Pharmacogenomic assessment of Mexican and Peruvian populations.
ABSTRACT: Clinically relevant polymorphisms often demonstrate population-specific allele frequencies. Central and South America remain largely uncategorized in the context of pharmacogenomics.We assessed 15 polymorphisms from 12 genes (ABCB1 3435C>T, ABCG2 Q141K, CYP1B1*3, CYP2C19*2, CYP3A4*1B, CYP3A5*3C, ERCC1 N118N, ERCC2 K751Q, GSTP1 I105V, TPMT 238G>C, TPMT 460G>A, TPMT 719A>G, TYMS TSER, UGT1A1*28 and UGT1A1 -3156G>A) in 81 Peruvian and 95 Mexican individuals.Six polymorphism frequencies differed significantly between the two populations: ABCB1 3435C>T, CYP1B1*3, GSTP1 I105V, TPMT 460G>A, UGT1A1*28 and UGT1A1 -3156G>A. The pattern of observed allele frequencies for all polymorphisms could not be accurately estimated from any single previously studied population.This highlights the need to expand the scope of geographic data for use in pharmacogenomics studies.
Project description:Genetic polymorphisms in drug metabolizing enzymes and drug transporters may affect irinotecan toxicity. Although genetic polymorphisms have been shown to influence the irinotecan toxicity, data are limited in Thai population. Thus, the aim of this study was to assess the allele and genotype frequencies and the relationship between CYP3A4/5, DPYD, UGT1A1, ABCB1, and ABCC2 genetic variations and irinotecan-induced toxicity in Thai colorectal cancer patients. One hundred and thirty-two patients were genotyped, and the effect of genetic variations on irinotecan-induced toxicity was assessed in 66 patients who received irinotecan-based chemotherapy. Allele frequencies of ABCB1 c.1236C?>?T, ABCB1 c.3435C?>?T, ABCC2 c.3972C?>?T, ABCG2 c.421C?>?A, CYP3A4*1B, CYP3A4*18, CYP3A5*3, DPYD*5, UGT1A1*28, and UGT1A1*6 were 0.67, 0.43, 0.23, 0.27, 0.01, 0.02, 0.64, 0.19, 0.16, and 0.09, respectively. DPYD*2A and DPYD c.1774C?>?T variants were not detected in our study population. The ABCC2 c.3972C?>?T was significantly associated with grade 1-4 neutropenia (P?<?0.012) at the first cycle. Patients carrying both UGT1A1*28 and *6 were significantly associated with severe neutropenia at the first (P?<?0.001) and second (P?=?0.017) cycles. In addition, patients carrying UG1A1*28 and *6 had significantly lower absolute neutrophil count (ANC) nadir at first (P?<?0.001) and second (P?=?0.001) cycles. This finding suggests that UGT1A1*28, *6, and ABCC2 c.3972C?>?T might be an important predictor for irinotecan-induced severe neutropenia.
Project description:INTRODUCTION:The human multidrug resistance gene ATP-binding cassette B1 (ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anticancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene that may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C-->T, 2677G-->T and 3435C-->T, have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related. METHODS:In this study, 95 individuals representative of the entire ethnic make-up of the USA were compared with 101 individuals from an Ashkenazi-Jewish population. These individuals were analyzed by genomic sequencing and polymerase chain reaction, using restriction fragment length polymorphisms, to calculate their genotype frequencies. RESULTS:A total of 25 SNPs were located in the exons of the ABCB1 gene. All of the polymorphisms identified were in parts of the ABCB1 gene product predicted to be intracellular, and 16 appear to be novel as compared with those listed by the National Center for Biotechnological Information. Frequencies of the 1236C-->T and 2677G-->T/A/C SNPs were similar for the US and Ashkenazi populations (64.2 and 60.4%, respectively for 1236C-->T [chi2: 0.30; p < or = 1]; 55.8 and 64.4%, respectively for 2677G-->T/A/C [chi2: 1.49; p < or = 1]), but were different for 3435C-->T (24.2% for the US population and 69.3% for the Ashkenazi population [chi2: 39.927; p < or = 0.001]). The 1236T/ 2677T/3435T haplotype occurred in 23.6% (standard error: 0.013) of the Ashkenazi population. CONCLUSION:The SNP at location 3435C-->T plays a significant role in the ABCB1 gene. The haplotype and genotype analysis from these data may be used as a basis for studies on the relationship between ABCB1 genotypes and drug efficacy, drug toxicity, disease susceptibility or other phenotypes.
Project description:AIMS:Some study found that ATP-binding cassette (ABC) efflux transporters play an important role in antiepileptic drug resistance, especially ABCB1 and ABCC2. The aims of this study were to evaluate the relationship between the genetic polymorphisms of ABCC2 and ABCB1 and the therapeutic efficacy of antiepileptic drugs (AEDs) in Chinese epileptic patients. METHODS:ABCB1 rs1045642 (3435C>T) and ABCC2 rs717620 (-24C>T), rs3740066 (3972C>T), and rs2273697 (1249G>A) polymorphisms loci in 537 Chinese epilepsy patients (217 drug resistant patients and 320 drug responders) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS:ABCC2 rs717620 -24TT genotype was significantly associated with drug resistant epilepsy (odds ratio [OR]= 4.06 [1.79-9.20], P= 0.001). The OR values of ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes were markedly higher in drug resistant patients (OR = 1.57 [1.08-2.29], P= 0.018; OR = 1.49 [1.02-2.18], P= 0.038, respectively) compared with responsive patients. ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not associated with drug resistant epilepsy. Linkage disequilibrium (LD) test showed that the ABCC2 rs717620 were in strong LD with rs2273697 (D'= 0.694) and rs3740066 (D'= 0.699). The frequencies of haplotypes TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients was significantly higher than those in responsive patients (21.0% vs. 14.2%, P < 0.05). CONCLUSION:ABCC2-24C>T, 3972C>T polymorphisms and one ABCC2 haplotype is associated with AED resistance; ABCC2 1249G>A and ABCB1 3435C>T polymorphisms are not associated with AED resistance in our study. These data suggest that ABCC2 polymorphisms and haplotype may affect the response of antiepileptic drugs.
Project description:The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine.Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain).Flupirtine IR was rapidly but incompletely absorbed (? 72%). Repeated administration of flupirtine MR showed lower bioavailability (? 60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2.Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1.
Project description:The role of ABCB1 single nucleotide polymorphisms (SNPs) in the development of Crohn's disease (CD) remains unclear. Due to inconsistent results of several European population-based studies and limited information on populations from Poland and Bosnia and Herzegovina (B&H), we conducted a preliminary association study of two main ABCB1 SNPs and CD. ABCB1 3435C>T and 2677G>T/A SNPs were analyzed in Polish and Bosnian patients with CD (n = 85 and n = 30, respectively) and controls (n = 82 and n = 30, respectively) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for 3435C>T and allele-specific PCR for 2677G>A/T SNP. A deviation from Hardy-Weinberg equilibrium was found for both SNPs in Polish patients with CD, and for 2677G>A/T in Polish control group. The allele and genotype frequencies of the two ABCB1 SNPs were not significantly different between the CD patients and controls in both populations (p > 0.05). Similarly, the genotype distribution of 3435C>T and 2677G>T/A SNPs was not significantly different between Polish and Bosnian patients with CD (p > 0.05). At least one mutated ABCB1 allele was carried by 97.7% of Polish and 90.0% of Bosnian patients with CD. No association was found between the ABCB1 SNPs and CD in the two populations. In conclusion, the two ABCB1 SNPs may not contribute to CD susceptibility in the populations of Poland and B&H. Further studies with larger samples in both populations are warranted.
Project description:In Argentina, porphyria cutanea tarda (PCT) is strongly associated with infection with human immunodeficiency virus (HIV); however, whether the onset of this disease is associated with HIV infection and/or the antiretroviral therapy has not been determined. The ABCB1 gene variants c.1236C>T, c.2677G>T/A and c.3435C>T affect drug efflux. The GSTT1 null, GSTM1 null and GSTP1 (c.313A>G) gene variants alter Glutathione S-transferase (GST) activity, modifying the levels of xenobiotics. The aim of the present study was to evaluate the role of genetic variants in initiation of PCT and to analyze the genetic basis of the PCT-HIV association. Control individuals, and HIV, PCT and PCT-HIV patients were recruited, PCR-restriction fragment length polymorphism was used to genotype the ABCB1 and GSTP1 variants, and multiplex PCR was used to study the GSTM1 and GSTT1 variants. The high frequency of c.3435C>T (PCT and PCT-HIV) and c.1236C>T (PCT) suggested that the onset of PCT were not specifically related to HIV infection or antiretroviral therapy for these variants. c.2677G>T/A frequencies in the PCT-HIV patients were higher compared with the other groups, suggesting that a mechanism involving antiretroviral therapy served a role in this association. PCT-HIV patients also had a high frequency of GSTT1 null and low frequency for GSTM1 null variants; thus, the genetic basis for PCT onset may involve a combination between the absence of GSTT1 and the presence of GSTM1. In conclusion, genes encoding for proteins involved in the flow and metabolism of xenobiotics may influence the PCT-HIV association. The present study is the first to investigate the possible role of GST and ABCB1 gene variants in the triggering of PCT in HIV-infected individuals, to the best of our knowledge, and may provide novel insights into the molecular basis of the association between PCT and HIV.
Project description:Direct oral anticoagulants (DOAC) are substrates for the ABCB1 transporter (also called P-glycoprotein), an active efflux pump. ABCB1 polymorphisms have been previously reported to influence the pharmacokinetics of several drugs such as immunosuppressants and tyrosine kinase inhibitors. Recently, in vivo studies have suggested that genetic variants might contribute to the inter-individual variability in DOAC plasma concentrations. Therefore, we evaluated the in vitro effect of the most common coding ABCB1 single nucleotide polymorphisms (SNP), 1236?C?>?T-2677G?>?T-3435C?>?T, and the coding ABCB1 1199?G?>?A SNP on the transport activity towards rivaroxaban. HEK293 cells were transfected to overexpress the ABCB1 wild-type (1236C-2677G-3435C, 1199?G) or variant proteins (1236C-2677G-3435T, 1236T-2677T-3435T or 1199?A). ABCB1 expression decreased the intracellular accumulation of rivaroxaban, when compared to control cells. This confirms the involvement of ABCB1 in the active transport of rivaroxaban. However, the ABCB1 1236?C?>?T-2677G?>?T-3435C?>?T and 1199?G?>?A SNPs had no significant influence on the intracellular accumulation of rivaroxaban when compared to the wild-type protein. These results suggest that the ABCB1 coding SNPs investigated in the present study are unlikely to contribute to the inter-individual variability in rivaroxaban plasma concentrations.
Project description:Cyclophosphamide is one of the most potent and reliable anti-cancer and immunosuppressive drugs. In our study, 33 individuals with different autoimmune diseases were treated with cyclophosphamide according to standard protocols. The responses to the treatments were determined by measuring the alteration of several typical parameters characterizing the given autoimmune diseases over time. We concluded that about 45% of the patients responded to the treatment. Patients were genotyped for polymorphisms of the CYP3A4, CYP2B6, GSTM1, GSTT1, and GSTP1 genes and disease remission cases were compared to the individual polymorphic genotypes. It was found that the GSTP1 I105V allelic variation significantly associated with the cyclophosphamide treatment-dependent disease-remissions. At the same time the GSH content of the erythrocytes in the patients with I105V allelic variation did not change. It appears that the individuals carrying the Ile105Val SNP in at least one copy had a significantly higher response rate to the treatment. Since this variant of GSTP1 can be characterized by lower conjugation capacity that results in an elongated and higher therapeutic dose of cyclophosphamide, our data suggest that the decreased activity of this variant of GSTP1 can be in the background of the more effective disease treatment.
Project description:Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians.CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects.Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27-2.40) for area under the concentration time curve (AUC)(0-12 h), 1.58 (1.03-2.42) for C(0), and 0.53 (0.31-0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027).Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.
Project description:Although several epidemiological studies have investigated the association between ATP-binding cassette subfamily B member 1 (ABCB1) gene polymorphisms and Alzheimer's disease (AD) susceptibility, controversial results exist. Here, we performed a meta-analysis to assess whether ABCB1 polymorphisms 3435C?>?T (rs1045642), 2677G?>?T/A (rs2032582), 1236C?>?T (rs1128503) and haplotypes were associated with AD risk. Nine independent publications were included and analyzed. Crude odds ratio (OR) and 95% confidence interval (CI) were applied to investigate the strength of the association. Sensitivity analysis was conducted to measure the robustness of our analysis. A funnel plot and trim and fill method were used to test and adjust for publication bias. The results showed a significant association between the 3435C?>?T single nucleotide polymorphism (SNP) and AD susceptibility (CT vs. CC: OR?=?1.24, 95%?CI?=?1.06-1.45, P?=?0.01; CT?+?TT vs. CC: OR?=?1.21, 95%?CI?=?1.04-1.41, P?=?0.01) in the total population, as well as in Caucasian subgroup. The 2677G?>?T/A SNP was related to a decreased AD risk in Caucasian subgroup (TT?+?TA?+?AA vs. GT?+?GA?+?GG: OR?=?0.68, 95%?CI?=?0.47-0.98, P?=?0.04). Moreover, the ABCB1 haplotype analysis showed that the 1236T/2677T/3435C haplotype was associated with a higher risk of AD (OR?=?1.99, 95%?CI?=?1.24-3.18, P?=?0.00). Our results suggest that the ABCB1 3435C?>?T SNP, the 2677G?>?T/A SNP and 1236T/2677T/3435C haplotype are significantly associated with AD susceptibility.