Multidrug Resistance 1 C3435T Research Articles

Association between the MDR1 rs1045642 polymorphism and breast cancer risk: An updated meta‑analysis.

Multidrug resistance 1 (MDR1) is a transmembrane transporter on the cell membrane. As an ATP-dependent efflux pump, MDR1 is mainly responsible for the adsorption, distribution, metabolism, excretion and transportation of anticancer drugs to cancer cells. Mutations of the MDR1 gene may be associated with the incidence of cancer. In the past decade, associations found between the MDR1 rs1045642 polymorphism and breast cancer have been inconsistent and inconclusive. Therefore, the present study performed a meta-analysis including studies published up until August 16, 2023 to systematically evaluate the association between the MDR1 rs1045642 polymorphism and breast cancer risk. A total of 21 published case studies involving 6,815 patients with breast cancer and 9,227 healthy participants were included in the meta-analysis. Overall, the MDR1 rs1045642 polymorphism was not significantly associated with breast cancer-associated risk. However, in the subgroup analysis, the MDR1 rs1045642 polymorphism was found to be notably associated with a higher risk of breast cancer among Asian populations in recessive models [TT vs. CT + CC; odds ratio (OR)=1.393; 95% confidence interval (CI), 1.143-1.698; P=0.001; I2<25%]. The MDR1 C3435T polymorphism was also associated with a notable decrease in the incidence of breast cancer in mixed ethnicity populations (TT and CT + CC; OR=0.578; 95% CI, 0.390-0.856; P=0.006; I2<25%). In Caucasian populations, the MDR1 rs1045642 polymorphism was not associated with breast cancer risk. In conclusion, the present meta-analysis demonstrated that the MDR1 rs1045642 polymorphism may increase the risk of breast cancer in Asian populations, is associated with a reduced risk of breast cancer in mixed populations but has no notable effect in Caucasian populations.

The Impact of Single Nucleotide Polymorphisms on the Pharmacokinetics of Tacrolimus in Kidney Allograft Recipients of Northern-West, Iran.

Purpose: Calcineurin inhibitors (CNIs) such as tacrolimus are a major immunosuppressive therapy after renal transplantation, which inhibit cytokine expression. The pharmacokinetics of such drugs is influenced by cytochrome P450 (CYP) enzymes, multi-drug resistance-1 (MDR-1), and C25385T pregnane X receptor (PXR). This study aimed to investigate the impact of single nucleotide polymorphisms (SNP) in these genes on the ratio of tacrolimus level per drug dosage (C/D ratio), acute graft rejection, and viral infections. Methods: Kidney transplantation recipients (n=65) under similar immunosuppressive treatment were included. Amplification refractory mutation systempolymerase chain reaction (ARMS-PCR) method was applied to amplify the loci containing the SNPs of interest. Results: Overall, 65 patients with a male/female ratio of 37/28 were included. The mean age was 38±1.75 years. The variant allele frequencies of CYP3A5*3, MDR-1 C3435T, and PXR C25385T were 95.38, 20.77, and 26.92%, respectively. No significant correlations were found between the studied SNPs and the tacrolimus C/D ratios. However, there was a significant difference in the C/D ratios at 2 and 8 weeks in homozygote CYP3A5 *3/*3 carriers (P=0.015). No significant association was found between the studied polymorphisms and viral infections and acute graft rejection (P>0.05). Conclusion: Homozygote CYP3A5 *3/*3 genotype could influence the tacrolimus metabolism rate (C/D ratio).

The association between MDR1 C3435T genetic polymorphism and the risk of multidrug-resistant epilepsy in Egyptian children

BackgroundEpilepsy is a chronic disease affecting about 2% of the population and is considered a serious neurological disease. Despite its good prognosis, 20–30% of epileptic patients were not cured of their seizures even with the many trials of antiepileptic drug (AED) therapy. The resistance mechanism is still unclear, maybe due to the effect of the genetic factors on the bioavailability of the drugs. Consequently, the association between therapy resistance and the presence of a gene called “multidrug resistance 1 (MDR1)” had been proposed. Thus, the present study aimed to understand the relationship between the genetic polymorphism of MDR1C3435T and the resistance to AEDs.ResultA non-significant association was found between MDR1 C3435T single-nucleotide polymorphism (SNP) and drug-resistant epilepsy. However, there was statistical significance in the association between the drug type and the genotype distribution, in cases that were maintained on sodium valproate and MDR1C3435T genotype.ConclusionPossible involvement of the MDR1 gene C 3435T polymorphism with sodium valproate resistance clarifies the importance of genetic variability in response to the drug and may help to find novel genetic therapy for epilepsy, by targeting the biological mechanisms responsible for epilepsy in each specific individual. Future studies with bigger sample sizes and in other racial populations will be necessary.

Relationship of MDR1 gene polymorphism and P-glycoprotein expression in Chinese refractory lupus nephritis

To evaluate the association of multidrug resistance 1 (MDR1) polymorphism and the expression of P-glycoprotein (Pgp) in Chinese refractory lupus nephritis (LN) patients. Polymerase chain reaction-direct sequencing was used to analyze MDR1 polymorphism. The genotype distribution of MDR1 polymorphism in 132 SLE (systemic lupus erythematosus) patients was evaluated. ELISA was used to measure the expression of Pgp. Relationship among Pgp expression, MDR1 polymorphism, SLEDAI (SLE disease activity index), and kidney pathological score was analyzed by using One-way ANOVA and Pearson linear correlation. The frequency distribution of the MDR1 gene was consistent with the Hardy-Weinberg equilibrium. Compared with CT and CC, patients with T/T homozygote in MDR1 C3435T had significantly increased Pgp expression in the refractory group (p < 0.05). Additionally, SLEDAI score was positively correlated with Pgp expression (r = 0.481, p < 0.05). Also, Pgp expression was positively correlated with renal pathological activity index (r = 0.76, p < 0.05). MDR1 C3435T polymorphism is significantly associated with Pgp expression in patients with refractory LN. Pgp expression is closely related to SLEDAI and renal pathological score. Thus, Pgp may be useful in evaluation of the prognosis of patients with refractory LN.

Genetic polymorphism in MDR1 C3435T is adeterminant of methotrexate cerebrospinal fluid concentrations in Chinese children with acute lymphoblastic leukemia .

This study aimed to investigate the influence of single-nucleotide polymorphism in exon 26 (C3435T) of multidrug resistance 1 (MDR1) transporter gene on the concentration of methotrexate (MTX) in Chinese childhood patients with acute lymphoblastic leukemia (ALL) receiving intravenous (IV) and intrathecal (IT) high-dose methotrexate (HDMTX) chemotherapy. MDR1 C3435T polymorphism was investigated in 60 patients with Chinese childhood ALL. The study also compared the MDR1; polymorphism between the patients with Chinese childhood ALL and the published data on Americans, Mexicans, Caucasians, and Thais. The C3435T polymorphism was identified using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequence analysis. Cerebrospinal fluid (CSF) and plasma concentrations of MTX were measured using high-performance liquid chromatography (HPLC). MTX concentrations were compared according to MDR1 C3435T genotypes. The frequencies of MDR1 C3435T genotype in male and female patients with Chinese childhood ALL were significantly different (p = 0.001). For the frequencies of MDR1 C3435T genotype in Hui and Han patients with Chinese childhood ALL there was no difference (p = 0.188). The distribution of allele frequencies in patients with Chinese childhood ALL was similar to the published data on Americans, Mexican, Caucasians, and Thais (p > 0.05). The CSF concentrations of MTX were found to be significantly different between the C allele (CC + CT) carriers and TT homozygous group (p = 0.04). The plasma concentrations of MTX had no significant difference between the C allele (CC + CT) carriers and TT homozygous group (p > 0.1). This study showed that the polymorphism of MDR1 C3435T influenced the CSF concentration of MTX in patients with Chinese childhood ALL receiving IV and IT HDMTX treatment.

Conversion from Twice-Daily Prograf® to Once-Daily Advagraf® in Multi-ethnic Asian Adult Renal Transplant Recipients With or Without Concomitant Use of Diltiazem: Impact of CYP3A5 and MDR1 Genetic Polymorphisms on Tacrolimus Exposure

Tacrolimus is the mainstay of immunosuppression in renal transplantation. Given that once-daily administration improves patient compliance, 1:1 dose conversion from twice-daily Prograf® to once-daily Advagraf® is recommended. Although cytochrome P450 (CYP) 3A5 and multi-drug resistance 1 (MDR1) polymorphisms influence tacrolimus concentrations, it is unknown if these impact on conversion. This study investigated the change in the pharmacokinetics of tacrolimus after conversion from Prograf® to Advagraf® and examined the impact of CYP3A5 and MDR1 C3435T polymorphisms on those pharmacokinetics. A prospective open-label pharmacokinetic study of 1:1 conversion from Prograf® to Advagraf® with or without diltiazem was conducted on 26 stable renal transplant recipients. Blood samples were collected over 24h during each phase, tacrolimus concentrations were assayed, and noncompartmental pharmacokinetic analysis was performed. All participants were genotyped for CYP3A5*3 and MDR1 C3435T. After conversion, without diltiazem, the area under the concentration-time curve at steady state from 0 to 24 h after dose administration (AUCss, 0-24) was significantly reduced [median224 (range172-366) vs. 184 (104-347) ng·h/mL, p = 0.006, n = 26]. A decrease in tacrolimus exposure (median 21%) was only evident among CYP3A5 expressors [227 (172-366) vs. 180 (104-347) ng·h/mL, p = 0.014, n = 18], not among non-expressors [215 (197-290) vs. 217 (129-281) ng·h/mL, p = 0.263, n = 8]. In contrast, among CYP3A5 expressors receiving diltiazem, AUCss, 0-24 did not change significantly upon conversion [229 (170-296) vs. 221 (123-342) ng·h/mL, p = 0.575, n = 10]. An independent effect was not evident for MDR1 C3435T polymorphism. The high prevalence of CYP3A5 polymorphism among Asians may lead to a significant reduction in tacrolimus exposure with 1:1 dose conversion of Prograf® to Advagraf®. These results advocate for CYP3A5 determination prior to conversion, and suggest that 1:1.25 conversion should be used for CYP3A5 expressors and 1:1 conversion for other patients.

MDR1 gene polymorphisms are associated with ulcerative colitis in a cohort of Serbian patients with inflammatory bowel disease.

BackgroundInflammatory bowel disease (IBD) is a chronic disease of unknown etiology in which genetic factors contribute to development of disease. Single nucleotide polymorphisms (SNPs) in multidrug resistance 1 (MDR1) gene encoding transporter P-glycoprotein have been associated with IBD, but their role in disease susceptibility remains unclear. Therefore, the aim of this study was to investigate the association of three MDR1 polymorphisms, C1236T (rs1128503), G2677T/A (rs2032582) and C3435T (rs1045642), with Serbian IBD patients.MethodsA total of 206 IBD patients, 107 Crohn's disease (CD) and 99 ulcerative colitis (UC), and 255 healthy controls were included in the study. All subjects were genotyped using TaqMan SNP genotyping assays. Comparisons between the groups were performed using the Pearson Chi-square test. False discovery rate according to Benjamini-Hochberg procedure was applied to adjust for multiple comparisons.ResultsCarriers of T allele of all three MDR1 SNPs were more common in UC patients compared to healthy controls, suggesting predisposing role of T allele of these SNPs in UC pathogenesis. Consistently, TT genotype of C1236T and TTT haplotype were also found more frequently in UC patients. On the other hand, C allele and CC genotype of C1236T and C3435T, as well as G allele and GG genotype of G2677T/A were more frequent in healthy subjects, implying protective role of these variants in UC. Likewise, CGC haplotype and CGC/CGC diplotype were more frequent in controls. Contrary to UC, no statistical difference was observed between CD patients and controls in any of the SNPs analyzed.ConclusionMDR1 gene variants and haplotypes were associated with UC in Serbian IBD patients, further supporting their potential role in susceptibility to UC.

Association between multidrug resistance-1 C3435T gene polymorphism and right ventricular dysfunction in patients with chronic obstructive pulmonary disease: cross-sectional study.

Right ventricular (RV) dysfunction may develop over the course of chronic obstructive pulmonary disease (COPD) and is an important predictor of morbidity and mortality. Polymorphism of the multidrug resistance-1 (MDR-1) gene has been correlated with worse clinical findings among patients with COPD. Our aim here was to investigate the relationship between MDR-1 C3435T gene polymorphism and RV dysfunction in COPD patients. This was a cross-sectional study investigating the relationship between RV dysfunction and genetic defects in COPD patients. Forty-one consecutive patients diagnosed with COPD and hospitalized due to acute exacerbation were enrolled. Polymorphism was analyzed using the strip assay technique. RV parameters were evaluated, and RV dysfunction was identified via transthoracic echocardiography. Patients were categorized into three groups according to gene polymorphism: MDR-1 CC (wild type, n = 9), MDR-1 CT (heterozygote mutant, n = 21) or MDR-1 TT (homozygote mutant, n = 11). The study included 14 males and 27 females (mean age 65 ± 11 years). The mean systolic pulmonary artery pressure was 31.4 ± 8 mmHg in the wild-type group, 42.2 ± 12 mmHg in the heterozygote mutant group and 46.5±14 mmHg in the homozygote mutant group (P = 0.027). Presence of RV dilatation was significantly different among the three groups (33%, 71%, and 100%, respectively; P = 0.005). In multiple logistic regression analysis, MDR-1 C3435T gene polymorphism (OR = 9.000, P = 0.019) was an independent predictor of RV dysfunction after adjustment for potential confounders. MDR-1 C3435T gene polymorphism was associated with RV dysfunction in patients with COPD.

Association of MDR1 C3435T and C1236T single nucleotide polymorphisms with male factor infertility.

Infertility affects 1 in 6 couples and approximately 1 in 25 men. Male factor infertility is a major cause of spermatogenic anomalies, the causes of which are largely unknown. Impaired repro-ductive functions in men might result from physiological, genetic, and/or environmental factors such as xenobiotics. The multi-drug re-sistance1 (MDR1) gene encodes a P-glycoprotein which has a role in the active transport of various substrates providing protection of somatic cells from potentially toxic substances, including xenobi-otics. MDR1 is highly expressed at the luminal surface of capillary endothelial cells, and is expressed in Leydig cells, testicular mac-rophages, and Sertoli cells. We performed genotype and haplotype analyses of MDR1 in 192 infertile and 102 fertile Turkish men for the genetic markers C1236T and C3435T, using polymerase chain reaction-restriction fragment length polymorphism analysis. In the overall population, correlations were analyzed in all genotype mod-els. We found that the C3435T polymorphism TT vs CT genotypes showed statistically significant differences in their association with infertility (P = 0.045), and that the CT genotype was associated with high sperm DNA damage (P = 0.02), suggesting that the CT genotype might be a susceptibility factor for infertility. Additionally, the T-T haplotype was significantly more frequent in the control group (13.2 vs 6.5%; odds ratio = 0.459, 95%CI = 0.259-0.814, P = 0.006). This study showed that MDR1 might have a role in male infertility. Fur-ther research in large cohorts with different populations is required to clarify the role of MDR in male fertility.

Association between multidrug resistance 1 gene polymorphisms and genetic susceptibility to sporadic colorectal adenocarcinoma

Objective To investigate the association between genetic polymorphism in exon 26 C3435T and exon 21 G2677T/A of the multidrug resistance 1 (MDR1) gene and the sporadic colorectal adenocarcinoma.Methods A total of 123 patients with colorectal adenocarcinoma and 86 healthy subjects as controls were included.Snapshot SNP typing was used to determine the allele and genotype frequencies of MDR1 C3435T,and G2677T/A.Results There was no significant difference in the distribution of MDR1 C3435T and G2677T/A alleles and genotypes frequencies between control group and case group.When stratified by clinicopathological features such as lesion distribution,differentiation degree and Duke' s stage in the patients with colorectal adenocarcinoma,the statistically significant differences were found in the frequency of C3435T genotype between patients with colon adenocarcinoma (CC 22.2％,CT 63.4％,and TT 14.8 ％) and rectal adenocarcinoma (CC 50.7％,CT 31.9％,and TT 17.4％) (P ＜ 0.01).The frequency of 3435T allele was decreased significantly in patiens with rectal adenocarcinoma (33.3％) as compared with colon adenocarcinoma (46.3％,P ＜0.05).And the frequency of 2677GT genotype was decreased significantly in patients with moderately-differentiated (26.9％) as compared with well-differentiated (46.4％) and poorly-differentiated (47.1％,P ＜ 0.05).Furthermore,the frequency of 2677GT genotype was increased significantly in patients with colon adenocarcinoma (46.3％) as compared with rectal adenocarcinoma (24.6％,P ＜ 0.05),and the frequency of 2677G allele was decreased significantly in patiens with poorly differentiated adenocarcinoma (3.7％) as compared with moderately-differentiated (28.5％) and well-differentiated adenocarcinoma (11.0％,P ＜ 0.05).Conclusion MDR1 C3435T and G2677T/A polymorphisms were found to be not associated with colorectal adenocarcinoma. Key words: Colorectal carcinoma; Multidrug resistance gene; Polymorphism

Implication of P-Glycoprotein in Formation of Depression-Prone Personality: Association Study between the C3435T MDR1 Gene Polymorphism and Interpersonal Sensitivity

Background and Aim: Interpersonal sensitivity is defined as undue and excessive awareness of, and sensitivity to, the behavior and feelings of others. Previous studies suggested that interpersonal sensitivity is one of the vulnerable factors to depression, and that genetic factors and cortisol are involved in the formation of interpersonal sensitivity. On the other hand, P-glycoprotein, which is encoded by the multidrug resistance 1 (MDR1) gene, serves as a barrier to entry and as an active eliminator for xenobiotics and cellular metabolites including cortisol, which is implicated in multiple brain functions. In the present study, we examined the effects of the MDR1 C3435T polymorphism (rs1045642) on interpersonal sensitivity in healthy subjects. Methods: The subjects were 842 healthy Japanese volunteers (mean age = 26.7 years, male/female ratio = 490/352). The C3435T polymorphism of MDR1 gene was detected by a PCR method, and interpersonal sensitivity was assessed by the Interpersonal Sensitivity Measure (IPSM). Results: The 2-factor analysis of covariance (ANCOVA) showed a significant main effect of the MDR1 genotype on the IPSM scores with a significant interaction between the genotype and gender. The subsequent 1-factor ANCOVA showed that in females the C/C genotype group had higher IPSM scores than the C/T genotype group (p < 0.001) and the T/T genotype group (p < 0.001), and the C/T genotype group had higher IPSM scores than the T/T genotype group (p = 0.014). In males no significant association was found between the MDR1 genotype and the IPSM scores. In allelic analyses using the χ² tests, the C allele frequency in females was significantly higher (p < 0.001) in the high IPSM group than in the low IPSM group, while there was no significant difference in the C allele frequency between the high and low IPSM groups in total subjects and males. Conclusion: The present study suggests that the C3435T polymorphism of the MDR1 gene affects the formation of a depression-prone personality trait in Japanese females.

Association of MDR1 gene C3435T polymorphism with childhood intractable epilepsy: a meta-analysis

Drug-resistant epilepsy is also referred to as intractable, medically refractory, or pharmacoresistant epilepsy. Approximately, one-third of patients with epilepsy have recurrent seizures despite therapy. Multidrug resistance 1 (MDR1) gene may play a role in drug-resistance in epilepsy. To assess the association between MDR1 C3435T polymorphism and the response to anticonvulsants in childhood intractable epilepsy, we conducted a systematic review and meta-analysis. Studies were obtained from the electronic database of PubMed, Medline, Embase and CNKI up to September 2013. All the case-control association researches evaluating the role of MDR1 C3435T polymorphism in childhood epilepsy to antiepileptic drugs were identified. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for comparisons of the alleles and genotypes with co-dominant (C/C vs. T/T, C/T vs. T/T), dominant (C/C + C/T vs. T/T), and recessive (C/C vs. C/T + T/T) models in overall and in ethnicity subgroups to measure the strength of genetic association. A total of 8 related studies, including 634 drug-resistant patients, 615 drug-responsive patients and 1,052 healthy controls were pooled in this meta-analysis. The allelic association of MDR1 C3435T with risk of drug-resistance was not significant (OR 1.03, 95% CI 0.87-1.22, P = 0.73; OR 1.00, 95% CI 0.86-1.16, P = 0.98) in overall and in the subgroup analysis by ethnicity (Asian: OR 0.95, 95% CI 0.77-1.18, P = 0.67; Caucasian: OR 1.18, 95% CI 0.89-1.57, P = 0.25). Neither association was found in other genetic models. Our results did not show a significant association between MDR1 C3435T polymorphism and response to anticonvulsant drugs, suggesting that this polymorphism may not be a risk factor to childhood intractable epilepsy.

The impact of genetic polymorphisms on time required to attain the target tacrolimus levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients

Recent pharmacogenetic studies involving various transplant recipients in diverse ethnic populations revealed contradictory findings regarding the impact of CYP3A5 and multidrug resistance-1 (MDR1) single nucleotide polymorphisms (SNPs) on the pharmacodynamics of tacrolmius (TAC). The aim of the current study was to evaluate the impact of these SNPs on the time required to attain target TAC levels and subsequent pharmacodynamic outcomes in pediatric kidney transplant patients. Thirty-eight patients were genotyped for CYP3A5FNx011 and FNx013, and MDR1 C3435T. Notably, none of the patients expressing CYP3A5 FNx011FNx011 or FNx011FNx013 achieved the target concentration of 10-20 ng/mL within the first 2 weeks or even the first month after transplant. However, 34.4% of CYP3A5 FNx013FNx013 achieved and maintained the target goal within the first and second weeks (P <0.05). In contrast, C3435T polymorphism had no significant influence on the proportion of patients achieving target TAC levels. An examination of the impact of genotype combinations on clinical outcomes revealed an increased incidence of acute, chronic rejection and graft loss in patients carrying heterozygous MDR1 C3435T alleles (CT); this indicates the possibility of an additive effect of this SNP on its concurrent combination with a FNx013FNx013 SNP. In conclusion, our study revealed trends toward unwanted outcomes in CYP3A5 non-expressers with an unexplained correlation with MDR1 C3435T polymorphisms. Recommending routine pharmacogenetic testing of the individual SNPs in renal transplant patients is not yet feasible as the relationship of cost-effectiveness to ultimate impact on graft or patient survival must be justified by further prospective clinical trials.

MDR1 C3435T Polymorphism is a Susceptible Marker for the Late Onset Japanese UC

Background: The multi-drug resistance 1 (MDR1) gene is reported to correlate with the function and the expression of P-glycoprotein (P-gp), and the carriers of MDR1 C3435T polymorphism are speculated to have an increased susceptibility to ulcerative colitis (UC) in western countries. The aim of this study is to investigate whether MDR1 C3435T polymorphism is a susceptible marker for the onset of UC in Japanese patients. Patients and Methods:We obtained blood samples from 38 patients with UC and that from 76 healthy controls, and genomic DNA from leucocytes was extracted. MDR1 C3435T polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism methods. The expression of P-gp was examined by immunohistochemistry in colonic tissues with UC. Results: Both the frequencies of TT genotype (p=0.023) and T allele (p=0.011) were significantly higher in the late onset UC groups than in the control group in Japanese UC patients. The protein of P-gp in colonic tissues showed lower expression in UC patients with TT genotype by immunohistological analysis. Conclusion: MDR1 C3435T polymorphisms are linked to the susceptibility of the late onset Japanese UC patients, probably via the lower exported activity of the related pathogenic environmental factors in colon.

The drug-transporter gene MDR1 C3435T and G2677T/A polymorphisms and the risk of multidrug-resistant epilepsy in Turkish children

One-third of all individuals with epilepsy are resistant to antiepileptic drug (AED) treatment. Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters. Several polymorphic variants within the multidrug resistance 1 (MDR1) gene, which encodes the major transmembrane efflux transporter P-glycoprotein, have been proposed to be associated with AED resistance in epilepsy patients. The aim of this study was to evaluate the effect of C3435T and G2677T/A polymorphisms of MDR1 on AED resistance in Turkish children with epilepsy. MDR1 C3435T and G2677T/A were genotyped in 152 patients with epilepsy, classified as drug-resistant in 69 and drug-responsive in 83. Genotypes of the C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction followed by restriction fragment length polymorphism. Genotype and allele frequencies of C3435T and G2677T/A polymorphisms of the MDR1 gene did not differ between drug-resistant and drug-responsive epilepsy patients. Our results suggest that MDR1 C3435T and G2677T/A polymorphisms are not associated with AED resistance in Turkish epileptic patients. To clarify the exact clinical implication of the MDR1 polymorphisms on the multidrug resistance in epilepsy, further investigations in various ethnic populations would be necessary.

The Relation between MultiDrugResistance-1 C3435T Polymorphism and Pulmonary Hypertension in Patients with Chronic Obstructive Pulmonary Disease

PP-093 Right ventricular (RV) dysfunction may develop in the course of chronic obstructive pulmonary disease (COPD) and it is important predictor of morbidity and mortality. The polymorphism of the gene of multidrug resistance-1 (MDR-1) responded to drug resistance have been associated with some

Do MDR1 and SLCO1B1 Polymorphisms Influence the Therapeutic Response to Atorvastatin? A Study on a Cohort of Egyptian Patients with Hypercholesterolemia

Statins are among the most prescribed drugs worldwide to reduce the risk of cardiovascular events. Interindividual variability in drug response is a major clinical problem and is of concern during drug development. Statins, such as atorvastatin, are taken orally and access to their site of action in the liver is greatly facilitated by both intestinal and hepatic transporters. To examine the impact of polymorphisms of the multidrug resistance 1(MDR1) and solute carrier organic anion transporter 1B1 (SLCO1B1) genes on the therapeutic response to atorvastatin as well as the presence of gender-gene interaction. Serum lipid levels were determined at baseline and 4weeks following 40mg/day atorvastatin treatment in 50 Egyptian hypercholesterolemic patients (27 males and 23 females). Identification of MDR1 C3435T and SLCO1B1 A388G gene polymorphisms was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Treatment with atorvastatin resulted in a mean reduction of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) of 8.7%, 9.2%, and 4.1%, respectively, and a mean increase of high density lipoprotein cholesterol (HDL-C) of 1%. Baseline and post-treatment HDL-C levels were statistically significantly higher in the MDR 1 TT homozygotes when compared with the CC wild type. The percentage change in TC, LDL-C, TG, and HDL-C did not show any statistically significant difference when compared among the different MDR 1 C3435T or SLCO1B1 A388G genotypes. The SLCO1B1 GG homozygotes showed a decrease in TG, whereas there was an increase in TG following atorvastatin treatment in AA and AG carriers in females; however, males did not show any statistically significant difference. There was no statistically significant association between either the coronary artery disease (CAD) risk factors (family history of CAD, hypertension, diabetes mellitus, smoking) or concomitant medications with the percentage change in different lipid parameters. MDR1 C3435T was associated with baseline and post-treatment HDL-C variation. SLCO1B1 A388G showed gender-related effects on TG change following atorvastatin treatment. None of the comorbidities or the concomitant medications influenced the percentage change of lipid parameters following atorvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipid response to atorvastatin treatment.

Effect of the C3435T polymorphism of the multidrug resistance 1 gene on the severity of inflammatory bowel disease in Iranian Azeri Turks

Background/Aim:Multidrug resistance 1 (MDR1) gene encodes for P-glycoprotein (P-gp), a transmembrane efflux pump transferring both exogenous and endogenous substrate from the cells. In the human gastrointestinal tract, P-gp is found in high concentrations on the epithelial cells of the colon and small intestine. It is hypothesized that the expression level of MDR1 gene is related to susceptibility of both forms of inflammatory bowel disease (IBD). The aim of this study was to investigate the association of C3435T Single Nucleotide Polymorphism in IBD patients with/without clinical symptoms in Iranian Azeri Turks.Settings and Design:A total of 116 patients with IBD and 92 healthy subjects were analyzed.Materials and Methods:We investigated the distribution of MDR1 C3435T polymorphism via polymerase chain reaction – Restriction Fragment Length Polymorphism technique.Statistical Analysis Used:All statistical analyses were calculated with the SPSS for Windows 16.0. The Fisher exact test was used to test for departure from Hardy-Weinberg equilibrium of the genotype frequencies (P > 0.05).Results:The data showed that IBD patient with homozygous variant carrying MDR1 3435 T/T genotype has elevated risk for development of routine IBD clinical symptoms like Abdominal pain (P = 0.005) and chronic Diarrhea (P = 0.013) compared with MDR1 3435 C/C homozygotes who has reduced risk for development of IBD symptoms.Conclusions:Our data showed that patients with MDR1 3435 T/T are more susceptible to the development of some routine IBD clinical symptoms (P < 0.05). This study suggests a protective role for the MDR1 3435 C/C versus MDR1 3435 T/Tgenotype and C versus T allele for the progression of IBD in this cohort.

MDR1 C3435T Polymorphism and Interaction with Environmental Factors in Risk of Parkinson's Disease: A Case-control Study in Japan

It has been suggested that P-glycoprotein (P-gp), the product of multidrug resistance 1 (MDR1) gene, regulates the brain entry of various xenobiotics. Impaired function of P-gp may be associated with an increased risk of Parkinson's disease (PD). The aim of this study was to investigate the impact of a MDR1 C3435T polymorphism on PD risk alone or in combination with environmental factors. A total of 238 patients with PD and 368 controls were genotyped for the MDR1 C3435T polymorphism. Subjects with the TT genotype of the C3435T polymorphism showed a nonsignificantly increased risk of PD [odds ratio (OR)=1.49, 95% confidence interval (CI)=0.85-2.25] compared with those with the CC genotype. A gene-environment interaction was suggested, with a combination of at least one T allele and ever drinking conferring significantly higher risk (OR=1.83, 95% CI=1.07-3.15, p=0.029), compared with the CC genotype and never drinking. No significant interaction of smoking or occupational pesticide use with the C3435T polymorphism was observed. Our results suggest that the C3435T polymorphism may not play an important role in PD susceptibility in Japanese. Evidence of an interaction between the C3435T polymorphism and alcohol consumption was suggested.

Relationship between genetic polymorphism of multidrug resistance 1 gene and the risk of childhood acute lymphocytic leukemia

To investigate the relationship between genetic polymorphism in exon 12 C1236T, exon 21 G2677T/A and exon 26 C3435T of the multidrug resistance 1 (MDR1) gene and the risk of childhood acute lymphocytic leukemia (ALL). A total of 176 patients with ALL and a cohort of 170 matched healthy subjects were included. SNaPshot SNP typing was used to determine the genotypes of MDR1 C1236T, G2677T/A, C3435T. Based on the clinical data, the relationship between genetic polymorphism of MDR1 and the risk of childhood ALL was analyzed. There was significant difference in the distribution of genotype of MDR1 C3435T between the group of controls and cases. The mutant homozygous TT genotype was found to be associated with occurrence of ALL (P = 0.000; OR = 4.504). The data show evidence of pairwise linkage disequilibrium between the three common SNPs (C1236T-G2677T/A-C3435T). The haplotypes of TTT, TGC, CGC and CAC were predominant. The haplotype CGT distributed significantly differently between the groups of controls and cases (P = 0.034). The frequency of the haplotype TTT/TTT in the high risk group was higher than the other groups (P = 0.037). The present findings suggest that 3435C→T polymorphism in MDR1 gene may be a genetic susceptibility factor for ALL. The haplotype of MDR1 (C1236T-G2677T/A-C3435T) could be the clinical parameter at diagnosis.