Polymorphisms Of Multidrug Resistance 1 Gene Research Articles

Multi-drug resistance 1 polymorphism is associated with reduced risk of gastric cancer in the Japanese population

Host genetic factors play a key role in gastric carcinogenesis, but the mechanism has not been clarified. The multi-drug resistance 1 (MDR1) gene mediates the expression of P-glycoprotein, which has a role in active transport of various substrates, including xenobiotics, and thus has a protective function in various tissues and organs like gastrointestinal epithelial cells. C3435T polymorphism in exon 26 of the MDR1 gene influences P-glycoprotein expression and activity in the gastrointestinal tract. We investigated the influences of MDR1 gene polymorphism on the risk of gastric cancer. The study was performed on 157 patients with gastric cancer (GC) and 104 patients without GC as the control group. C3435T polymorphism of MDR1 was investigated by PCR-RFLP in all of the patients. The MDR1 3435 TT genotype showed a significantly higher frequency in controls than in GC patients (OR = 0.43; 95% CI = 0.23-0.79). There were no significant differences of the CT and CC genotype frequencies between GC patients and controls. We also found that the 3435TT genotype of MDR1 was associated with a lower risk of non-cardiac cancer (OR = 0.42; 95% CI = 0.23-0.79), middle-third cancer (OR = 0.36; 95% CI = 0.17-0.77), advanced cancer (OR = 0.31; 95% CI = 0.13-0.73), venous invasion (OR = 0.30; 95% CI = 0.10-0.91), and lymph node metastasis (OR = 0.28; 95% CI = 0.13-0.65). Our data suggest that 3435T/T polymorphism of MDR1 is associated with a reduced risk of gastric cancer in the Japanese population.

Regulatory polymorphisms of multidrug resistance 1 ( MDR1) gene are associated with the development of childhood acute lymphoblastic leukemia

The aim of this study is to determine whether the polymorphisms of the MDR1 gene are associated with the development of childhood acute lymphoblastic leukemia (ALL). The MDR1 gene polymorphisms, −2352 G > A, −934A > G, −692T > C (5′ regulatory region) and 3435C > T (exon 26), were examined in 157 ALL patients and 96 healthy children. The amounts of MDR1 mRNA were quantified in 54 healthy individuals using normal peripheral blood mononuclear cells to evaluate the effect of each polymorphism on the gene expression. The frequency of the G/G genotype of the −2352 G > A was significantly higher in ALL than in controls (74/109 versus 52/96, p = 0.04). The frequency of the T/T genotype of the 3435C > T was also significantly higher in ALL (29/118 versus 10/96, p = 0.006). In a haplotype analysis using the 5′ regulatory sites, the frequency of a certain haplotype was higher in ALL than in controls (59/90 versus 42/88, p = 0.048). When the −2352G > A was examined in different age groups, patients aged six or older were found to have the G/G genotype more frequently than the controls (42/51 versus 52/96, p = 0.0014), while no difference was observed in the younger age group. The amounts of MDR1 mRNA were significantly higher in either G/G or G/A genotype of the −2352 G > A than in A/A genotype ( p = 0.04). The present study suggests that the genetic background of MDR1 may be associated with the development of childhood ALL, possibly due to a quantitative change in the MDR1 gene resulting from genetic polymorphisms.

MDR1 gene polymorphisms and risk of recurrence in patients With hepatocellular carcinoma after liver transplantation

Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) remains a major cause of post-LT death. However, currently there is still lacking the markers to reliably predict recurrence. This study was undertaken to evaluate the association between three polymorphisms (C1236T, G2677A/T, C3435T) of Multidrug resistance 1 (MDR1) gene and the risk of recurrence after LT. Genomic DNA of 99 HCC patients undergoing LT was extracted from peripheral blood lymphocytes and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assay. Cox proportional hazard model was used to estimate the hazard ratios associated with polymorphisms. During a mean follow-up of 14.9 months, 49 patients experienced recurrence. The association between recurrence-free and 2677A carrier (carrying at least one variant A allele) was significant (P = 0.019). However, no significant association was observed in other polymorphisms. Patients with 2677A carrier conferred a 63% reduction in recurrence risk compared with 2677A non-carrier (odds ratio: 0.374; 95% confidence interval: 0.177-0.788; P = 0.010). The median recurrence-free survival for 2677A carrier group was significantly longer than that for 2677A non-carrier group (44.2 vs. 10.5 months, P = 0.015). The polymorphism of MDR1 gene may be a valuable molecular marker for HCC recurrence after LT.

Multidrug resistance 1 genotype and disposition of budesonide in early primary biliary cirrhosis

Budesonide, which is a dual substrate of P-glycoprotein, the product of the multidrug resistance 1 (MDR1) gene, and cytochrome P450 3A (CYP3A) has been proposed for treatment of early primary biliary cirrhosis (PBC). Recently, MDR1 gene polymorphisms have been discussed as a potential cause of glucocorticoid resistance. We tested the hypothesis that MDR1 gene polymorphisms affect absorption of oral budesonide. In 21 patients with histologically proven early-stage (I/II) PBC and nine healthy subjects, we evaluated the impact of MDR1 single nucleotide polymorphisms (2,677G>T,A and 3,435C>T) on disposition of a single oral dose of 3 mg budesonide. CYP3A5 gene polymorphisms (6,986A>G) were analyzed in parallel. In MDR1 2,677 GG and 3,435 CC genotypes, absorption and elimination of budesonide were not significantly different from those in corresponding homozygous variants. Peak plasma levels and areas under the plasma concentration time curves (AUC) of budesonide were not lower in MDR1 3,435 CC with putatively high intestinal expression of P-glycoprotein than in MDR1 3,435 TT. Interestingly, in two CYP3A5*1/*3 carriers with high enzyme activity, lower AUC was noted than in 28 CYP3A5*3/*3 carriers with a deficient enzyme. Common MDR1 gene polymorphisms do not affect disposition of budesonide in early PBC.

Association between multidrug resistance 1 ( MDR1) gene polymorphisms and therapeutic response to bromperidol in schizophrenic patients: A preliminary study

The drug-transporting P-glycoprotein transports drugs against a concentration gradient across the blood–brain barrier back into the plasma and thereby reduces the bioavailability in the brain. Polymorphisms in the MDR1 gene regulating P-glycoprotein expression can be associated with differences in drug disposition in the brain. The present study was therefore designed to examine whether the major polymorphisms of MDR1 gene, C3435T and G2677T/A are related to therapeutic response to neuroleptics in the treatment of schizophrenia. Subjects consisted of 31 acutely exacerbated schizophrenic inpatients treated with bromperidol (6–18 mg/day). Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The C3435T and G2677T/A genotypes were determined by a polymerase chain reaction method. Schizophrenic symptoms were allocated into 5 clusters: positive, excitement, cognitive, negative, and anxiety–depression symptoms. Patients were C/C in 12, C/T in 12 and T/T in 7 cases for C3435T genotype and G/G in 3, G/T or A in 17 and T or A/T or A in 11 cases for G2677T/A genotype. There were a tendency of difference, but not statistically different, in the percentage improvement or the improved scores of 5 sub-grouped symptoms after the 3-week treatment between C3435T genotypes and between G2677T/A genotypes. Multiple regression analyses including age, body weight, gender and drug concentration showed significant correlations between the percentage improvement and the improved scores of cognitive symptoms and C3435T genotypes. The present results suggest that the C3435T polymorphism is associated with some therapeutic response to bromperidol in schizophrenic patients, possibly by different drug concentration in the brain.

MDR1 gene polymorphisms and risk of gingival hyperplasia induced by calcium antagonists

Gingival overgrowth is a common side effect of calcium antagonists. Although the pathogenesis is unknown, several lines of evidence point to a modulation of inflammatory processes. Because the calcium antagonists, albeit to a variable degree, act as inhibitors of P-glycoprotein (P-gp), the gene product of multidrug resistance 1 (MDR1), and inflammation may modify P-gp expression, we analyzed the MDR1 polymorphisms as risk factors for gingival overgrowth induced by calcium antagonists. Clinical, laboratory, and anamnestic data including periodontal parameters and use of calcium antagonists were assessed in a cross-sectional epidemiologic investigation (N = 1484). MDR1 polymorphisms in exon 21 G2677T/A and exon 26 C3435T were determined. P-gp expression was detected in gingival tissues. In a matched-pair analysis, 93 subjects using calcium antagonists and 186 not using them were compared. P-gp is expressed in the endothelial layers of blood vessels obtained from healthy or inflamed gingiva. Subjects treated with calcium antagonists had significantly deeper gingival pockets than their drug-free counterparts (P <.0001). This drug-related side effect was associated with the MDR1 2677G/G or G/TA genotype (P <.001) but not with the variant genotype T/TA. This drug effect was proved by multiple regression analysis with adjustment for the risk factors of periodontitis (age, sex, smoking, and education) (P <.0001) and was associated with elevated C-reactive protein levels. The association of probing depth with the MDR1 polymorphism was confirmed in the matched-pair analysis (P <.0001). Treatment with calcium antagonists leads to gingival hyperplasia, which is associated with the MDR1 G2677T/A polymorphism. The MDR1 genotype may modify the inflammatory response to the drugs.

Multidrug Resistance-1 Gene Polymorphism Associated with the Outcomes after Allogeneic HLA-Identical Stem Cell Transplantation.

Background: The pharmacokinetic impact of multidrug resistance-1 (MDR1) gene single nucleotide polymorphisms (SNPs) has been already investigated in solid organ transplantation field, however, data is still lacking in an allogeneic stem cell transplantation (SCT) setting.Methods: A total of 82 patients receiving an allogeneic HLA-identical sibling (n=70) or unrelated SCT (n=12) with graft-versus-host disease (GVHD) prophylaxis of cyclosporine-A (CSA) plus methotrexate (MTX) were included in the current study. Two SNPs of MDR1 gene (C3435T and G2677T/A) were analyzed using PCR/RFLP assay.Results: As regards G2677T/A SNP, GG genotype showed a higher incidence of NRM compared to non-GG genotype (67% vs. 32%, p=0.0073), yet not C3435T (p=0.2026) or MDR1 haplotype (p=0.2238). Accordingly, overall survival (OS) was significantly correlated with G2677T/A genotype (p=0.0048), yet not with C3435T (p=0.5041) or MDR1 haplotype (p=0.4086). However, no difference in the relapse incidence was noted according to G2677T/A, C3435T genotype or MDR1 haplotype. In a multivariate analysis, those patients without GG genotype at G2677T/A were found to have favorable prognosis in terms of OS (p=0.003) or NRM (p=0.031) along with occurrence of chronic GVHD (p<0.001 for OS, p=0.001 for NRM), standard disease risk (p=0.045 for OS) or acute grade 0,1 GVHD (p=0.019 for NRM). However, no correlation was found between the blood concentrations of CSA and MDR1 genotype and CSA neurotoxicity and MDR1 genotype.Conclusion: The G2677T/A genotype seemed to be associated with the transplantation outcomes, especially NRM. Further study is warranted to clarify its mechanism of MDR1 SNPs other than pharmacokinetic aspects. [Display omitted]

Multidrug resistance-1 gene polymorphism associated with the treatment outcomes in de novo acute myeloid leukemia

6550 Background: Multidrug resistance (MDR) is one of the important mechanisms of treatment failure of acute myeloid leukemia (AML). Recently, MDR-1 gene single nucleotide polymorphism (SNP) has be...

Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis

Background & Aims: The human multidrug resistance 1 (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics. The finding that mdr1a knockout mice develop a form of colitis that is similar to ulcerative colitis, which can be prevented by antibiotics, indicates a barrier function for P-glycoprotein against the invasion of bacteria or toxins. Because the MDR1 single nucleotide polymorphism C3435T is associated with lower intestinal P-glycoprotein expression, we tested whether this polymorphism predisposes to development of ulcerative colitis. Methods: Allele frequencies and genotype distributions of the C3435T single nucleotide polymorphism were investigated in 149 patients with ulcerative colitis, 126 patients with Crohn's disease, and sex-matched healthy controls. Results: Significantly increased frequencies of the 3435T allele and the 3435TT genotype were observed in patients with ulcerative colitis compared with controls (3435T: P = 0.049; odds ratio, 1.4; 95% confidence interval, 1.02–1.94; 3435TT: P = 0.045; odds ratio, 2.03; 95% confidence interval, 1.04–3.95). In contrast, frequencies of the T allele and the TT genotype were the same in patients with Crohn's disease as in controls (P = 0.66 and P = 0.59, respectively). In comparison to 998 non–sex-matched controls, the effect for the TT genotype in ulcerative colitis patients was more pronounced (P = 0.0055; odds ratio, 2.1). Conclusions: The higher frequency of the 3435TT genotype in patients with ulcerative colitis corroborates the findings from the mdr1a knockout mice. The results support the notion that P-glycoprotein plays a major role in the defense against intestinal bacteria or toxins. Impairment of barrier function in 3435TT subjects could render this genotype more susceptible to the development of ulcerative colitis.GASTROENTEROLOGY 2003;124:26-33