C3435T Polymorphism Of MDR1 Gene Research Articles

DGI-068 The Effect of Main Gene Polymorphisms on Stable Doses of Acenocoumarol in Long-Term Anticoagulation Treatment

BackgroundSeveral variants in CYP2C9 (CYP2C9*2 and especially the CYP2C9*3 allele) and VKORC1 genes (especially the 1639G>A polymorphism) are associated with effective coumarin derivative dose. The rs2108622 polymorphism in the gene...

MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 34 case–control studies

P-glycoprotein, the product of the MDR1 gene, is a transmembrane active efflux pump for a variety of environmental toxins and xenobiotics. Epidemiological studies have evaluated the association between MDR1 C3435T polymorphism and cancer susceptibility. However, published data are still inconclusive. To derive a more precise assessment of this relevance, we performed a meta-analysis, up to September 2010, of 5,196 cases with different cancer types and 6,827 controls from 34 published case-control studies. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for MDR1 C3435T polymorphism and cancer were estimated using fixed- and random-effects models when appropriate. The overall results suggested that the variant was associated with a moderately increased cancer risk in all comparison models tested (OR = 1.26, 95% CI: 1.06-1.50 for TT vs. CC; OR = 1.19, 95% CI: 1.04-1.37 for CT vs. CC; OR = 1.15, 95% CI: 1.01-1.32 for recessive model; OR = 1.21, 95% CI: 1.06-1.38 for domain model, and OR = 1.14, 95% CI: 1.04-1.26 for allele contrast). In the subgroup analysis by cancer types, significant associations were found in breast cancer (OR = 1.66, 95% CI: 1.24-2.21 for TT vs. CC; OR = 1.44, 95% CI: 1.14-1.82 for recessive model; OR = 1.41, 95% CI: 1.10-1.81 for domain model; and OR = 1.31, 95% CI: 1.13-1.52 for allele contrast) and renal cancer (OR = 1.99, 95% CI: 1.37-2.90 for TT vs. CC; OR = 1.74, 95% CI: 1.25-2.42 for domain model; OR = 1.43, 95% CI: 1.09-1.88 for recessive model; and OR = 1.40, 95% CI: 1.17-1.68 for allele contrast). However, no significant associations were found in colorectal cancer, gastric cancer, and acute lymphoblastic leukemia for all genetic models. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the dominant model, homozygote comparison, CT versus CC comparison, and allele comparison. In summary, this meta-analysis suggests that the MDR1 C3435T polymorphism is associated with cancer susceptibility, increasing the risk of breast and renal cancer.

Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

To assess the role of MDR1 and gamma-aminobutyric acid receptor-gamma 2 sub unit (GABRG2) gene polymorphism in seizure susceptibility in generalized seizure (GS) and febrile seizure (FS) patients and to evaluate MDR1 C3435T gene polymorphism's role in absorption of the anti-epileptic drug, phenytoin (PHT) in a cohort of patients. One hundred twenty-seven cases of seizure (86 GS and 41 FS) patients were analyzed for MDR1 C3435T and GABRG2 C588T gene polymorphisms using restriction fragment length polymorphism-polymerase chain reaction. Serum PHT levels were analyzed. The T allele of MDR1 C3435T and GABRG2 C588T gene polymorphism was higher in GS in the Indian population compared with controls. From the data in GS, CT and TT genotype carriers of the MDR1 gene and TT genotype carriers of the GABRG2 gene had more recurrent seizures compared with others. MDR1 T allele carriers in the seizure reoccurrence (SR) group of GS and FS were high compared with the well-controlled seizure group (with no seizures after treatment). TT genotype carriers in SR group were high in FS (with regard to MDR1 gene polymorphism) and GS (with regard to GABRG2 gene polymorphism) compared with a well-controlled seizure group. MDR1 C3435T gene polymorphism affects serum PHT levels (p<0.015). Association of dose PHT ratio and genotype groups of MDR1 C3435T gene polymorphism showed a significant association (p<0.05). MDR1*CC genotype was more common in cases with low serum PHT levels.In addition, it is evident that CT and TT genotype carriers have a high percentage of SR with elevated serum PHT levels. Our results show that the MDR1 3435T and GABRG2 588T alleles play a role in seizure occurrence. Moreover, the MDR1 3435T allele also affects PHT absorption. We suggest MDR1 C3435T and GABRG2 C588T genotyping would be of value in order to lower the risk of concentration-dependent drug toxicity and for better patient management.

Multi-drug resistance 1 genetic polymorphism and prediction of chemotherapy response in Hodgkin's Lymphoma

BackgroundThe human multi-drug resistance gene (MDR1), which encodes the major trans-membrane transporter P-glycoprotein (P-gp), was found to be associated with susceptibility to cancer and response to chemotherapy. The C3435T Polymorphism of MDR1 gene was correlated with expression levels and functions of P-gp. Here, we studied the association between MDR1 C3435T polymorphism and susceptibility to Hodgkin lymphoma (HL) and patient's response to ABVD chemotherapy regimen.Methodsa total of 130 paraffin embedded tissue samples collected from HL patients were analyzed to identify the C3435T polymorphism. As a control group, 120 healthy subjects were enrolled in the study. The C3435T Polymorphism was genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism.Resultsthese studies revealed that the frequency of T allele was significantly higher in HL patients compared to the controls (P < 0.05). In addition, the frequency of CT and TT genotypes were also significantly higher in HL patients compared to the controls (P < 0.05). No association between C3435T polymorphism and response to ABVD was detected among HL patients (P > 0.05).Conclusionsthese results suggest that MDR1 C3435T polymorphism might play a role in HL occurrence; however this polymorphism is not correlated with the clinical response to ABVD.

Polymorphisms of glutathione S-transferase μ and θ, MDR1 and VEGF genes as risk factors of bladder cancer: A case-control study

ObjectiveThe present study was aimed at examining the local distribution of GSTM1, GSTT1, MDR1, and VEGF gene polymorphisms as possible risk factors contributing to the development of bladder cancer among the population from Canary Islands, Spain. Materials and methodsThe genotypes were determined by PCR-based methods in a hospital-based case-control study consisting of 119 cases and 110 controls. The socio-demographic and clinicopathologic data were collected, including the smoking habits of the population covered in the study. ResultsThe observed allelic frequencies were (%): GSTM1-GSTT1, (positive) 54 and (null) 46 in cases, and 65 and 35, respectively, in controls (P = 0.144); MDR1 C3435T, (C) 57 and (T) 43 in cases, and 54 and 46, respectively, in controls (P = 0.633); VEGF A2578C, (A) 40 and (C) 60 in cases, and 51 and 49, respectively, in controls (P = 0.221). Among Canary Islands subjects, GSTT1-null genotype appeared as a significant risk factor for bladder cancer (odds ratio (OR) 2.0; 95% confidence interval (CI), 1.0–3.7; P = 0.041), in multivariate analysis adjusted by age and smoking habits. No statistical changes in genotype distribution of GSTM1, MDR1 C3435T, and VEGF A2578C gene polymorphisms were observed between cases and controls. The distribution of the initial clinical stage, clinical grade, or recurrence status was not significantly different among the polymorphic variants in the case group (P = NS). ConclusionsSubjects with the GSTT1-null genotype might be at an increased risk of bladder cancer in Canary Islands, Spain. However, extensive studies are required for accurate confirmation of these results.

Renal artery stenosis—when to suspect and how to diagnose

Some patients show warfarin resistance needing more than 70 mg of warfarin per week. In this study, we examined if C3435T polymorphism of MDR1 gene could be a factor of warfarin resistance.We examined 196 blood specimens from the patients who took warfarin more than 42 mg/week for at least 1 year. The subjects consisted of 74 European Americans, 59 African Americans, 42 Hispanic Americans and 21 Asian Americans. Genotype of C3435T polymorphism was determined by using real-time polymerase chain reaction (PCR).Ninety (45.9%) of the 196 patients had C3435T genotype and the remaining patients had C3435C genotype (35.7%) and T3435T genotype (18.4%). Mean dose of warfarin of patients with C3435C, C3435T and T3435T genotypes were 59.5 mg/week, 56.9 mg/week and 55.6 mg/week, respectively. There was no statistical difference in the dose of warfarin between the 3 genotypes within each race.Our results suggest that C3435T polymorphism of MDR1 gene is not associated with warfarin resistance.

Evaluation of C3435T &lt;i&gt;MDR1&lt;/i&gt; Gene Polymorphism in Adult Patient with Acute Lymphoblastic Leukemia

Background: P-glycoprotein (P-gp) is a transmembrane pump encoded by MDR1 gene. It contributes in protection of the cells against xenobiotic and toxic compounds. P-gp also contributes in multidrug resistance in acute lymphoblastic leukemia (ALL). Human MDR1 polymorphism include C to T exchange at position 3435, individuals with TT polymorphism have lower expression of P-gp than the others with CC genotypes. Accumulation of xenobiotics in the cells can cause some diseases like cancers.Materials and Methods: To evaluate MDR1C3435T gene polymorphism in adult patients with ALL, 54 patients and 96 healthy controls were involved in our survey. Genotyping of ALL patients and healthy controls was performed by Polymerase Chain Reaction – Restriction Fragment- Length Polymorphism (PCR-RFLP). Data analysis was done by SPSS software through T-test and Chi- Square. Results: No significant difference was found between C3435T MDR1 gene polymorphisms and incidence of ALL in adult patients. Also there was not any significant difference between T and C alleles and incidence of ALL. Conclusion: C3435T MDR1 polymorphism is not associated with the incidence of ALL in the population studied. Keyword: P-gp; C3435T; MDR1; ALL; polymorphism DOI: 10.3329/jom.v12i1.5541J Medicine 2011; 12 : 3-6

MDR1 C3435 Gene Polymorphism in Adult and Childhood Acute Lymphoblastic Leukemia of an Ethnic Iranian Population

Abstract Multidrug resistance protein 1 (MDR1, Pgp, ABCB1) is a membrane efflux transporter protein encoded by the MDR1 gene. The overexpression of this gene has been linked with the resistance to a variety of cancer chemotherapeutic agents in cancer patients. It also has an important role in tissue and cell defense against xenobiotics and toxic-compounds insult. A gene polymorphism in exon 26 of MDR1 (C3435T) has been reported to be associated with a decreased expression of MDR1 in TT genotype carriers compared with those of the CC genotype. In the present study, the MDR1 C3435T polymorphism of an ethnic Iranian population with acute lymphoblastic leukemia (ALL) was studied, and the incidence of the genotypes was compared among patients in different age groups: ≥ 20 years of age (A) and 1-19 years of age (B). The percent distribution of genotypes were found to be TT (A: 21.4; B: 26.0), TC (A: 57.1; B: 60.0), and CC (A: 21.4; B: 14.0). The B group ALL patients (1-19 years) were further divided into 2 groups of 1-9 (Y) and 9-19 (Z) years of age, and their MDR1 C3435T genotypes were analyzed. The distribution of the genotypes were found to be as follows: TT (Y: 27.9; Z: 23.1), TC (Y: 60.7.1; Z: 59.0), and CC (Y: 11.5; Z: 17.9). No significant differences were found among different genotypes in the studied age groups. It was concluded that in the studied population no specific genotype (either TT, TC, or CC) in MDR1 C3435T gene polymorphism was associated with the incidence of ALL. Further studies will shed light on the possible importance of these findings.

Association of the colorectal cancer and MDR1 gene polymorphism in an Iranian population

The human multidrug resistance (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics, bacterial toxins, drugs and other biologically active compounds, possibly carcinogens. In this study, an association of MDR1 gene polymorphism and the occurrence of colorectal cancer were evaluated. In this case-control-designed 118 unrelated colorectal cancer and 137 sex-and-ages matched healthy controls were enrolled. The C3435T MDR1 gene polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism method. Significantly increased frequencies of the 3435T allele and the 3435TT were observed in patients with colorectal cancer compared with controls (P = 0.03; OR, 95% CI; 1.46 for 3435T allele and P = 0.003; OR, 95% CI; 2.2 for 3435TT genotype). In contrast, frequency of genotype TT was significantly higher in controls compared to colorectal cancer (P = 0.006; OR, 95% CI; 0.49 for TC genotype). In this study suggest that C3435T MDR1 polymorphism has an association with colorectal cancer. The results support that the presence of allele C results in decreased susceptibility to colorectal cancer.

Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients

One of the limitations in the treatment of cancer patients with chemotherapy is the development of multidrug resistance (MDR). A well-known mechanism responsible for drug resistance is over-expression of ABC-transporter genes such as MDR1. This gene encodes p-glycoprotein (P-gp), a transmembrane glycoprotein that transports many hydrophobic substrates and anti-cancer drugs out of the cell. MDR1 gene polymorphisms could alter the expression level of P-gp and consequently result in drug resistance. We investigated a possible association between MDR1 gene C3435T polymorphism and its expression in Iranian breast cancer patients. PCR-RFLP was used for the detection of C3435T single nucleotide polymorphism in 54 breast cancer patients and 50 healthy individuals. The expression level of MDR1 was determined by real-time quantitative PCR. We observed no difference in the frequency of C3435T polymorphism between breast cancer patients and healthy controls. However, there was a significant association between MDR1 expression levels and C3435T polymorphism in the patients. C3435T polymorphism may play a role in inducing drug resistance by altering the expression level of the MDR1 gene.

Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia: Role of the NPM1 Mutations May Be Different in Different Races.

Abstract 4684 IntroductionRecent advances in molecular characterization of acute myeloid leukemia (AML) have led to molecular classification of normal karyotype (NK) AML. Mutations of the NPM1 gene showed a good response to induction therapy and had a favorable prognosis, especially in the absence of a FLT3-ITD mutation, in the studies of NK AML. However, most studies regarding the NPM1 gene mutations have come from the Western countries. Thus we investigated role of the NPM1 mutations in Korean patients with NK AML. Patients and MethodsInclusion criteria of this retrospective study was the followings: a new patient (1) with NK AML, (2) receiving standard induction chemotherapy ('7+3' regimen), and (3) with DNA from leukemic blasts at diagnosis being available. Polymorphisms of 4 genes (GSTT1, GSTM1, GSTA1, MDR1 [C3435T]) and mutations of 2 genes (FLT3, NPM1) were analyzed using PCR (GSTT1, GSTM1, FLT3-ITD), RFLP (GSTA1, MDR1 [C3435T]), and direct sequencing (NPM1). Clinico-laboratory data were retrieved from the Asan Medical Center Leukemia Registry. ResultsThis study included a total of 102 patients who were newly diagnosed as NK AML in the Asan Medical Center, Seoul, Korea between May 1999 and December 2006. Median age of the patients, 63 males and 39 females, was 44 years (range, 15-80). Null genotype of GSTM1 and GSTT1 was observed in 41.2% and 52.0% of the patients, respectively. Genotype of GSTA1 was CC in 75.3% and CT in 24.7%, and C3435T polymorphism of MDR1 gene was CC in 52.2%, CT in 39.1% and TT in 8.7%. FLT3-ITD was detected in 22.8% and NPM1 was mutated in 36.5%. Baseline clinico-laboratory data were not significantly different according to the genotype or mutational status of the genes except significantly higher leukocyte counts at diagnosis in patients with FLT3-ITD compared to those without the mutation (mean, 77000/mcL vs. 33000/mcL, P=0.019). For total patients, the rate of complete remission (CR) was 78.9%, and survival probabilities at 5-year were 39.9% for overall survival (OS), 57.9% for relapse-free survival (RFS), and 42.5% for event-free survival (EFS). Table 1 shows the clinical outcomes according to the polymorphism or mutation of the genes analyzed in this study. Multivariate analyses demonstrated independently significant prognostic factors for clinical outcomes of NK AML as followings: (1) for the induction of CR, no independently significant factor, (2) for OS, age (year, < 60 vs. 60 or more, 45.4% vs. 15.4%, RR 2.710, P=0.003) and FLT3-ITD (absent vs. present, 43.1% vs. 30.4%, RR 1.947, P=0.025), (3) for RFS, age (year, < 60 vs. 60 or more, 64.7% vs. 11.4%, RR 6.333, P<0.001), FLT3-ITD (absent vs. present, 43.1% vs. 30.4%, RR 3.658, P=0.002), and uric acid level (mg/dL, < 7.0 vs. 7.0 or more, 61.2% vs. 34.3%, RR 2.833, P=0.027), and (4) for EFS, age (year, < 60 vs. 60 or more, 47.8% vs. 9.1%, RR 3.422, P=0.003), FLT3-ITD (absent vs. present, 46.0% vs. 31.6%, RR 2.655, P=0.005), and C3435T of MDR1 (CC vs. CT/TT, 29.1% vs. 56.3%, RR 0.449, P=0.013). ConclusionMutations of the NPM1 gene did not show significant impact on clinical outcomes in Korean patients with NK AML, whereas presence of a FLT3-ITD mutation was significantly associated with inferior survivals. Clinical significance of genetic alterations in NK AML might be different in different races and the racial differences should be considered before molecular classification is established in NK AML.Table 1Clinical outcomes according to the polymorphism or mutation of selected genesCR ratePOS, 5-yPRFS, 5-yPEFS, 5-yPGST M1, Present vs. Null80.0%76.2%.64540.4% 9.4%.86258.7%7.2%.74442.4%43.3%.927GST T1, Present vs. Null81.6%75.5%.45047.9%33.2%.32461.6%54.2%.50046.3%39.2%.455GST A1, CC vs. CT80.8%75.0%.54138.2%50.0%.32461.4%50.5%.54043.0%41.7%.917MDR3435, CC vs. CT/TT81.3%79.5%.83731.4%51.4%.04450.6%65.5%.11529.1%56.3%.019FLT3-ITD, Absent vs. Present78.2%82.6%.64743.1%30.4%.07462.7%43.6%.01446.0%31.6%.036NPM1, Wild vs. Mutant73.8%88.6%.08639.7%39.3%.55462.6%55.9%.41345.3%41.4%.394 Disclosures:Lee:Janssen Korea: Consultancy, Honoraria.

Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: A case-control study

Breast cancer (BC) is a complex disease influenced by environmental and genetic factors. The disease has important genetic and environmental components, most of them are still unknown. An important role of gene polymorphisms related to the risk of developing BC has been reported. However, the results have been controversial. We investigated the association of TSER, MTHFR C677T, p53 codon 72 and MDR1 C3435T gene polymorphisms with breast carcinoma in women from Canary Islands (Spain). Blood samples collected from 135 patients with BC and 304 healthy controls all of them Caucasian, were analyzed through polymerase chain reaction-restriction fragment length polymorphism. Subsequently, a structured questionnaire including patient history and risk factors in relation to BC development was filled out. Allelic frequencies of these genetic variations were: TSER, (2) 0.55 and (3) 0.45 in cases, 0.49 and 0.51 respectively in controls (P=0.240); MTHFR C677T, (C) 0.63 and (T) 0.37 in cases, 0.60 and 0.40 respectively in controls (P=0.568); p53 Arg72Pro, (Arg) 0.74 and (Pro) 0.26 in cases and controls (P=0.910); MDR1 C3435T, (C) 0.52 and (T) 0.48 in cases, 0.55 and 0.45 respectively in controls (P=0.523). We did not observe any gene polymorphism as a risk factor to develop BC. A statistical association was observed between p53 codon 72 polymorphism and family history of breast cancer in both groups, as well as between MDR1 C3435T and smoking habits in cases (P<0.05). Gene polymorphisms vary by regions. The present study contributes to the characterization of the genetic pattern of the Canary population.

C3435T Polymorphism of MDR1 Gene Is Not Associated with p-Glycoprotein Function of Leukemic Blasts and Clinical Outcomes in Patients with Acute Myeloid Leukemia.

P-glycoprotein (P-gp) function of leukemic blasts is associated with chemotherapy resistance in acute myeloid leukemia (AML). The C3435T polymorphism in the human MDR1 gene has been studied in AML and contradictory results were reported regarding clinical implications of the polymorphism. We investigated the association of C3435T polymorphism of MDR1 gene with P-gp function of leukemic blasts and clinical outcomes in patients with AML excluding M3 subtype. A total of 200 patients, 127 males and 73 females, were included in this study. Median age was 44 years (range, 14–75). All patients were newly diagnosed and were treated with standard ‘7+3' induction chemotherapy regimens at the Asan Medical Center, Seoul, Korea between May 1999 and November 2006. The C3435T polymorphism was analyzed with PCR/RFLP method. P-gp function of leukemic blasts was measured at diagnosis by the rhodamine-123 efflux assay. The clinico-laboratory data at diagnosis and data on clinical outcomes were obtained from the AMC Leukemia Registry. Genotype frequency of C3435T polymorphism was 71 (35.5%) for CC, 93 (46.5%) for CT, and 36 (18.0%) for TT. There were no significant differences between different genotypes of C3435T polymorphism regarding age, sex, FAB subtypes, initial leukocyte counts, percentages of blasts in bone marrow or blood at diagnosis, and cytogenetic risk groups. P-gp function of leukemic blasts was not significantly different according to the genotype of C3435T polymorphism: 32.2 ± 24.0% for CC, 35.8 ± 21.4% for CT, and 29.1 ± 24.0% for TT (P=0.370). Complete remission was induced in 79.2% for CC, 79.8% for CT, and 77.8% for TT (P=0.969). Overall, relapse-free and event-free survival probabilities at 5 years were 47.6%, 55.4% and 51.0% for CC, 51.3%, 51.0% and 42.5% for CT, and 53.1%, 60.0% and 55.0% for TT (P= 0.594, 0.932 and 0.764, respectively). In conclusion, C3435T polymorphism does not have significant clinical implications in AML regarding P-gp function of leukemic blasts and clinical outcomes.

MDR1 C3435T Polymorphism in Patients with Breast Cancer

The human multidrug-resistant gene (MDR1) encodes P-glycoprotein (Pgp), a membrane-bound efflux transporter conferring resistance to a number of natural cytotoxic drugs and potentially toxic xenobiotics. Single-nucleotide polymorphisms (SNPs) in MDR1 gene are associated with phenotypic variation in Pgp expression levels of tissue. SNPs may alter the physiological protective role of Pgp and, therefore, influence disease risk. In our study we identified the MDR1 C3435T polymorphism in breast cancer patients (n = 57) and healthy subjects (n = 50). DNA was extracted from peripheral blood samples by standard phenol/chloroform extraction method. Polymerase chain reaction-restriction fragment length polymorphism was used for the detection of C3435T single nucleotide polymorphism. We obtained CC, CT and TT genotype frequencies in breast cancer patients as 12.3%, 57.9% and 29.8%, respectively. In the control group, frequencies of genotypes were found as 36% for CC, 46% for CT and 18% for TT. We observed difference in SNPs in MDR1 gene C3435T polymorphism between breast cancer patients and healthy controls (chi(2) = 8.66, df = 2, p = 0.013). The C allele frequency was found in 41.2% and the T allele frequency was found in 58.8%. C3435T MDR1 gene allele frequencies in breast cancer patients as compared to results in control group were as follows: [OR = 1.5 (95% CI: 1.09-1.96)]. In the patient group, T allele frequency was significantly higher than controls (p <0.01). Clinicopathological parameters of patients with breast cancer were compared for C3435T polymorphism. We did not find any significant difference between clinicopathological parameters and MDR1 phenotype of breast cancer patients. The progression-free survival rate in a subgroup analysis based on MDR1 genotypes with CC genotype was 71.4%, CT genotype was 75.7%, and TT genotype was 88.2%, respectively. This difference was not statistically significant (log rank p = 0.63). Results of the present study demonstrated a 1.5-fold increased risk for development of breast cancer in T allele carriers.

The frequency of C3435T MDR1 gene polymorphism in Iranian patients with ulcerative colitis

The MDR1 (multidrug resistance) gene, located on chromosome 7, is in one of the inflammatory bowel disease susceptibility loci. It produces P-glycoprotein, a transmembrane efflux pump, transferring drugs and toxins from intracellular to extracellular domains. In the human gastrointestinal (GI) tract, P-glycoprotein is found in high concentrations on the epithelial cells of the colon and small intestine. MDR1 gene polymorphisms such as C3435T are associated with lower P-glycoprotein expression, and thus it is suggested to have an association with ulcerative colitis. We tried to determine the frequency of C3435T polymorphism of the MDR1 gene in Iranian patients with ulcerative colitis and to compare it with a healthy control population. In this case-control-designed study, 300 unrelated ulcerative colitis patients and 300 sex-and-age-matched healthy controls were enrolled. They were visited at a tertiary center during a 2-year period (2003-2005). DNA of patients and controls was amplified by polymerase chain reaction with specific primers, and C3435T polymorphism was detected by the restriction fragment length polymorphism method. The frequency of the 3435T allele was significantly higher in ulcerative colitis patients compared to the controls (p < 0.001). The frequency of homozygote T/T and heterozygote C/T genotypes were also significantly higher in Iranian patients with ulcerative colitis (p = 0.044 and 0.041, respectively). This study suggests that C3435T polymorphism of the MDR1 gene has an association with ulcerative colitis in Iranian population as previously reported in western countries.

Tacrolimus Dosing in Chinese Renal Transplant Patients Is Related to MDR1 Gene C3435T Polymorphisms

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

The Frequency of C3435T MDR1 Gene Polymorphism in Iranian Patients with Ulcerative Colitis

The Frequency of C3435T MDR1 Gene Polymorphism in Iranian Patients with Ulcerative Colitis

MDR‐1 C3435T gene polymorphism does not correlate with P‐Glycoprotein expression and function in acute myeloid leukemia

Clinical Pharmacology &amp; Therapeutics (2003) 73, P58–P58; doi:

Frequency of C3435T polymorphism of MDR1 gene in African people

The variability of P-glycoprotein expression between individuals is linked to a C3435T polymorphism of the human MDR1 gene. Concentration of P-glycoprotein in intestinal epithelial cells and in a subset of lymphoid cells is substantially lower in people with the T/T genotype than those with the C/C genotype. We compared allele frequencies of the C3435T polymorphism in random samples of west African, African American, white, and Japanese people. We recorded a significantly higher frequency of the C/C genotype in West Africans and African Americans (142 of 172 [83%] and 25 of 41 [61%], respectively), than in white people (139 of 537 [26%]) (p<0.0001). These findings could affect use of drugs that are P-glycoprotein substrates (such as HIV-1 protease inhibitors and ciclosporin) in African populations.