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.     

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.     

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.     

Tacrolimus dosing in Chinese renal transplant patients is related to MDR1 gene C3435T polymorphisms

Tacrolimus is an immunosuppressive drug with narrow therapeutic range and wide interindividual variations in its pharmacokinetics. P-glycoprotein (P-gp) plays an important role in the absorption metabolism of tacrolimus. The polymorphism C3435T of MDR1, the gene coding P-gp, may influence the expression and activity of P-gp. The aim of this study was to evaluate whether C3435T polymorphism was associated with the tacrolimus concentration/dose ratio. Sixty-six Chinese renal transplant patients enrolled in this study were surveyed for body weight and dosage and concentration of tacrolimus as well as MDR1 genotype by polymerase chain reaction followed by restriction fragment length polymorphism analysis. The results showed a significant association between tacrolimus levels per dose mg/kg/d and MDR1 gene C3435T polymorphism (P < .05). The CC patients displayed a lower tacrolimus level per dose than CT/TT patients. Pharmacogenetic methods might be employed prospectively to help dose selection and to individualize immunosuppressive therapy.     

Tacrolimus Dosing in Pediatric Heart Transplant Patients is Related to CYP3A5 and MDR1 Gene Polymorphisms

Tacrolimus is a substrate for P-glycoprotein (P-gp) and cytochrome (CYP) P4503A. P-gp is encoded by the multiple drug resistance gene MDR1 and CYP3A is the major enzyme responsible for tacrolimus metabolism. Both MDR1 and CYP3A5 genes have multiple single nucleotide polymorphisms. The objective of this study was to evaluate whether the MDR1 exon21 and exon26 polymorphisms and the CYP3A5 polymorphism are associated with tacrolimus disposition in pediatric heart transplant patients. At 3, 6 and 12 months post transplantation, a significant difference in tacrolimus blood level per dose/kg/day was found between the CYP3A5 *1/*3 (CYP3A5 expressor) vs. *3/*3 (nonexpressor) genotypes with the *1/*3 patients requiring a larger tacrolimus dose to maintain the same blood concentration. There were no significant differences in tacrolimus blood level per dose/kg/day between MDR1 exon21 G2677T and exon 26 C3435T at 3 months, but both were found to have a significant association with tacrolimus blood level per dose/kg/day at 6 and 12 months. We conclude that specific genotypes of MDR1 and CYP3A5 in pediatric heart transplant patients require larger tacrolimus doses to maintain their tacrolimus blood concentration, and that this information could be used prospectively to manage patient's immunosuppressive therapy.     

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.     

Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors

Except for hereditary disease, genetic factors that contribute to the development of renal epithelial tumors are unknown. There is a possibility that the MDR1 encoded plasma membrane transporter P-glycoprotein (PGP) influences the risk of development of renal neoplasms. PGP is known to be involved in uptake, binding, transport, and distribution of xenobiotics. There is evidence that the MDR1(C3435T) polymorphism drives expression and modulates disease risk. In an explorational case-control study, constitutional genotype frequencies were established at MDR1(C3435T) of 537 healthy control subjects and compared with those of 212 patients with renal epithelial tumors. There were 179 clear cell renal cell carcinoma (CCRCC) and 33 tumors collectively assigned as non-CCRCC. In a second study, genotypes of another 150 healthy control subjects and 50 patients with three non-CCRCC types (26 papillary RCC, 11 chromophobe RCC, and 13 renal oncocytic adenoma) were compared. PCR-restriction fragment length polymorphism-based analysis of constitutional DNA, and statistical analysis were applied. PGP expression was analyzed by quantitative immunohistochemistry. The explorational study showed a significant association between T allele frequency and the occurrence of tumors (P = 0.007). When tumors were histopathologically distinguished into frequent CCRCC and less frequent non-CCRCC, both patient groups contributed to this effect with a seemingly strong influence by the latter (P = 0.0419). The second study established the T allele as a risk factor especially for non-CCRCC (P = 0.0005) with the highest risk for homozygote TT allele carriers (P < 0.0001). Independently, MDR1(C3435T) genotype associated variations in PGP expression were shown in normal renal parenchyma with a 1.5-fold difference of median values (TT, 1.9; CC, 2.8; P = 0.0065). The data provide evidence for PGP to influence the susceptibility to develop renal epithelial tumors by virtue of its MDR1(C3435T) polymorphism and changes in expression. Especially T and TT carriers are at risk for developing non-CCRCC, i.e., papillary and chromophobe RCC as well as oncocytic adenomas.     

The MDR1/ABCB1 gene, a high-impact risk factor for cardiac transplant rejection

BACKGROUND: Variations in the expression and activity levels of the multidrug-resistance MDR1/ABCB1 encoded P- glycoprotein (P-gp) have an impact on the therapeutic efficacy of many drugs. C3435T and G2677 polymorphisms of the MDR1/ABCB1 gene correlate with cellular expression levels of P-gp, a membrane-bound efflux pump which removes a multitude of drugs, including chemotherapy drugs and immunosuppressants, from cells. We aimed to investigate whether the phenomenon of drug resistance, mediated by the MDR1/ABCB1 gene and seen in tumor cells to chemotherapeutic agents, is important in the field of transplantation, predisposing some patients to resistance to immunosuppressants. METHODS: G2677 and C3435T polymorphisms of the ABCB1 gene were determined by PCR in 170 heart transplant recipients. We examined the relationship between MDR1/ABCB1 polymorphisms and endomyocardial biopsy-proven rejection (EBPR) determined by biopsy performed at set intervals according to a standard protocol. RESULTS: A significant relationship was found between a patient's C3435T genotype and freedom from first grade > or =3A rejection episode. 3435-CC recipients were 1.8 times (1.05-3.09; P = 0.03) more likely to undergo a > or =3A rejection episode in the first 12 months. Haplotypes derived from the G2677 and C3435T polymorphisms (GG/CC, GT/CT and TT/TT) amplified this phenomenon further (log rank, P = 0.03; HR 2.18; 1.21-4.26; P = 0.02). CONCLUSIONS: ABCB1 polymorphisms correlate with freedom from grade > or =3A EBPR and we believe that this may be attributed to MDR1/ABCB1 encoded P-gp mediating the efflux of immunosuppressants out of leukocytes, with depleted immunosuppressant levels in leukocytes manifesting as increased cellular rejection.     

The impact of pharmacogenomic factors on acute persistent rejection in adult lung transplant patients

Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective of this study was to evaluate the risk factors, including human multidrug resistance gene (MDR1), cytochrome P4503A5 (CYP3A5) and cytokine gene polymorphisms, associated with acute persistent rejection (APR) in lung transplant patients. One hundred and twenty-five adult lung transplant patients were studied. MDR1 G2677T, C3435T and CYP3A5 polymorphisms were assessed by direct sequencing of the polymorphic region in patient DNA. Cytokine genotyping for five cytokines was performed using the polymerase chain reaction-sequence specific primers (PCR-SSP) technique. Multivariate regression analysis was used to identify the predictors of acute persistent rejection. The dependent variable was the presence or absence of acute persistent rejection based on lung biopsies during the first postoperative year. The independent variables were MDR1 G2677T and C3435T, CYP4503A5 and cytokine polymorphisms, survival status, age, gender, survival days and HLA mismatches. The MDR1 C3435T polymorphism and age were independently associated with acute persistent rejection (p = 0.025, odds ratio = 0.29, 95% CI 0.1-0.86 and p = 0.016, odds ratio = 0.94, 95% CI 0.89-0.98, respectively). For the MDR1 C3435T polymorphism, 72% of patients with the C allele had acute persistent rejection in comparison to 52% for TT patients (p = 0.04). For age, a significant difference was found between the nonrejection group and the rejection group (mean+/-S.D. 52.1+/-11.2 vs. 44.4+/-12.3, p = 0.01). This is the first report of the association of a drug disposition genotype with drug-resistant acute rejection in organ transplant patients. The major predictor of acute persistent rejection in the first postoperative year for lung transplant patients was the MDR1 C3435T genotype. This association could be due to drug resistance, altered drug disposition or other immunologic effects associated with P-glycoprotein (P-gp) function. Future prospective treatment algorithms should be developed that will incorporate the knowledge of gene polymorphisms into treatment regimens to improve the outcome following lung transplantation.     

Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients

The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.     

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。     

Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients

BACKGROUND: Several single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene may play a role in the interindividual variation of cyclosporine A (CsA) absorption in renal transplant patients. METHODS: An analysis of CsA absorption measured by the dose- and weight-adjusted 4 hr area under the time-concentration curve, AUC(0-4)/mg doseCsA/kg, was conducted on day 3 after transplantation, in 69 de novo renal transplant patients who were genotyped for MDR1 SNPs. Follow-up pharmacogenomic analysis at 1 month posttransplant was performed utilizing dose- and weight-adjusted 2-hour postdose CsA concentration (C2). RESULTS: AUC(0-4)/mg doseCsA/kg was significantly higher (P=0.024) in (C/C)3435 individuals than in a grouped population of (C/T)3435 and (T/T)3435 patients on postoperative day 3. G2677T variants were not significantly correlated with CsA absorption (P=0.084). The number of C3435-G2677 haplotypes was the best predictor of CsA exposure. At 1 month posttransplant, no correlation was seen between MDR1 SNPs and CsA exposure. The frequency of wild-type variants for C3435T and G2677T were 61% and 77.6%, respectively. SNPs at G2677T and C3435T loci were found to be in linkage disequilibrium. CONCLUSIONS: MDR1 polymorphisms are associated with differences in CsA exposure only in the first posttransplant week.     

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.     

MDR1 C3435T polymorphisms correlate with cyclosporine levels in de novo renal recipients

BACKGROUND: Single nucleotide polymorphisms (SNPs) in the multidrug resistance (MDR1) gene correlate with the intestinal function of P-glycoprotein (PGP). PGP serves as a hydrophobic export pump that extrudes cyclosporine (CsA) across the luminal membrane thus preventing CsA absorption. These genetic variants may predict CsA exposure levels in the early posttransplantation period. METHODS: CsA absorption profiles were established in 75 renal transplant patients using total daily dose and body weight adjusted 4-hour area under the time-concentration curve, AUC(0-4)/mg dose/kg body weight, on posttransplant day 3. These patients were subsequently genotyped for C3435T and G2677T polymorphisms using real-time polymerase chain reaction. An analysis was conducted to assess the independent impact of C3435T and G2677T SNPs on CsA bioavailability. RESULTS: C3435T polymorphisms were found to be an independent predictor of CsA AUC(0-4)/mg dose/kg levels on postoperative day 3. An inverse correlation was found between the number of T alleles and AUC values such that every T allele was associated with an approximate 15% decrement in AUC(0-4)/mg dose/kg (P = .034). A similar nonsignificant trend was observed for G2677T polymorphisms. CONCLUSIONS: MDR1 SNPs are correlated with CsA exposure in the early post-transplant period. Polymorphisms, in conjunction with other criteria, may become a useful tool to optimize initial drug dosing in renal transplantation.     

MDR基因多态性对肾移植受者环孢素A急性肾毒性发生率的影响

目的 探讨供、受者细胞膜P-糖蛋白(P-gp)的编码基因(MDR基因)多态性对肾移植受者环孢素A(CsA)急性肾毒性发生率的影响.方法 采用聚合酶链反应/限制性片段长度多态性(PCR/RFLP)方法分析173例肾移植供、受者MDR基因外显子26(exon26)基因型;分别以供者和受者exon26基因型进行分组,观测术后3个月内受者血尿素氮、血肌酐和24 h尿量等指标与供、受者exon26基因型之间的关系.结果 供者和受者exon26基因型均为CC、CT和TT三种类型.173例供者中,CC、CT和TTr型比例分别为:28.3%(49/173)、41.6%(72/173)和30.0%(52/173);173例受者中,CC、CT和TT基因型比例分别为:27.7%(48/173)、40.5%(70/173)和31.8%(55/173).供、受者间exon26基因型的类型和分布比例相似,差异无统计学意义(P>0.05).肾移植术后,共有48例受者符合CsA急性肾毒性诊断标准.按受者CC、CT、TT型分组时,各组受者CsA急性肾毒性的发生率分别为25.0%(12/48)、41.7%(20/48)和33.3%(16/48),各组间比较,差异无统计学意义(P>0.05);按供者CC、CT和TT基因型分组时,各组受者术后CsA急性肾毒性的发生率分别为14.6%(7/48)、50.0%(24/48)和35.4%(17/48),CC与CT和TT型之间比较,差异有统计学意义(P<0.05).而且.受者CC型组肾功能异常发生率明显高于供者CC型组(P<0.05).结论 MDR基因多态性对肾移植受者CsA急性肾毒性发生率具有明显的影响,而发挥作用是供者MDR基因多态性.     

Serum amyloid A1 -13 T/C alleles in Turkish familial Mediterranean fever patients with and without amyloidosis

Previously reported studies concerning the effect of homozygosity of the 1.1 allele of the SAA gene found a correlation between this haplotype and susceptibility to amyloidosis in FMF patients. Another report revealed a strong association between SAA1 -13T/C and secondary amyloidosis in the rheumatoid arthritis patient group. In this study, we aimed to determine the effect of SAA1 -13T/C in FMF patients with and without amyloidosis. The study cohort, consisting of 166 patients with FMF was divided into two groups, according to the presence (n=66) or absence (n=100) of renal amyloidosis at study entry. MEFV gene mutation analysis and allelic variant of SAA1 gene -13 T/C was analyzed according to the previously described techniques. SAA1 -13 T allele frequencies were 0.5816, 0.23 and 0.4242 in controls, FMF patients and FMF-amyloidosis patients respectively. The difference between controls vs. FMF patients and FMF-amyloidosis patients were 0.0002 and 0.1673 respectively. It was 0.0071 for FMF-patients vs. FMF-amyloidosis. When 694 M/V homozygous nonamyloid-FMF group was compared with 694 M/V carriers of the FMF-amyloidosis group, the difference was 0.049. When carrying TT allele was considered, the difference between controls vs. FMF patients and FMF-amyloidosis patients were 0.0001 and 0.58. It was 0.0003 for FMF patients vs. FMF-amyloidosis. When 694 M/V homozygous nonamyloid-FMF group was compared with 694 M/V carriers of the FMF-amyloidosis group, the difference was 0.03. Carrying SAA -13T in homozygote state revealed a 7.9 (95% CI 3.6 -17.5) fold risk for the occurrence of amyloidosis when compared with FMF patients without amyloidosis. This was 8.75 (95% CI 3.0 - 25.1) when 694 M/V homozygotes were taken into consideration. Our data revealed that the genotype SAA1 -13T has at least an effect on the development of amyloidosis. As more data on this polymorphism accumulate, we will understand its effect on the pathogenesis of amyloidosis in FMF.     

The Role of MDR1 C3435T Gene Polymorphism on Gingival Hyperplasia in Turkish Renal Transplant Patients Treated With Cyclosporine in the Absence of Calcium Channel Blockers

Objective

To investigate the occurrence of MDR1 C3435T gene polymorphisms in the Turkish renal transplant patients treated with cyclosporine (CsA), and correlate these findings with prevalence and degree of gingival hyperplasia (GH).

Methods

Before to renal transplantation, dental treatment and oral hygiene education of 300 renal disease patients was completed. Peripheral blood samples were collected from 154 renal transplant recipients on CsA treatment without calcium channel blockers. MDR1 C3435T gene polymorphism and GH were analyzed at posttransplant month 6.

Results

No difference was detected among groups for age, posttransplant period, creatine levels, serum concentration of CsA, or plaque and bleeding indices (P > .05). Out of all transplanted patients, 42.8% were found to have the heterozygote genotype. This was reduced to 37.5% when individuals with GH were taken into account. However, when degree of GH was analyzed, those with severe GH were found to have the heterozygote genotype significantly more often (P < .05).

Conclusions

The MDR1 gene polymorphism is not associated with GH frequency, but may be associated with GH severity.     

Polymorphisms of the MDR1 and MIF genes in children with nephrotic syndrome

Oral steroid treatment is the first line of therapy for childhood nephrotic syndrome (NS). Nonetheless, some patients are resistant to this treatment. Many efforts have been made to explain the differences in the response to steroid treatment in patients with NS based on the genetic background. We have investigated single nucleotide polymorphisms of the MDR1 [C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642)] and MIF (G-173C, rs755622) genes in 170 children with NS. Of these children, 69 (40.6%) were initial steroid non-responders, and 23 (13.5% of total) developed chronic kidney disease. Renal biopsy findings, which were available for 101 patients, showed that 35 patients had minimal change lesion and 66 had focal segmental glomerulosclerosis. The frequencies of the MDR1 1236 CC (18.8 vs 7.2%) or TC (53.5 vs 43.5%) genotype and C allele (45.5 vs 29.0%) were significantly higher in the initial steroid responders than in the non-responders. Analysis of MDR1 three-marker haplotypes revealed that the frequency of the TGC haplotype was significantly lower in the initial steroid responders than in the non-responders (15.8 vs 29.0%). There was no association between the MIF G-173C polymorphism and clinical parameters, renal histological findings, and steroid responsiveness. These data suggest that the initial steroid response in children with NS may be influenced by genetic variations in the MDR1 gene.     

Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients

Calcineurin inhibitors (CNI) are metabolized by cytochrome-P4503A (CYP3A) enzymes and extruded into the intestinal lumen by the drug efflux pump, P-glycoprotein (P-gp). The impact of single nucleotide polymorphisms (SNPs) of genes encoding CYP3A5 and P-gp on CNI dosing was examined among Asian renal transplant recipients. Frequencies of CYP3A5*1 versus *3 and MDR1-C3435T were correlated with tacrolimus (TAC) and cyclosporine (CSA) concentration-to-dose (C/D) ratios. Among 82 recipients (49% male; 88% Chinese), the majority were CYP3A5 expressors (*1*1 and *1*3, 11% and 40%, respectively) and 49% were nonexpressors (*3/*3). The prevalence of MDR-1-C3435T variants was 3435CC (41%), 3435CT (46%), and 3435TT (13%). Among 18 TAC-treated recipients, all receiving Diltiazem (DTZ), the median C/D ratio was lower for CYP3A5 *1/*1 versus *1/*3 versus *3/*3 (1.9, 4.6, and 13.5 ng/mL per 0.1 mg/kg/d, respectively; P = .001). The median C/D ratio was higher for TAC-treated patients with MDR-1-3435CC (14.1, 7.3, and 2.2 ng/mL per 0.1 mg/kg/d for CC, CT, and TT, respectively; P = .023). Neither CYP3A5 nor MDR-1-C3435T variants had an impact on CSA C/D ratios. Thus, CYP3A5 SNP has a significant impact on TAC dosing in Asian renal transplant recipients, which was likely to facilitate TAC metabolism. Although MDR-1-3435CC with higher P-gp expression should experience more TAC efflux and, therefore, lower TAC C/D ratios, all MDR-1-3435CC carriers were CYP3A5 nonexpressors; the latter ultimately contributed to the observed higher TAC C/D ratios in this population. This study advocates starting with a higher TAC dose for CYP3A5 expressors. Coadministration of DTZ may further optimize the TAC level through preferential P-gp binding and CYP3A4 inhibition.     

Impact of CYP3A5 and MDR1(ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients

OBJECTIVE: The objective of this study was to assess the influence of CYP3A5 and MDR1 genetic polymorphisms on tacrolimus pharmacokinetics in Japanese renal transplant recipients. METHOD: The pharmacokinetic parameters of tacrolimus were calculated in steady-state on day 28 after transplantation. Polymerase chain reaction-restriction fragment length polymorphism and direct sequence methods were used for CYP3A5 and MDR1 polymorphisms, respectively. RESULTS: The dose-adjusted area under the concentration-time curve (AUC0-12) was significantly lower among CYP3A5*1 carriers than those bearing CYP3A5*3/*3. (0.570 +/- 0.105 vs 0.865 +/- 0.343 ng.h/mL per mg/kg, P = .00322). The daily tacrolimus dose per body weight was significantly higher in CYP3A5*1 carriers than those of CYP3A5*3/*3 carriers (0.271 +/- 0.110 vs 0.150 +/- 0.056 mg/kg, P = .00016). In this study, a distinction was made between carriers of CYP3A5*1/*1+*1/*3 and CYP3A5*3/*3 to investigate the influence of the MDR1 C3435T mutation on tacrolimus pharmacokinetics. The MDR1 C3435T polymorphisms did not affect any tacrolimus pharmacokinetic parameter in either group. CONCLUSIONS: Renal transplant recipients who were CYP3A5*1 carriers required a higher dose of tacrolimus than CYP3A5*3/*3, indicating a significantly lower dose-adjusted AUC0-12 of tacrolimus. In contrast, MDR1 C3435T polymorphism was not an important factor in tacrolimus pharmacokinetics.