Multidrug Resistance 1 Polymorphisms Research Articles

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 polymorphisms and multiple myeloma risk: a meta-analysis.

Previous researches exploring associations between multiple myeloma (MM) and genetic polymorphisms showed controversial results. In this investigation, we aimed to make a meta-analysis to assess the association between MM risk and genetic polymorphisms. We searched for articles on genetic polymorphism and MM risk in Web of Science and PubMed databases from 1951 to August 2019. We computed the odds ratio (OR) and 95% confidence intervals (CI) extracted from included articles. The meta-analysis showed no significant associations between MM risks and tumor necrosis factor (TNF)-α (rs1800629/rs361525/rs1799724), interleukin (IL)-6 (rs1800795), multidrug resistance 1 (MDR1) (rs1045642), Methylenetetrahydrofolate reductase (MTHFR) (rs1801131/rs1801133) polymorphisms. In summary, the study shows that the TNF-α (rs1800629/rs361525/rs1799724), IL-6 (rs1800795), MDR1 (rs1045642), and MTHFR (rs1801131/rs1801133) polymorphisms may not be associated with MM susceptibility. Thus, we do not need more expensive and useless studies to explore the associations between MM risks and these genetic polymorphisms.

Effects of MDR1 (C3435T) Polymorphism on Resistance, Uptake, and Efflux to Antiepileptic Drugs.

P-glycoprotein (P-gp), encoded by the MDR1 (multidrug resistance 1) gene, involves in the efflux of multiple compounds, such as certain antiepileptic drugs. The aim of this research was to observe the impacts of MDR1 (C3435T) variant on the efflux of phenytoin, carbamazepine, valproate, and phenobarbital in vitro. Stable recombinant LLC-PK1 cell systems transfected with MDR13435C (wild-type allele) and MDR13435T (variant allele) were constructed. The influences of MDR1 (C3435T) variant on the sensitivity, intracellular accumulation, and transepithelial permeability of antiepileptic drugs were assessed. The recombinant MDR13435T cells showed higher resistance to carbamazepine compared with MDR13435C cells in the cytotoxicity assay (p < 0.01). The intracellular accumulation of carbamazepine was significantly decreased in cells transfecting with MDR13435T allele when compared with recombinant MDR13435C cells (p < 0.01). These results also indicate that the efflux activity of P-gp-mediated carbamazepine in recombinant MDR13435T cells was greatly increased compared with MDR13435C cells (p < 0.01), whereas the transport ability of P-gp-dependent phenobarbital in recombinant MDR13435T cells was significantly lower than MDR13435C cells (p < 0.01). However, the effects of MDR1 (C3435T) polymorphism on the resistance, intracellular accumulation, and efflux of phenytoin and valproate were not found in this study. MDR13435T variant allele might be more efficient to transport carbamazepine, whereas reduces the efflux activity of P-gp-mediated phenobarbital. Collectively, MDR1 (C3435T) polymorphism might impact the P-gp activity and antiepileptic agents efflux with drug specificity.

Association between MDR1 gene polymorphism and clinical course of pediatric pulmonary arterial hypertension

Abstract Pulmonary arterial hypertension (PAH) is a progressive disease with a complex pathogenesis. The polymorphism of the gene of multidrug resistance-1 (MDR1) has been associated with many diseases including PAH. Objective. In this study we aimed to investigate the relevance of the MDR1 polymorphism to pediatric PAH clinical course. Methods. A total of 40 pediatric patients with PAH (secondary to congenital heart defects or idiopathic) and 40 control subjects were enrolled. Patients with PAH were divided into 2 groups, according to their evolution: 28 patients who remained clinically stable at 12-months (non-worsening group) and 12 patients who presented clinical worsening at 12-months (worsening group). Genomic DNA was genotyped for MDR1 gene polymorphisms as follows: C1236T, G2677T and C3435T. Results. There were no significant differences between PAH children groups (clinical worsening and non-worsening) nor between PAH children and controls in terms of frequency distribution of the three studied genotypes or alleles. Conclusions. The MDR1 polymorphism could not be correlated with the clinical evolution of pediatric PAH patients in our study.

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.

Multidrug resistance 1 (MDR1/ABCB1) gene polymorphism (rs1045642 C > T) and susceptibility to multiple myeloma: a systematic review and meta-analysis

ABSTRACTIntroduction: Several studies have evaluated the association between the multidrug resistance 1 (MDR1) polymorphism (rs1045642 C > T) and multiple myeloma (MM). However, the results were not consistent. Therefore, to reach a comprehensive and reliable answer we determined the association of the MDR1 (rs1045642 C > T) polymorphism and MM in the context of meta-analysis.Methods: All eligible studies published in EMBASE, PubMed, and Web of Science databases before July 2017 were reviewed. Subsequently, to assess the strength of association in the dominant model, recessive model, allelic model, homozygotes contrast, and heterozygotes contrast, pooled odds ratios and 95% confidence intervals (CIs) were calculated by the fixed effects model.Results: A total of four case–control studies with 395 MM cases and 418 healthy controls were included in the meta-analysis. The overall results showed no significant association between the MDR1 (rs1045642 C > T) polymorphism and the risk of MM in genetic models (dominant model: OR = 1.04, 95% CI = 0.78–1.38; recessive model: OR = 0.74, 95% CI = 0.52–1.06; allelic model: OR = 0.90, 95% CI = 0.73–1.11; TT vs. CC: OR = 0.80, 95% CI = 0.51–1.25; and CT vs. CC: OR = 1.12, 95% CI = 0.77–1.62). No evidence of publication bias was detected except for the analysis of the recessive model.Conclusion: This meta-analysis suggests that the MDR1 C > T polymorphism was not associated with the risk of MM. To confirm these findings, further comprehensive and well-designed studies are needed.

MDR1 polymorphisms affect the outcome of Chinese multiple myeloma patients

ObjectiveTo illustrate the association of MDR1 (Multidrug Resistance 1) polymorphisms at loci 1236, 2677, 3435 and the prognosis of multiple myeloma (MM) in Jiangsu population. MethodsA total of 129 MM patients were recruited from Jiangsu Province, China. The DNA was extracted from white blood cells (WBC) of peripheral blood and was amplified by polymerase chain reaction-allele specific primers (PCR-ASP). MDR1 polymorphisms at 3 loci were analyzed by electrophoresis followed by photograph or DNA direct sequencing. The association between the MDR1 and clinical outcomes were calculated by Graphpad and SPSS. ResultsMDR1 alleles at locus C1236T with T had significant lower calcium level in MM patients compared with C. The genotype CT had a significantly prolonged progress free survival (PFS) compared genotype CC at locus C1236T (median time: 48 months vs. 28 months, respectively; p=0.0062; HR=0.21; 95%CI0.061–0.715) while patients carrying T allele (CT and TT) at locus C3435T had a longer PFS than patients without T allele (CC) (median time: 60 months vs. 29 months, respectively; p=0.038; HR=0.508; 95%CI 0.264–0.978). And a borderline significance was found in haplotype at loci 2677-3435 and PFS. No significant findings were revealed between OS and MDR1 polymorphisms. ConclusionMDR1 polymorphisms could affect the prognosis of multiple myeloma whereas more samples and a longer follow-up are also needed.

The relationship between Multidrug Resistance Protein 1(rs1045642) and Cholesterol 24-hydroxylase (rs754203) genes polymorphism with type 2 diabetes mellitus

Background: The involvement of genetic factors like gene polymorphisms has been found to contribute significantly to the development and progression of type 2 diabetes (T2DM). Thousands of single nucleotide polymorphisms in various genes have been found to be associated with risk of T2DM. The present study was aimed to investigate association of Multidrug resistance 1 (MDR1) (rs1045642) and CYP46A1 (rs754203) genes polymorphism with T2DM.Subjects & Methods: Study includes 333 subjects, 183 T2DM cases and 150 healthy controls. Single nucleotide polymorphism was evaluated by PCR-PFLP. Alleles and genotype frequencies between cases and controls were compared using χ2 and Student’s t-tests. Odds ratios and 95% confidence intervals were calculated by logistic regression to assess the relative association between disease and genotypes.Results: In case of CYP46A1 gene, CC (p < 0.001) and CT (p = 0.001) genotypes and C allele (p < 0.001) were found to be a positive risk factor and TT genotype (p < 0.001) and T allele (p < 0.001) as negative risk factor for T2DM whereas, no association of MDR1 gene was found with T2DM (P values of all genotypes and alleles were greater than 0.001). MDR1 (rs1045642) and CYP46A1 (rs754203) genes polymorphism was not found associated with Fasting Blood Sugar (FBS), Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP).Conclusion: CYP46A1 gene polymorphism is associated with the risk of T2DM whereas, MDR1 gene polymorphism was not found to confer any risk of T2DM in North Indian Ethnic group.

MDR1 polymorphisms have an impact on the prognosis of Chinese diffuse large B cell lymphoma patients.

MDR1 (multidrug resistance 1) encodes an adenosine triphosphate (ATP)-dependent efflux transporter that plays a fundamental role in transportation of harmful compounds outside cells to maintain optimal health. The present study was aimed to investigate whether the MDR1 gene single nucleotide polymorphisms (SNPs) were associated with the prognosis of diffuse large B cell lymphoma (DLBCL). Three common SNPs, including C1236T, G2677T/A, and C3435T were focused on, and a total of 150 DLBCL patients from Jiangsu Han population were successively genotyped by polymerase chain reaction-allele-specific primers (PCR-ASP) method or DNA direct sequencing. At locus C1236T, patients carrying T allele (genotype CT and TT) had a prolonged overall survival (OS) when compared with patients with CC genotype (2-year OS 82.6 vs. 60.0%, respectively; hazard ratio (HR) = 0.1, 95% confidence interval (CI) 0.01-0.6, p = 0.016). At locus C3435T, complete remission/ complete remission unconfirmed (CR/CRu) rate in C allele group was significantly higher than T allele group (66.7 vs. 51.9%, respectively; p = 0.009). The progression-free survival (PFS) curves of with T (genotype CT and TT) and without T (genotype CC) were significantly different (2-year PFS 46.4% in with T group vs. 73.7% in without T group, respectively; HR = 1.9, 95% CI 1.0-3.6, p = 0.045). At locus G2677T/A, the age for genotypes AG and AT groups was significantly younger than the other genotypes (51.1 ± 12.6 vs. 57.7 ± 13.4years, respectively; p = 0.033). In the haplotype analysis of loci 1236-3435, compared with T-C group, the C-T group displayed an inferior PFS rate (2-year PFS 23.0 vs. 50.6%, respectively; HR = 7.8, 95% CI 1.9-32.6, p = 0.005), while C-C and T-T groups showed an intermediate PFS rate. Our findings demonstrate that genotype CT + TT at locus C1236T, allele C, and genotype CC at locus C3435T might contribute to a relatively superior prognosis in DLBCL, as well as haplotype of T-C in loci 1236-3435. Besides, genotypes at locus G2677T/A might affect age at diagnosis, which has important prognostic value for DLBCL.

Contribution of MDR1 gene polymorphisms on IBD predisposition and response to glucocorticoids in IBD in a Chinese population.

The cornerstone of conventional treatment for inflammatory bowel disease (IBD) is glucocorticoid (GC). Single nucleotide polymorphisms (SNPs) of genes such as multidrug resistance 1 (MDR1) are related to patient's response to GC, and MDR1 polymorphisms are associated with susceptibility to IBD in Caucasians. We aimed to investigate whether the polymorphisms of five genes including MDR1 influence the response to GC in Chinese patients and the relationship between MDR1 and IBD susceptibility. SNPs were selected and genotyped in 156 IBD patients treated with GC and 223 healthy controls. Patients were evaluated and classified as GC-dependent, GC-resistant or responsive to GC after treatment. The CC genotypes of rs1128503 and rs1045642 in MDR1 gene were more frequent in Crohn's disease (CD) patients who were GC-dependent than in those responsive to GC (odds ratio [OR] 6.583, 95% confidence interval [CI] 1.760-24.628, P = 0.019 and OR 3.873, 95% CI 1.578-9.506, P = 0.009, respectively). The G allele of MDR1 rs2032582 was less frequent among CD patients than in controls (OR 0.668, 95% CI 0.484-0.921, P = 0.014). G allele carriers were also less likely to develop non-stricturing and non-penetrating CD (OR 0.661, 95% CI 0.462-0.946, P = 0.023) and ileocolonic CD (OR 0.669, 95% CI 0.472-0.948, P = 0.024). Polymorphisms of MDR1 are associated with patient's GC response and a predisposition to CD in Chinese population. Further studies are needed to elucidate the role of MDR1 polymorphisms in IBD and that as genetic markers for GC response.

Association study between the MDR1 gene and clinical characteristics in schizophrenia.

Schizophrenia is a complex psychiatric disorder, characterized by disturbed patterns of thought and affecting 0.3-2.0% of the world population. Previously, the multidrug resistance 1 (MDR1) gene has been associated with schizophrenia in treatment response studies in psychotic patients. The aim of this study was to determine the association between MDR1 gene polymorphisms and clinical characteristics in patients with schizophrenia. Positive and negative symptoms of schizophrenia were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS) in 158 Mexican patients with schizophrenia. Analyses of MDR1 gene polymorphisms were performed using TaqMan technology. A multivariate ANOVA was performed with MDR1 polymorphisms and gender as independent variables. Males with the G/G genotype of MDR1 rs2032582 presented significantly higher levels of delusions (p = 0.02). When comparing female vs. male groups, the difference was statistically significant (p = 0.0003). Analyses of the MDR1 gene rs1045642 variant showed no significant differences. Our findings suggest that male carriers of the G allele of variant rs2032582 exhibit greater severity of delusions; however, these results should be taken as preliminary, and replication studies in other populations of different ethnic origins are required to confirm these findings.

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications including the lipid lowering drug, atorvastatin. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the lipid lowering effect of atorvastatin among Jordanians. Lipid and lipoproteins were measured in blood samples collected from patients (n=201) at baseline and during atorvastatin treatment. MDR1 polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. Both the TT genotype of G2677T and the TT genotype of the C3435T polymorphisms were associated with lower levels of low-density lipoproteins after atorvastatin treatment. However, the effects of atorvastatin on the levels of total cholesterol, triglycerides, and high-density lipoprotein, were not correlated with any of the genotypes in both polymorphisms. Finally, the C1236T polymorphism was not associated with the lipid lowering effect of atorvastatin. In conclusion, the MDR1 gene polymorphisms G2677T, and C3435T, but not C1236T were associated with the lipid lowering effect of atorvastatin among Jordanians.

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 role of multidrug resistance-1 (MDR1) variants in response to fexofenadine among Jordanians

The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications, including the antiallergic drug fexofenadine. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the anti-allergic effect of fexofenadine among Jordanians. An assessment of the severity of allergic rhinitis symptoms was performed for all patients (n = 260) pre- and 7 days into fexofenadine. MDR1 polymorphisms were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Relative to baseline, fexofenadine treatment was associated with significant reduction in allergic individual and total scores (p < 0.0001). Male gender was associated with less mean reduction in total allergic rhinitis symptoms score than in female (p < 0.05). In multivariate analysis, male gender was negatively correlated with response to fexofenadine (p = 0.01). The MDR1 gene C1236T polymorphism showed significant correlation with changes in total symptoms score from baseline in males (p < 0.05) but not in females. No significant correlation between fexofenadine response parameters and G2677T or the C3435T polymorphism was observed. The MDR1 gene polymorphism C1236T was associated with the anti-allergic effect of fexofenadine among male Jordanians.

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.

Multidrug resistance 1 (MDR1) 3435C/T genotyping in childhood drug-resistant epilepsy

IntroductionA mutation at nucleotide position 3435 in exon 26 of the multidrug resistance 1 (MDR1) gene is the most frequently studied polymorphism in relation to multidrug resistance. However, there are conflicting data as to whether the CC or TT genotype of the 3435C>T polymorphism is associated with drug resistance. Methods and results: We investigated the association between this polymorphism in drug-resistant childhood epilepsy by comparison with drug-responsive patients. In total, 59 patients with drug-resistant epilepsy, defined as having four or more seizures within a 12-month period while using three or more AEDs, 60 children with drug-responsive epilepsy who had remained seizure-free for 12months on their current AED regimen and 76 healthy children were involved in this study. Genotype frequencies in drug-resistant patients were as follows: 32.2% CC, 44.1% CT, 23.7% TT; in the drug-responsive group: 20.0% CC, 50.0% CT, 30.0% TT; in the control group: 24.3% CC, 50.0% CT, 25.7% TT. Comparison of drug-resistant and drug-responsive patients revealed no significant difference in genotype frequency. The findings of the epilepsy patients were not significantly different from those of the healthy control subjects. Conclusions: Our study does not support any significant association between the MDR1 polymorphism and drug-resistant childhood epilepsy.

945 – Association study between the c3435t polymorphism of the multidrug resistance 1 (mdr1) and interpersonal sensitivity

P-glycoprotein, which is encoded by the multidrug resistance 1 (MDR1) gene, serves as a barrier to entry and as an active elimination for xenobiotics and cellular metabolites including cortisol, which is implicated in multiple brain functions. Meanwhile, previous studies suggested that genetic factors and cortisol are involved in formation of interpersonal sensitivity, a personality trait predisposing to depression. In the present study, we examined the effects of the C3435T MDR1 polymorphism on interpersonal sensitivity. The subjects were 842 healthy Japanese volunteers. The mean age ±SD of the subjects was 26.7±8.1 (490 males and 352 females). The C3435T polymorphism of MDR1 gene was detected by a PCR method, and interpersonal sensitivity was assessed by the Interpersonal Sensitivity Measure (IPSM). In total subjects, the C allele of the C3435T MDR1 polymorphism was associated with higher scores of the IPSM. In females the C/C genotype group had higher IPSM scores than the C/T genotype group and the T/T genotype group, and the C/T genotype group had higher IPSM scores than the T/T genotype group. In males no significant association was found between the MDR1 genotype and the IPSM scores. The present study suggests that the C3435T polymorphism of the MDR1 gene affects formation of a depression-prone personality trait in Japanese females.

CYP3A5*3 and C3435T MDR1 Polymorphisms in Prognostication of Drug-Resistant Epilepsy in Children and Adolescents

Drug-resistant epilepsies still remain one of the most profound problems of contemporary epileptology. Several mechanisms of drug resistance are possible; among them, genetic factors have a prominent place. Much importance is attached to genes, which encode enzymes that metabolize antiepileptic drugs CYP 3A, which belong to the family of cytochromes P450 and the genome of multidrug resistance, such as multidrug resistance 1 (MDR1) that expresses P-glycoprotein (P-gp), a drug transporter protein. The aim of the study was to assess the relation between polymorphism of gene CYP3A5 and polymorphism C3435T of MDR1 gene with the occurrence of focal, drug-resistant epilepsy in children and youths up to 18 years of age. The study comprised 85 patients, and their age range was from 33 months to 18 years of age, suffering from epilepsy, partly responding well to treatment, partly drug resistant. The polymorphism of both genes has been analysed using the PCR-RFLP method. The study failed to corroborate association between polymorphism CYP3A5∗3 and C3435T polymorphism in MDR1 gene and pharmacoresistant epilepsy. The results of our research do not confirm the prognostic value of the polymorphisms examined in the prognostication of drug resistance in epilepsies.

P-0022 Association Between C3435T Single Nucleotide Polymorphism of Multi-Drug Resistance 1 Gene and Risk of Gastric Cancer

ABSTRACT Introduction Gastric cancer (GC) is the fourth most common cancer in the world and the second leading cause of death due to cancer. The Multi-Drug Resistance 1 (MDR1) gene encodes P-glycoprotein, which confers resistance to antineoplastic drugs, but also affects the kinetic disposition of some drugs and carcinogens. The C3435T polymorphism of the MDR1 gene may influence the transport and excretion of carcinogens, increasing the risk of cancer. The aim of this study was to evaluate the association between this polymorphism and the risk of gastric cancer and tumor aggressiveness. Methods A case-control study was conducted. The case group consisted of patients with non-cardia adenocarcinoma. The control group consisted of healthy subjects. Serology was performed by ELISA for the investigation of infection with Helicobacter pylori. DNA was extracted from peripheral venous blood leukocytes collected with EDTA. The MDR1 polymorphism was analyzed by PCR-RFLP. After amplification, the products were digested with 5 units of the restriction enzyme MboI (New England Biolabs). Genome sequencing was used to confirm the PCR and RFLP techniques using random samples of the two groups. The PCR product of the MDR1 gene was purified using the Big Dye XTerminator Kit and sequenced in an ABI Prism 3100 sequencer. The reverse primer was used for sequencing. The electropherogram was analyzed with the Sequence Scanner v1.0 program. Results Ninety eight patients with non-cardia GC and 203 healthy subjects participated in the study. There was no difference in gender (p=0.12) or age (p=0.125) between the two groups. The genotypes in the control group were in Hardy-Weinberg equilibrium and the frequency of TT, CC and CT genotypes was 19.2%, 33.0% and 47.8%, respectively. In the GC, the frequency of TT, CC and CT genotypes was 15.3%, 32.7% and 52.0%, respectively. No significant difference in the genotypes (p=0.668) or alleles (p=0.745) was observed between the groups. There was no association between the genotypes and the risk of GC in patients infected with H. pylori (p=0.662). Patient survival was not correlated with the genotypes studied (p=0.454). Conclusion The present results provide evidence that the C3435T polymorphism of the MDR1 gene is not associated with GC risk or prognosis in the population studied. No correlation was observed between this polymorphism and infection with H. pylori.

Association between the C3435T single-nucleotide polymorphism of multidrug resistance 1 gene and risk of gastric cancer

The multidrug resistance 1 (MDR1) gene encodes P-glycoprotein, which confers resistance to antineoplastic drugs, but also affects the kinetic disposition of certain drugs and carcinogens. The C3435T polymorphism of the MDR1 gene may influence the transport and excretion of carcinogens, increasing the risk of cancer. The aim of this study was to evaluate the association between this polymorphism and the risk of gastric cancer (GC). Ninety-eight patients with non-cardia GC and 203 healthy subjects participated in the study. DNA was extracted from leukocytes and the MDR1 polymorphism was analyzed using PCR-RFLP. Serology was performed by ELISA for the investigation of infection with Helicobacter pylori. No significant difference in the genotype (p=0.668) or allele (p=0.745) frequency of the C3435T polymorphism was observed between the GC and control groups. There was no association between the genotypes studied and the risk of GC in patients infected with H. pylori (p=0.662). Patient survival was not correlated with the genotypes studied (p=0.454). No correlation was observed between the C3435T polymorphism of the MDR1 gene and GC risk or prognosis in the population studied.