MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia

Functional single nucleotide polymorphism (SNP) C3435T in exon 26 of the MDR1 ( ABCB1 ) gene encoding the xenobiotic transporter P-glycoprotein (P-gp, MDR1, ABCB1) may influence susceptibility to several diseases as well as clinical outcome of treatment with P-gp substrates. Exposure to environmental chemicals is thought to be involved in the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) and P-gp-transported drugs are used in its treatment; however, little is known about the impact of the C3435T MDR1 SNP in B-CLL. In this study, 110 Caucasian B-CLL patients and 201 healthy controls were genotyped for the MDR1 C3435T SNP. Additionally, P-gp activity was assessed in malignant lymphocytes of 22 untreated B-CLL patients. We observed a higher frequency of carriers of at least one 3435T allele (3435CT and 3435TT genotypes) among B-CLL patients as compared to normal individuals (76% vs . 63%, p=0.027). The genotypes 3435CT and 3435TT were associated with B-CLL, (odds ratio=1.8, 95% confidence interval = 1.1-3.0). Moreover, P-gp activity in B-CLL cells depended on MDR1 genotype, with the highest P-gp activity in 3435CC homozygotes, intermediate in 3435CT heterozygotes and the lowest in 3435TT homozygotes (p=0.042). P-gp activity was also significantly lower in carriers of the T-allele (3435CT/TT genotype) as compared to the non-carriers (3435CC genotype), (p=0.029). Taken together, these data indicate that the MDR1 C3435T SNP may carry an increased risk of developing B-CLL, possibly by virtue of decreased protection against P-gp-substrate carcinogens. The differences in P-gp activity in B-CLL tumor cells related to MDR1 genotype may have implications to the response to chemotherapy with P-gp transported anticancer agents.     

ABCB1 C3435T polymorphism is associated with susceptibility to major depression,but not with a clinical response to citalopram in a Turkish population

BackgroundThe ATP-binding cassette sub-family B member 1 (ABCB1) gene, which encodes the p-glycoprotein at the blood–brain barrier, is investigated for patients’ susceptibility to major depressive disorder (MDD) and their therapeutic response to antidepressants. However, there is an inconsistency between the studies of different ethnic groups. The current study aimed to determine the potential correlations of the ABCB1 gene C3435T polymorphism with the susceptibility to MDD and the therapeutic response to citalopram in a Turkish population.MethodsFifty-four patients with MDD who received citalopram and 70 controls from the Turkish population were genotyped for ABCB1 C3435T polymorphism. To assess the therapeutic response to citalopram, all patients were rated baseline, first, second, fourth and sixth weeks according to the 17-item Hamilton Rating Scale for Depression (HAMD-17).ResultsThere was a significant correlation between the patient and control groups for ABCB1 C3435T polymorphism. Distribution of CC genotype and C allele frequency were higher in the patients than in the control group (p = 0.006, p = 0.020, respectively). However, no correlation between ABCB1 C3435T polymorphism and a therapeutic response to citalopram was observed.ConclusionOur results suggested that C3435T polymorphism in the ABCB1 gene may be an indicator of the susceptibility to major depression, without a likely treatment response to citalopram in a Turkish population. These findings should be replicated in studies on larger patient groups with different ethnicities.     

Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T polymorphisms and P-glycoprotein inhibitors on salivary digoxin secretion in congestive heart failure patients

The aim of the present study was to evaluate the effects of ABCB1 ( MDR1 ) gene polymorphism on P-glycoprotein model substrate, i.e. digoxin, salivary secretion. The study was carried out in 77 patients diagnosed with congestive heart failure administered digoxin, who were subdivided into two groups: 1) co-administered P-glycoprotein inhibitors and 2) without any known P-glycoprotein inhibitors. The ABCB1 2677G >A,T and 3435C >T polymorphisms were evaluated using PCR-RFLP methods. Steady-state digoxin concentrations were measured in blood serum as well as in unstimulated and stimulated saliva using FPIA method. It was found that values of Pearson's coefficient were significantly higher in patients co-administered P-glycoprotein inhibitors in comparison with subjects who were not administered any inhibitor both for stimulated (Pearson's coefficient r = 0.832, p < 0.01) and unstimulated saliva (r = 0.812, p < 0.01). Evaluation of the impact of ABCB1 2677G >A,T and 3435C >T polymorphism on salivary digoxin secretion revealed significant differences in digoxin stimulated saliva/serum ratio between patients stratified by 2677G >A,T genotype (TT, TA> GT, GA> GG, p < 0.01). The results from the present study suggest that administration of P-glycoprotein inhibitors as well as ABCB1 gene polymorphism may affect salivary digoxin secretion.     

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.     

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.     

Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients

Objective The P-glycoprotein, a product of MDR1 (multiple drug resistance 1) gene, is a membrane efflux pump localized in epithelial cells in the small and large intestine, a part of the gastrointestinal barrier that protects cells against xenobiotics from our diet, bacterial toxins, drugs and other biologically active compounds, possibly carcinogens. In the present study, an association of MDR1 gene polymorphism and the occurrence of colon cancer were evaluated.Methods The study population consisted of 184 unrelated sporadic colon cancer patients and 188 healthy unrelated controls. Colon cancer patients were also subdivided into two subgroups, i.e., diagnosed before and after 50 years of age, and compared with age-stratified controls. The C3435T MDR1 gene polymorphism was identified using the polymerase chain reaction–restriction fragment length polymorphism method.Results The distribution of wild-type and mutated genotypes was similar in the colon cancer patients and in the healthy controls. However, when patients diagnosed before 50 years of age were compared with the healthy population, carriers of MDR1 3435TT genotype or 3435T allele were at 2.7-fold (P<0.05) and 1.7-fold (P<0.05) higher risk of the disease development, respectively.Conclusions Genetic testing for C3435T MDR1 gene polymorphism may be a suitable test to evaluate the risk for colon cancer in patients under 50 years of age.     

Variable expression of P-glycoprotein in the human placenta and its association with mutations of the multidrug resistance 1 gene (MDR1, ABCB1)

The MDR1 gene product P-glycoprotein in the human placenta is important for protecting the fetus from unintended, harmful drug exposure, but also for limiting the access of therapeutic drugs to the fetus after maternal drug intake. A polymorphism in exon 26 of the MDR1 gene (C3435T) has previously been shown to be associated with reduced P-glycoprotein expression in the small intestine, kidney and lymphocytes. In the present study, we examined systematically whether MDR1 polymorphisms also have an impact on P-glycoprotein expression in the human placenta. MDR1 mRNA and P-glycoprotein were analysed in 73 full-term human placentas of Caucasians, as well as respective MDR1 genotypes/haplotypes, for the C3435T and G2677T/A polymorphisms of mothers and infants. MDR1 mRNA levels were not different between these genotype groups. However, P-glycoprotein expression was significantly lower when both mother and infant were homozygous for the 3435T allele (TT/tt) compared to maternal and fetal homozygotes for the C-allele (0.40 +/- 0.18 a.u. for TT/tt versus 0.66 +/- 0.30 a.u. for CC/cc, P = 0.01). Moreover, placentas from mothers carrying both polymorphisms (3435T and 2677T; TT/TT) also had a significantly lower P-glycoprotein expression (0.31 +/- 0.12 a.u.) compared to placentas of wild-type individuals (CC/GG, 0.71 +/- 0.31 a.u., P = 0.02). Taken together, the MDR1 polymorphisms C3435T and G2677T are associated with altered P-glycoprotein expression in the human placenta, and may have clinical consequences due to genetically determined, variable drug exposure of the fetus.     

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 polymorphism of multi-drug resistance 1 gene (MDR1) does not influence the pharmacokinetics of dexamethasone loaded into autologous erythrocytes of patients with inflammatory bowel disease

BACKGROUND: We have recently demonstrated that low doses of Dexamethasone 21-P (Dex 21-P), loaded in autologous erythrocytes and administered at monthly intervals, have been able to maintain steroid-dependent patients with Crohn's disease (CD) and ulcerative colitis (UC) in clinical remission with a progressive and complete tapering of systemic steroids. AIM: Since multi-drug resistance 1 gene (MDR1) has a potential influence on Dexamethasone (Dex) bioavailability, we designed this study to investigate the correlation between MDR1 genotype and Dex pharmacokinetic after its delivery in patients with inflammatory bowel disease (IBD). MATERIALS AND METHODS: Seventeen steroid-dependent consecutive patients with IBD (10 UC mean age 36 +/- 12, and 7 Crohn's disease mean age 31 +/- 5) were consecutively recruited. The C3435T polymorphism of MDR1 gene was studied by Denaturing High Performance Liquid Chromatography (DHPLC). Serum level of Dex were determined at the end of the infusion and after 15 days by high performance liquid chromatography electrospray mass spectrometry. RESULTS: The mean dose of Dex 21-P administered was 9.9 mg +/- 4 (range 2.7-20.3), while the mean levels of Dex at the end of the infusion and after 15 days were 0.66 +/- 0.23 mM and 0.06 +/- 0.06 mM, respectively. Concerning the C3435T genotype, two patients were wild-type, eleven heterozygotes, and four homozygotes. No correlation between basal or 15-days plasma level of Dex and MDR1 genotype was found (r = 0.19 and r = 0.21, respectively). CONCLUSION: Our findings demonstrated that Dex plasma level, after infusion of autologous erythrocytes loaded with Dex 21-P are completely independent by the MDR 1 gene polymorphism. This could be another potential advantage of this modality of drug delivering.     

MDR1 C3435T polymorphism is predictive of later onset of ulcerative colitis in Japanese

Recently, a silent polymorphism of C3435T of the MDR1 gene, encoding the multidrug resistant transporter MDR1/P-glycoprotein, has been found to be associated with susceptibility to ulcerative colitis (UC), but this remains controversial. This study was conducted to find a possible reason for the discrepancies, and it was suggested that the age of onset was important for the association, namely, C3435T was predictive of susceptibility to later onset UC, but not for early onset UC. Linkage disequilibrium of C3435T with T-129C, C1236T and G2677A, T was suggested to be altered in UC, but the analysis of their haplotype provided no advantage in terms of prediction over that with only C3435T. The effect of C3435T on susceptibility could not be explained by that on mRNA expression in rectal mucosa, but it was greater in the C(3435)-noncarriers in the early onset group, allowing the individualization of steroid-based pharmacotherapy.     

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.     

C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation

The bioavailability of structurally unrelated drugs is limited by active secretion via the multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) from enterocyte into lumen as well as intestinal metabolism by cytochrome P450 IIIA4 (CYP3A4). In the present study, we analyzed whether genetic polymorphism of the MDR1 had some influence on the intestinal expression levels of Pgp and CYP3A4 and the tacrolimus concentration/dose ratio over the first postoperative days in recipients of living-donor liver transplantation (LDLT). Genotyping assays were performed for the major 10 polymorphisms in the MDR1 gene by the polymerase chain reaction-restriction enzyme length polymorphism method. The allele frequencies of variations at five positions were almost comparable with those in the former studies in Caucasians and Japanese, but there was no variation at the other five positions. Although no polymorphism correlated with the intestinal expression of MDR1 mRNA or the tacrolimus concentration/dose ratio in the LDLT recipients, the C3435T polymorphism significantly affected the intestinal expression level of CYP3A4 mRNA as follows; 3435C/C>3435C/T (P < 0.05 vs. 3435C/C)>3435T/T (P < 0.01 vs. 3435C/C). Therefore, the identified polymorphisms including C3435T in the MDR1 gene were indicated to have no influence on the intestinal expression level of Pgp or the tacrolimus concentration/dose ratio in the recipients of LDLT. On the other hand, the C3435T polymorphism of MDR1 was suggested to correlate with the enterocyte expression of CYP3A4 rather than Pgp linking unknown genetic variation in CYP3A4 gene.     

Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver

AIMS: The aim of the study was to determine whether a correlation exists between MDR1 (ABCB1) gene polymorphisms at positions 3435 (C3435T) and 2677 (G2677T(A)) and the expression of human hepatic P-glycoprotein (P-gp). METHODS: P-gp protein expression in 26 human livers was assessed by Western blotting and ABCB1 mRNA expression was determined by real time RT-PCR. The C3435T and G2677T(A) polymorphisms were identified by RFLP and direct sequence analysis, respectively. RESULTS: The C and G allele frequencies for the C3435T and G2677T(A) polymorphisms were 0.48 and 0.79, respectively, and the genotypes were in Hardy-Weinberg equilibrium. There was a 200- and 20-fold variation in the expression of ABCB1 mRNA and Pgp protein expression, respectively. There were no differences in mRNA and protein expression identified amongst the different genotypes attributable to the C3435T and G2677T(A) polymorphisms in the ABCB1 gene. Exposure to a PXR ligand prior to death did not influence mRNA or protein expression. CONCLUSIONS: There is substantial variability in the expression of Pgp in human liver, but this is not due to the presence of C3435T and G2677T(A) polymorphisms in the ABCB1 gene, although our study is limited by a small sample size.     

MDR1 Genotype-Related Pharmacokinetics of Digoxin After Single Oral Administration in Healthy Japanese Subjects

Purpose. To evaluate the MDR1 genotype frequency in the Japanese population and to study the relationship between the MDR1 genotype and the pharmacokinetics of digoxin after single oral administration in healthy subjects. Methods. The MDR1 genotype at exon 26 was determined in 114 healthy volunteers by polymerase chain reaction-restriction fragment length polymorphism. The serum concentration-time profile of digoxin was examined after single oral administration at a dose of 0.25 mg. Results. It was found that 35.1 % (40/114) of subjects were homozygous for the wild-type allele (C/C), 52.6 % (60/114) were compound heterozygotes with a mutant T-allele (C3435T) (C/T), and 12.3 % (14/114) were homozygous for the mutant allele (T/T). There was no effect of gender or age on the distribution. The serum concentration of digoxin after a single oral administration increased rapidly, attaining a steady state in all subjects; however, it was lower in the subjects harboring the T-allele. AUC_{0-4 h} values (±SD) were 4.11 ± 0.57, 3.20 ± 0.49, and 3.27± 0.58 ng h/ml, respectively, with a significant difference between C/C and C/T or T/T. Conclusions. The serum concentration of digoxin after single oral administration was lower in the subjects harboring a mutant allele (C3435T) at exon 26 of the MDR1 gene.     

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.     

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.     

MDR1基因多态性对口服环孢素A药代动力学的影响

目的非线性混合效应模型(NONMEM)考察中国健康人多药耐药基因(MDR1)中26外显子的C3435T多态性与环孢素A (CsA)药代动力学特性间的关系。方法HPLC法测定20名健康男性单次口服CsA微乳溶液制剂500 mg后24 h内不同时间点的药物浓度。MDR1的基因多态性测定采用DNA限制性片段长度多态性法，并用基因测序法验证。数据处理与模型拟合采用NONMEM法。结果中国健康人中含MDR1 C3435T CC或CT型的相对生物利用度较TT型高40%。结论MDR1中C3435T多态性是个体间CsA相对生物利用度差异的影响因素。     

Association analysis of three ABCB1 (MDR1) gene variants (C1236T,G2677A/T and C3435T) and their genotype/haplotype combinations with the familial Mediterranean fever

Abstract

1. Familial Mediterranean fever (FMF) is considered an autosomal recessive disorder, associated with a single gene named Mediterranean fever (MEFV). The aim of this study was to perform genotyping and haplotyping analysis of the multidrug resistance (ATP-binding cassette, subfamily B, member 1 – ABCB1) gene in FMF patients.

2. Three ABCB1 gene polymorphisms (C1236T, G2677T/A and C3435T) were analyzed in 309 FMF patients and 250 healthy control subjects. All subjects were genotyped by PCR–restriction fragment length polymorphism analysis, and statistical analysis was performed using the Arlequin 3.1.1 and SPSS 16.0 software packages.

3. The CT genotype frequency of the C3435T polymorphism (p?=?0.003), the CT–GT–CT (C1236T–G2677T/A–C3435T) triple genotype (p?=?0.001) and the C–G (C1236T–G2677T/A) haplotype (p?=?0.030) were more common in the FMF patients. The CT–GG–CC triple genotype and T–G–C, C–T–T and T–G–T haplotypes (C1236T–G2677T/A–C3435T) were higher in the control subjects (p?=?0.011, 0.001, 0.009 and 0.000, respectively). The CT–GG binary genotype and C–T and T–G haplotypes for C1236T–G2677T/A polymorphisms may have a high degree of protective effect against FMF (p?=?0.0005, 0.002 and 0.000, respectively).

4. Our study showed that genotypes and haplotypes of ABCB1 gene polymorphisms may affect patients’ FMF susceptibility.     

MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine

AIMS: The C3435T polymorphism in the human MDR1 gene is associated with lower intestinal P-glycoprotein expression, reduced protein function in peripheral blood cells and higher plasma concentrations of the P-glycoprotein substrate digoxin. Using fexofenadine, a known P-glycoprotein substrate, the hypothesis was tested whether this polymorphism also affects the disposition of other drugs in humans. METHODS: Ten Caucasian subjects homozygous for the wild-type allele at position 3435 (CC) and 10 individuals homozygous for T at position 3435 participated in this study. A single oral dose of 180 mg fexofenadine HCl was administered. Plasma and urine concentrations of fexofenadine were measured up to 72 h using a sensitive LC/MS method. In addition, P-glycoprotein function was assessed using efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ cells. Results Fexofenadine plasma concentrations varied considerably among the study population. However, fexofenadine disposition was not significantly different between the CC and TT groups (e.g. AUC(0,infinity) CC vs TT: 3567.1+/-1535.5 vs 3910.1+/-1894.8 ng ml-1 h, NS; 95% CI on the difference -1364.9, 2050.9). In contrast, P-glycoprotein function was significantly decreased in CD56+ cells of the TT compared with the CC group (rhodamine fluorescence CC vs TT: 45.6+/-7.2% vs 61.1+/-12.3%, P<0.05; 95% CI on the difference 5.6, 25.5). Conclusions In spite of MDR1 genotype-dependent differences in P-glycoprotein function in peripheral blood cells, there was no association of the C3435T polymorphism with the disposition of the P-glycoprotein substrate fexofenadine in this German Caucasian study population. These data indicate that other mechanisms including uptake transporter function are likely to play a role in fexofenadine disposition.     

No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells

Inherited differences in xenobiotic transport and metabolism may play an important role in the development of adult acute myeloid leukemia (AML) and response to the chemotherapy. An ATP-binding cassette (ABC) family transporter P-glycoprotein (P-gp or ABCB1), encoded by ABCB1 (MDR1) gene, is involved in the protection against xenobiotics and multi-drug resistance. The aim of this study was to investigate the potential involvement of the ABCB1 gene exon 26 3435C>T single nucleotide polymorphism (SNP) in the genetic susceptibility to AML and regulation of P-gp expression and activity in AML cells. A total of 180 adult AML patients and 180 sex-matched controls were genotyped using PCR-RFLP method. Moreover, in 40 AML patients ABCB1 gene expression was studied by real-time RT-PCR and P-gp expression and activity were assessed by flow cytometry assays. The prevalence of 3435C>T ABCB1 polymorphism was similar in patient and control cohorts (P = 0.16). Furthermore, the carriers of different ABCB1 genotypes did not differ significantly according to ABCB1 gene expression (P = 0.99), P-gp expression (P = 0.42) and P-gp activity (P = 0.83) in leukemic cells. The authors conclude that isolated 3435C>T ABCB1 SNP is not a major factor of the genetic susceptibility to adult AML, and that genotyping of this polymorphism does not allow predicting P-gp expression or activity in AML cells.