中国朝鲜族人群MDR1基因多态性与环孢素A谷浓度的相关性研究

目的:研究中国朝鲜族肾移植术后患者服用环孢素A(CsA)的谷浓度与多药耐药基因(MDR1)C3435T多态性的相关性。方法:选择中国朝鲜族同种异体肾移植术后患者75例,采用聚合酶链反应(PCR)扩增MDR1C3435T基因,利用DNA限制性片段长度多态性(RFLP)方法对MDR1C3435T基因进行分型,结合口服CsA的谷浓度,判断二者是否存在关联。结果:75例患者中,C/C型31例(41.3%),C/T型37例(49.3%)和T/T型7例(9.3%)。C3435T基因多态性与CsA谷浓度差异无统计学意义(P>0.05)。结论:C3435T基因多态性可能不是影响中国朝鲜族肾移植术后患者CsA谷浓度的主要因素。     

中国汉族肾移植术后稳定期患者MDR1基因多态性与口服环孢素A谷质量浓度的相关性探讨

目的研究中国汉族肾移植术后稳定期(>1 a)患者服用环孢素A(cyclosporine A,CsA)的谷质量浓度与多耐药基因(multidrug resistance gene,MDR1)C3435T多态性的相关性。方法采用聚合酶链反应结合限制性片段长度多态性(PCR-RFLP)分析法检测87例肾移植术后患者MDR1C3435T基因多态性,结合口服环孢素A的谷质量浓度,判断二者是否存在关联。所有血样均为肾移植术后稳定期患者的血样。结果 87例患者中,C/C型36例(41.4%),C/T型42例(48.3%)和T/T型9例(10.3%)。87例患者CsA谷质量浓度的均值为(169.5±71.8)μg.L-1(中位数为157.4μg.L-1;范围为76.6~410.9μg.L-1)。C3435T基因多态性与CsA谷质量浓度无显著性差异(P>0.05)。结论 C3435T基因多态性不是影响中国肾移植稳定期患者口服CsA谷质量浓度的主要因素。     

细胞色素P450 3A5和多药耐药基因遗传变异的联合效应对克拉霉素药代动力学的影响

目的 观察CYP3A5*3和MDR1 C3435T遗传变异的联合效应对中国健康受试者克拉霉素(大环内酯类抗生素)药代动力学的影响.方法 45名受试者服用单剂量克拉霉素胶囊250 mg,HPLC-MS法测定血药浓度.PCR-ASA法和PCR-RFLP法分别测定受试者CYP3A53和MDR1 C3435T的基因型,按基因型分组,比较基因多态性对克拉霉素药代动力学的影响.结果 在45名受试者中,CYP3A5*3各基因型分布,不受MDR1 C3435T基因型的影响;而2者的基因突变均不同程度地协同影响克拉霉素药代动力学参数Cmax、AUC0-24和tmax.结论 CYP3A5*3和MDR1 C3435T遗传变异及协同作用是影响克拉霉素药代动力学特性的重要因素.     

MDR1基因多态性与晚期胃癌化疗敏感性的关系

目的研究多药耐药(MDR1)基因C3435T多态性与晚期胃癌患者对5-氟尿嘧啶(5-FU)/奥沙利铂(OXA)为基础的方案化疗敏感性的关系。方法病理学确诊晚期胃癌患者82例,化疗前采集外周静脉血,提取DNA,采用RT-PCR技术检测MDR1C3435T基因型。分析基因型与化疗疗效的关系。结果 82例晚期胃癌患者中,35例(42.68%)为MDR1C3435TC/C基因型,34例(41.46%)为C/T基因型,13例(15.85%)为T/T基因型。其中,2例完全缓解(CR),30例部分缓解(PR),25例稳定(SD),25例进展(PD);总有效率为39.02%(32/82)。C/C基因型患者的化疗有效率57.14%,高于C/T基因型的26.47%和T/T基因型的23.08%(P<0.05)。结论 MDR1基因C3435T多态性与晚期胃癌患者对5-FU/OXA为基础方案的化疗敏感性相关。     

CYP3A5和MDR1基因多态性对中国肝移植患者他克莫司药动学的影响

目的探讨细胞色素P450酶3A5（CYP3A5）基因和多药耐药基因（MDR1）C1236T、G2677T／A、C3435T多态性对肝移植患者口服他克莫司（TAC）后体内药动学参数的影响。方法采集28例肝移植患者手术后第1周和第3周血标本,采用LC—MS／MS法检测TAC血药浓度,计算主要药动学参数。采用聚合酶链反应结合基因测序分析28例肝移植患者CYP3A5＊3和MDR1主要基因型。结果携带MDR1 3435T基因型的肝移植患者口服TAC后,药动学参数AUC0→1和ρmax明显高于3435CC型患者,而CYP3A5＊3、MDR1 C1236T和G2677T／A基因多态性对TAC的药动学参数无明显影响。结论携带MDR1 3435T基因型肝移植患者比3435CC型患者需要较高剂量才能达到目标浓度。     

肾移植中环孢素的血药浓度与多药耐药基因多态性的关系

目的 探讨肾移植术后患者的MDR1C3435T、G2677T/A和C1236T位点的基因多态性对环孢素(CsA)血药浓度的影响.方法 使用荧光偏振免疫分析法(AxsYM)测定65例肾移植患者在术后1 wk和1 mo时的CsA血药浓度(包括峰浓度ρ2和谷浓度ρ0),使用等位基因特异扩增法(ASA-PCR)对患者进行MDR1基因分型,比较不同基因型之间CsA浓度剂量比的差异.结果 在65例患者中,C3435T,CC型25例(38.5%),CT型35例(53.8%),TT型5例(7.7%);G2677T/A,GG型15例(23.1%),GT型21例(32.3%),TT型10例(15.4%),GA型12例(18.5%),AT型6例(9.2%),AA型1例(1.5%);C1236T,CC型10例(15.4%),CT型32例(49.2%),TT型23例(35.4%).C3435T的CT型患者的CsA浓度剂量比略大于CC型和TT型;G2677T/A的从型患者的CsA浓度剂量比略大于其他基因型;C1236T的TT型患者的谷浓度剂量比略大于CC型和CT型,CC型患者的峰浓度剂量比略大于CT型和TT型,但差异均无统计学意义(P＞0.05).结论 在肾移植患者中,MDR1多态性与CsA血药浓度无明显相关性,有待进一步确认.     

MDR1基因C3435T多态性对替米沙坦稳态血药浓度及降压疗效的影响

目的：探讨多药耐药基因MDR1 C3435T（exon 26）位点基因多态性对替米沙坦在原发性高血压患者中的稳态血药浓度及降压疗效的影响。方法：采用聚合酶链反应（PCR）和限制性内切酶片段多态性（RFLP）的方法对连续30 d每天口服40 mg替米沙坦的61名高血压患者的MDR1C3435T位点进行基因分型。使用高效液相色谱-荧光检测法（HPLC-FLD）测定高血压患者的稳态血药浓度,使用水银血压计测量治疗前、后高血压患者的血压值。比较不同基因型间高血压患者的稳态血药浓度及降压疗效的差异。结果：在61例中老年原发性高血压患者中,MDR1 C3435T CC型纯合子的频率为39.34%,TT型纯合子的频率为11.48%,CT型杂合子的频率为49.18%,MDR1C3435T位点等位基因发生率在健康人群和高血压患者间差异无统计学意义。3种基因型高血压患者的稳态血药浓度及降压有效率间差异无统计学意义（P〉0.05）。结论：MDR1 C3435T位点的基因多态性与高血压患者的稳态血药浓度及降压疗效间无相关性。     

多药耐药基因多态性和单倍体对肾移植患者他克莫司血药浓度的影响

目的 研究多药耐药基因(MDR1)单核苷酸多态性及单倍体对中国汉族肾脏移植人群术后稳定期与他克莫司(免疫抑制剂)血药浓度的关系.方法 用基质辅助激光吸收电离子化-飞行时间质谱技术,分析63例肾移植患者的MDR1 exon12 C1236T、exon 21 G2677T/A、exon 26 C3435T的基因型,结合其口服他克莫司12 h后血药浓度,判断两者是否存在关联.结果 MDR1 C3435T基因多态性与他克莫司血药浓度/(剂量×体表面积)具有相关性,比值由小到大顺序:野生型纯合子＜杂合子＜突变型纯合子,差异具有统计学意义(P＜0.05).MDR1 C1236T、G2677T/A及单倍体型各组之间比较均无明显差异.结论 中国汉族肾移植患者稳定期,MDR1 C3435T与他克莫司血药浓度的个体差异具有相关性.     

多药耐药基因MDR1 C3435T基因多态性对质子泵抑制剂三联方案根除幽门螺杆菌疗效影响的Meta分析

目的:系统评价多药耐药基因MDR1 C3435T基因多态性与质子泵抑制剂三联方案根除幽门螺杆菌疗效的关系,为临床提供循证参考。方法:计算机检索Pub Med、EMBase、中国生物医学文献数据库(CBM)、中国期刊全文数据库(CJFD)、万方数据库、中文科技期刊数据库(VIP),收集MDR1 C3435T基因多态性对质子泵抑制剂三联方案根除幽门螺杆菌感染疗效的临床研究,提取资料并按照STREGA声明评价质量,采用Rev Man 5.3统计软件进行Meta分析。结果:共纳入7项研究,合计1 019例患者。按照患者MDR1 C3435T基因型检测结果分为野生纯合子基因(CC)型组,突变杂合子基因(CT)型组与突变纯合子基因(TT)型组。Meta分析结果显示,MDR1 C3435T基因多态性中CC组、CT组与TT组患者幽门螺杆菌根除率比较,差异均无统计学意义[CC vs.CT:OR=0.99,95%CI(0.69,1.42),P=0.95;CC vs.TT:OR=1.44,95%CI(0.66,3.15),P=0.36;CT vs.TT:OR=1.54,95%CI(0.86,2.73),P=0.14];亚组分析发现,亚洲人群中CT组患者幽门螺杆菌根除率显著高于TT组,差异有统计学意义[OR=2.35,95%CI(1.53,3.62),P<0.001]。结论:MDR1 C3435T基因多态性基本不影响质子泵抑制剂三联方案根除幽门螺杆菌的疗效,但亚洲人群进行治疗时,参考基因检测结果有一定意义。     

MDR1 C1236T、G2677T/A、C3435T的基因多态性对中国汉族肾移植患者环孢素药动学的影响(英文)

目的探讨中国汉族人中肾移植患者的多药耐药基因(MDR1)外显子exon12 C1236T、exon21 G2677T/A、exon26 C3435T的单核苷酸多态性对免疫抑制剂环孢素(CsA)药动学的影响。方法采用聚合酶联反应和限制性内切片段长度多态性(PCR-RFLP)的方法对89例肾移植术后的患者进行MDR1基因分型。单克隆抗体荧光免疫偏振法测定患者术后CsA的谷浓度(c0)及服药后2 h浓度(c2)。比较不同基因型之间CsA浓度剂量比值的差异。结果在89例肾移植患者中,等位基因1236T、2677T、2677A、3435T突变频率分别为66%、43%、18%和37%。肾移植术后1 mo内,G2677T/A基因多态性与CsA的药动学有相关性,2个等位基因都发生突变的患者,其剂量校正c0,在术后1~7 d、8~15 d和16~30 d比野生型分别提高51%(P=0.005)、32%(P=0.002)和63%(P<0.001)。在术后16~30 d,无论携带有1个或2个突变等位基因的患者,剂量校正c2都要比野生型患者高26%(P=0.007)和19%(P=0.041)。C1236T的剂量校正c0在术后8~15...     

The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients

Variability in CYP3A (CYP3A4/5) and P-glycoprotein (human MDR1 gene product) activity underlies interindividual differences in oral cyclosporine (CsA) bioavailability. Racial differences in polymorphic expression of CYP3A5 and MDR1 may explain observed interracial variability in oral bioavailability. Our objective was to evaluate the effect of CYP3A5 and MDR1 polymorphic expression on CsA oral disposition. Steady-state plasma concentration profiles (n = 19) were sampled in renal transplant recipients receiving concentration-adjusted CsA maintenance therapy. CsA plasma concentrations were measured by fluorescence polarization immunoassay. CYP3A5 and MDR1 genotypes were determined by real-time polymerase chain reaction. Noncompartmental pharmacokinetic analysis and nonlinear mixed-effects modeling (NONMEM) were performed to assess the effect of genotype on CsA pharmacokinetics. MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. CsA oral clearance was significantly higher in subjects who carried at least one 3435T allele compared to homozygous wild-type individuals (40.0 +/- 2.2 vs. 26.4 +/- 3.1 L/h, p = 0.007). MDR1 C3435T genotype accounted for 43% of the interindividual variability of CsA oral clearance in the study population after accounting for interoccasion variability. The authors were unable to independently assess whether CYP3A5 correlated with any CsA pharmacokinetic parameter since all CYP3A5 nonexpressors were also 3435T allele carriers. MDR1 3435T allele carriers have enhanced oral clearance compared to individuals with the CC genotype. The frequency of the 3435T allele is lower in African Americans compared to Caucasians. Thus, the MDR1 C3435T genotype offers a potential mechanistic basis to explain interracial differences in CsA oral bioavailability. Further studies are needed to explore the relationship between CYP3A5 and MDR1 genotype and phenotype.     

Distribution of allelic variants of functional C3435T polymorphism of drug transporter MDR1 gene in a sample of Polish population

P-glycoprotein (P-gp), the protein product of MDR1 gene, is an important factor regulating the bioavailability of many therapeutics. Recently, the C3435T polymorphism of MDR1 was correlated to altered expression and function of P-gp in normal tissues. In this study, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was applied to assess C3435T MDR1 polymorphism in 122 healthy individuals of Slavic origin from the population of central Poland (Lód? and surrounding areas). The detected genotype variant frequencies were as follows: CC in 42%, CT in 41%, and TT in 17% of the tested subjects (C-allele frequency was 0.62). The frequency of the C-allele is similar to Japanese population and significantly higher than in Caucasians from Western Europe. The results of this study give basis for large-scale C3435T MDR1 genotype-phenotype correlation investigations in Polish population that may be useful to individualize therapy of cancer, HIV-1 infection and some other diseases.     

The MDR1 3435 polymorphism in patients with rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a multifactorial disease, the pathogenesis of which involves immunological, genetic and environmental factors. P-glycoprotein (P-gp) encoded by the MDR1 gene, is an important transporter for many drugs, xenobiotics and cytokines and may be associated with many immunological processes and apoptosis. The activity of P-gp is genetically determined. Naturally occurring MDR1 polymorphisms have been described and correlated with potential clinical effects. Several mutations in the MDR1 gene have been recognized, but only some of them are associated with P-gp expression. The C3435T polymorphism was found to correlate with the activity of P-glycoprotein. The aim of the study was to evaluate the C3435T MDR1 polymorphism in patients with rheumatoid arthritis and to investigate a possible correlation with disease susceptibility, activity and severity. METHODS: The study was carried out in 92 patients with rheumatoid arthritis and 97 healthy subjects as a control group. The C3435T polymorphism was determined using the PCR-RFLP method. RESULTS: The distribution of C3435TT MDR1 genotypes in RA patients did not differ significantly from that in a control group and was as follows: 3435CC in 25 (26.9%) subjects, 3435CT in 50 (53.8%) and 3435TT in 17 (18.3%). The probability of remission of RA symptoms after therapy with methotrexate and glucocorticosteroids however, was 2.89-fold greater in patients with the 3435TT genotype compared to patients with the genotypes 3435CC and 3435CT. The risk of having an active form of rheumatoid arthritis resistant to therapy with disease-modifying antirheumatic drugs in patients with 3435CC and 3435CT genotypes was 2.89 times greater than in homozygous 3435TT subjects. CONCLUSION: We suggest that the C3435T MDR1 polymorphism is not an important genetic risk factor for RA susceptibility, but that this polymorphism may have an influence on the activity of the disease and its response to therapy with disease-modifying antirheumatic drugs.     

Polymorphism in the P-glycoprotein drug transporter MDR1 gene in renal transplant patients treated with cyclosporin A in a Polish population

P-glycoprotein (P-gp), the product of MDR1 gene, is a protein which mediates transmembrane transport of a great number of xenobiotics including cyclosporin A used as an immunosuppressive drug in patients with allogenic kidney grafts. The P-gp activity and expression is dependent on the MDR1 gene polymorphism in position C3435T of exon 26. In this study, C3435T polymorphism was analyzed in 116 patients with allogenic kidney graft treated with cyclosporin Aand 144 randomly selected healthy individuals. The prevalence of MDR1 gene genotypes 3435CC, 3435CT, 3435TT were also compared in patients after allogenic kidney graft with both acute and chronic graft rejection (48 patients with acute and 76 with chronic graft rejection) and control groups (respectively 139 and 112). The results of the study demonstrated that the allelic frequency and MDR1 genotype distribution were similar in all evaluated groups. It was revealed that MDR1 gene polymorphism was not a predisposing factor for terminal kidney failure leading to renal transplantation. Moreover, evaluation of C3435T polymorphism of MDR1 gene will probably not be useful for characterization of groups of patients at increased risk of acute and chronic kidney graft rejection.     

MDR1基因C3435T多态性对替米沙坦血药浓度与药动学的影响

目的：探讨健康志愿者和高血压患者的多药耐药基因26（exon26）C3435T基因多态性对替米沙坦的血药浓度和药动学的影响。方法：采用聚合酶链反应（PCR）和限制性内切片段多态性（RFLP）的方法对19例健康志愿者和66例高血压患者进行MDR1基因分型。使用HPLC-MS法测定健康志愿者单剂量口服40mg替米沙坦48h内血药浓度和高血压患者的稳态血药浓度。比较不同基因型之间替米沙坦在健康志愿者的药物动力学的差异,和高血压患者的稳态血药浓度差异。结果：C3435T发生率在健康人群和高血压患者之间没有明显的差异,C3435T的3个不同基因型健康志愿者的Cmax,tmax,AUC0-48,AUC0-∞,CL差异无统计学意义（P〉0．05）。3个基因型的高血压患者的稳态血药浓度差异无统计学意义（P〉0．05）。结论：MDR1C3435T基因多态性对替米沙坦的血药浓度和药动学无影响。     

C3435T polymorphism of the ABCB1/MDR1 gene encoding P-glycoprotein in patients with inflammatory bowel disease in a Polish population

BackgroundInflammatory bowel disease (IBD) belongs to the group of chronic diseases of the gastrointestinal tract, prevalence of which is increasing in the Polish population. The two main clinical types of IBD are ulcerative colitis (UC) and Crohn’s disease (CD). The expression level of the ABCB1/MDR1 gene which encodes P-glycoprotein seems to be of great prognostic relevance while evaluating patients’ susceptibility to UC or CD. One of the most significant ABCB1/MDR1 gene mutations is the C3435T polymorphism. A decreased expression of the ABCB1/MDR1 gene and lower P-glycoprotein activity has been associated with the 3435T variant. The aim of the study was to evaluate the C3435T polymorphism in the IBD patients and to investigate a possible correlation with disease susceptibility.MethodsThe study was performed on 108 patients with IBD and on 137 healthy individuals. All the participants were of Caucasian origin and came from central Poland. The C3435T polymorphism was analyzed by using the PCR-RFLP method.ResultsOur results showed that ORs for IBD development (including UC and CD) were elevated in individuals both with the 3435CC genotype and the 3435C allele. The differences in genotype and allele frequencies were not significant.ConclusionsThe C3435T polymorphism of the ABCB1/MDR1 gene is not a risk factor for IBD, including UC and CD, in the population coming from central Poland.     

Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson's disease

P-glycoprotein is a membrane protein encoded by the MDR1 gene, which demonstrates functional polymorphism. It is present in endothelial cells of the blood-brain barrier, thus limiting accumulation of its substrates in the central nervous system. Many epidemiological studies suggest an association between pesticides, which are substrates for P-glycoprotein, and Parkinson's disease. It was hypothesized that polymorphism of the MDR1 gene could modulate interindividual susceptibility for the disease in subjects exposed to pesticides. In a pilot case-control study involving 107 Parkinson's disease patients (30 early onset and 77 late onset patients; 59 exposed to pesticides and 48 non-exposed) and 103 controls, C3435T polymorphism of the gene was analysed. No statistically significant correlation between MDR1 gene polymorphism and Parkinson's disease was found. The 3435TT genotype was noted more frequently, but not significantly, in patients with early onset compared to late onset disease (23.3% versus 10.4%, respectively). A significant association between patients with parkinsonism exposed to pesticides and C3435T polymorphism of the MDR1 gene was found. Comparing the exposed and non-exposed patients, a statistically higher frequency of heterozygous subjects was observed (72.9% versus 47.9%, respectively). This genotype was associated with a significant, almost three-fold increased risk of disease. Similarly, a higher frequency of 3435TT subjects was revealed in exposed subjects (15.5%) compared to non-exposed patients (12.5%). In exposed versus non-exposed subjects, patients carrying at least one 3435T allele (i.e. homozygous and heterozygous) had a significant, five-fold higher risk of Parkinson's disease. Thus, it appears that mutation of the MDR1 gene predisposes to damaging effects of pesticides, and possibly other toxic xenobiotics transported by P-glycoprotein, leading to Parkinson's disease.