocol.     

过氧化物酶体增殖物激活受体γC161T基因多态性与糖皮质激素性骨质疏松症的关系

目的 探讨中国人过氧化物酶体增殖物激活受体γ(PPARγ)基因外显子6 C161T多态性与糖皮质激素性骨质疏松症(GIO)的相关关系。方法 应用聚合酶链反应-限制性片段长度多态性(PCR-RELP)方法测定208例正常健康人（Ⅰ组）、168例非GIO患者（Ⅱ组）和104例GIO患者（Ⅲ组）PPARγ基因外显子6 C161T的基因型。应用双能X线骨密度仪(DEXA)测定股骨、腰椎等部位的骨密度。 结果 外显子6 C161T有CC、CT、TT 3种基因型。GIO组CC基因型频率显著低于正常对照组；CT和TT基因型频率显著高于正常对照组。非GIO组、应用激素组（GIO组＋非GIO组）与正常对照组比较，各基因型频率差异均无统计学意义。正常对照组C161T的CC基因型组各部位的骨密度有高于CT和TT基因型组的趋势，但差异无统计学意义。非GIO组和GIO组C161T的CC基因型组腰椎的骨密度明显高于CT和TT基因型组 (P ＜ 0.05)，分别为非GIO组CC型（1.04±0.17） g/cm2，CT+TT型（1.02±0.07） g/cm2；GIO组CC型（0.94±0.12） g/cm2，CT+TT型（0.83±0.08） g/cm2。经年龄、体重指数等因素校正后，差异仍有统计学意义(P ＜ 0.05）。 结论 PPARγ基因C161T基因型在正常人和应用激素患者之间无明显差异，它可能与肾小球肾炎的发病无关。C161T基因型在GIO组和正常对照组之间差异有统计学意义，它可能与糖皮质激素性骨质疏松症的发病有关。PPARγ基因C161T多态性与应用糖皮质激素患者腰椎的骨密度有关。等位基因C可能是骨量的保护因子，它可能与应用糖皮质激素后骨量的丢失有关。     

Association of cadherin23 single nucleotide polymorphism with age-related hearing impairment in han chinese

Objective Genetic variation of cadheri23 (cdh23; 753G>A in exon 7) has been implicated with age-related hearing impairment (ARHI) in mice. This study aimed to test the association of the CDH23 tag single nucleotide polymorphism (SNP) in intron 7 with ARHI in Han Chinese. Study Design Individual cohort study. Setting Tertiary medical center. Subjects and Methods A total of 1175 Han Chinese subjects were divided into the case group (n = 310, 26% with poorest hearing) and the control group (n = 308, the 26% with best hearing) according to the Z(high) score converted from the original frequency-specific hearing thresholds. The CDH23 SNP locus (rs7087735: C/T) in intron 7 (coordinate: 72996763) shown in the HapMap was genotyped with correlation to the hearing phenotype. Results The genotype distributions of CDH23 (CC/CT/TT) were not significantly different between the case and control group (P = .489). Compared with genotype CC, the odds ratios of the genotypes CT and TT for ARHI were not significantly different after adjustment for other environmental factors (P = .299 for CT; P = .610 for TT). Conclusions Despite that the Ahl allele of Cdh23 had been implicated with ARHI in mice, we found no positive association of the CDH23 tag SNP in intron 7 with ARHI in Han Chinese.     

The effect of MDR1 (ABCB1) polymorphism on the pharmacokinetic of tacrolimus in Turkish renal transplant recipients

There is marked interindividual variability in trough blood levels of tacrolimus (TRL) following standard dosing. TRL is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1)(ABCB1) gene. P-gp acts as a membrane efflux pump, which affects TRL absorption from the gut. Some of the single nucleotide polymorphisms (SNP) of ABCB1 gene are associated with pharmacokinetic characteristics of TRL. The objective of this study was to determine the role of ABCB1 C3435T polymorphism on TRL dose requirements, trough values and dose-adjusted trough TRL concentrations among Turkish renal transplant recipients. Renal transplant recipients receiving TRL (n=92) were genotyped for ABCB1. TRL daily doses, trough concentrations, dose-adjusted trough concentrations, demographic features, and clinical data were obtained at 1, 6, and 12 months after renal transplantation. The frequency of the ABCB1 3435 CC genotype was 30.4%, whereas 47.8% of patients were 3435 CT and 21.7% of patients were 3435 TT. TRL daily doses were significantly lower among patients with the 3435 TT genotype at months 1 and 6. At 6 and 12 months after transplantation patients who were homozygous for the ABCB1 3435 CC showed significantly lower dose-adjusted trough TRL concentrations compared with subjects of 3435 TT and CT genotypes. Knowledge of ABCB1 genotype may be useful to adjust the optimal dose of TRL in transplant patients, thereby rapidly achieving target concentrations.     

The influence of G-protein beta3-subunit gene and endothelial nitric oxide synthase gene in exon 7 polymorphisms on progression of autosomal dominant polycystic kidney disease

BACKGROUND: A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). The variability cannot be fully explained by the genetic heterogeneity of the disease. We examined the influence of G-protein beta3-subunit C825T polymorphism and endothelial nitric oxide synthase Glu298Asp polymorphism on the progression of ADPKD towards end stage renal failure (ESRF). METHODS: 306 ADPKD patients (pts) were analyzed; 261 pts (136 males, 125 females) with ESRF, with subgroup of 73 pts (44 males, 29 females) with ESRF before 45 years (rapid progressors), 46 pts (20 males, 26 females) with ESRF later than in 63 years (slow progressors) and 45 ADPKD pts (17 males, 28 females) in mean age 51 years with serum creatinine under 110 micromol/L (slow progressors) and 100 genetically unrelated healthy Czech subjects. DNA samples from collected blood were genotyped for G-protein beta3-subunit C825T genotype in exon 10 and for endothelial nitric oxide synthase Glu298Asp genotype in exon 7. RESULTS: The G-protein beta3-subunit C825T genotype exhibited no significant differences among the groups of slow progressors (6.6% (6/91) TT, 54.9% (50/91) CT, 38.8% (35/91) CC), rapid progressors (9.6% (7/73) TT, 46.6% (34/73) CT, 43.8% (32/73) CC), ADPKD group with ESRF between 40-63 years (9.2% (13/142) TT, 50% (71/142) CT, 40.8% (58/142) CC) and control group (12% TT, 44% CT, 44% CC). When comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages: males TT--51.7+/-8.8 years, CT--51.9+/-10.3 years, CC--49.7+/-10.2 years and females TT--56+/-9.9 years, CT--53.2+/-8.5 years, CC--53.9+/-8.7 years. The endothelial nitric oxide synthase Glu298Asp and Asp29Asp genotypes were significantly more frequent in rapid progressors (9.6% (7/73) Asp/Asp, 39.7% (29/73) Asp/Glu, 50.7% (37/73) Glu/Glu) and in ADPKD group with ESRF between 40-63 years (11.3% (16/142) Asp/Asp, 41.5% (59/142) Asp/Glu, 47.2% (67/142) Glu/Glu) in comparison with slow progressors (8.8% (8/91) Asp/Asp, 24.2% (22/91) Asp/Glu, 67.0% (61/91) Glu/Glu) and with control group (8% Asp/Asp, 32% Asp/Glu, 60% Glu/Glu) (Chi-square test, p<0.05). Comparing the ages of ESRF of all patients with ESRF, we did not find significant differences in the ages in males with Asp/Asp--54.9+/-10.4 years, Asp/Glu--50.2+/-9.4 years, Glu/Glu--51.0+/-10.4 years. We found out in homozygous Asp/Asp females significantly earlier onset of ESRF (49.2+/-5.6 years) in comparison with heterozygous females (53.3+/-7.2 years) and with Glu/Glu homozygous females (54.8+/-9.7 years) (t-test, p<0.05). CONCLUSION: We excluded the significance of G-protein beta3-subunit C825T polymorphism on the progression of ADPKD. We established the negative prognostic value of the carriers of Asp variant of eNOS polymorphism. Finding of new modifiers could have in future clinical consequences for ADPKD patients.