ABCB1 Genetic Variants Research Articles

Association of ABCB1 genetic variants 3435C>T and 2677G>T to ABCB1 mRNA and protein expression in brain tissue from refractory epilepsy patients

There is evidence from studies in rodents that P-glycoprotein (P-gp) overexpression is implicated in the causation of refractory epilepsy. Genetic variants in the human ABCB1 (MDR1) gene were shown to affect the expression levels of the transporter in various tissues and to be associated with refractory epilepsy. However, the effect of the genetic variants on the P-gp level in epileptogenic brain tissue is poorly investigated. In the present study, we examined the impact of putatively functional polymorphisms 3435C>T and 2677G>T in the ABCB1 gene on the ABCB1 mRNA expression and P-gp content in human brain tissue from epileptogenic foci of the patients with refractory epilepsy. Fresh brain tissue specimens were obtained from therapy-refractory epilepsy patients during neurosurgery of the epileptogenic focus. We determined the ABCB1 mRNA expression in 23 samples using 5' exonuclease-based real-time polymerase chain reaction (PCR) as well as the P-gp content in 32 samples determined by immunohistochemistry, genotyping was performed by PCR/restriction fragment length polymorphism (RFLP). There was lack of association of 3435C>T and 2677G>T as well as diplotype configurations on ABCB1 mRNA expression and P-gp content in epileptogenic brain tissues. We cannot exclude an association of ABCB1 variants on P-gp function, but our results suggest that brain ABCB1 mRNA and protein expression is not substantially influenced by major ABCB1 genetic variants thus explaining in part results from case-control studies obtaining lack of association of ABCB1 polymorphisms to the risk of refractory epilepsy.

Association of ABCB1genetic variants with renal function in Africans and in Caucasians

BackgroundThe P-glycoprotein, encoded by the ABCB1 gene, is expressed in human endothelial and mesangial cells, which contribute to control renal plasma flow and glomerular filtration rate. We investigated the association of ABCB1 variants with renal function in African and Caucasian subjects.MethodsIn Africans (290 subjects from 62 pedigrees), we genotyped the 2677G>T and 3435 C>T ABCB1 polymorphisms. Glomerular filtration rate (GFR) was measured using inulin clearance and effective renal plasma flow (ERPF) using para-aminohippurate clearance. In Caucasians (5382 unrelated subjects), we analyzed 30 SNPs located within and around ABCB1, using data from the Affymetrix 500 K chip. GFR was estimated using the simplified Modification of the Diet in Renal Disease (MDRD) and Cockcroft-Gault equations.ResultsIn Africans, compared to the reference genotype (GG or CC), each copy of the 2677T and 3435T allele was associated, respectively, with: GFR higher by 10.6 ± 2.9 (P < 0.001) and 4.4 ± 2.3 (P = 0.06) mL/min; ERPF higher by 47.5 ± 11.6 (P < 0.001) and 28.1 ± 10.5 (P = 0.007) mL/min; and renal resistances lower by 0.016 ± 0.004 (P < 0.001) and 0.011 ± 0.004 (P = 0.004) mm Hg/mL/min. In Caucasians, we identified 3 polymorphisms in the ABCB1 gene that were strongly associated with all estimates of GFR (smallest P value = 0.0006, overall P = 0.014 after multiple testing correction).ConclusionVariants of the ABCB1 gene were associated with renal function in both Africans and Caucasians and may therefore confer susceptibility to nephropathy in humans. If confirmed in other studies, these results point toward a new candidate gene for nephropathy in humans.

ABCB1 (MDR1) genetic variants are associated with methadone doses required for effective treatment of heroin dependence

Methadone is a mu-opioid receptor agonist used for treating opiate dependence. The range of effective methadone doses is broad. Part of the large inter-individual variability in efficacy may be accounted for by genetic factors. Methadone is a substrate of the transporter P-glycoprotein (P-gp) 170 that is encoded by the ABCB1 (MDR1) gene. Thus, P-gp variants may play a role in methadone absorption and distribution. We assessed the association between ABCB1 polymorphisms and methadone dose requirements in 98 methadone-maintained patients. The stabilizing methadone doses were normally distributed with a mean and median dose of 160 mg/day (range 30-280 mg/day). Statistical analysis showed significant difference in genotype frequencies between the 'higher' (>150 mg/day) and 'lower' (< or =150 mg/day) methadone dose groups for single nucleotide polymorphism (SNP) 1236C>T (rs1128503) (experiment-wise P = 0.0325). Furthermore, individuals bearing the 3-locus genotype pattern TT-TT-TT (rs1045642, rs2032582 and rs1128503) have an approximately 5-fold chance of requiring the 'higher' methadone dose, while individuals heterozygous for these three SNPs have an approximately 3-fold chance of stabilizing at the 'lower' methadone dose (point-wise P-value = 0.026). These data suggest that specific ABCB1 variants may have clinical relevance by influencing the methadone dose required to prevent withdrawal symptoms and relapse in this population.

The Effects of ABCB1 3′-Untranslated Region Variants on mRNA Stability

Genetic variation in ABCB1, encoding P-glycoprotein (P-gp), is a potential cause of interindividual variation in drug response. Numerous studies have focused on the effects of coding region variants on P-gp expression and function, whereas few noncoding region variants have been investigated. The 3'-untranslated region (UTR) regulates mRNA levels or stability via RNA-protein interactions with mRNA degradation machinery. mRNA stability is a key regulatory step controlling ABCB1 mRNA expression that ultimately affects P-gp levels and function. We hypothesized that ABCB1 3'-UTR polymorphisms alter mRNA stability by disrupting RNA-protein interactions. An ethnically diverse panel of DNA samples was sequenced to identify 3'-UTR polymorphisms and determine allele frequencies. The three most common variants, along with reference ABCB1, were stably expressed in cells in order to measure mRNA half-life. The calculated half-life for ABCB1 reference in HEK293 cells was 9.4 +/- 1.3 h and was similar to that estimated for the 3'-UTR variants. Endogenous ABCB1 mRNA decay was similar in lymphoblastoid cell lines carrying 3'-UTR variant and reference alleles. Although the examined ABCB1 3'-UTR variants have no effect on ABCB1 mRNA stability, these data represent one of the first attempts to determine the influence of genetic variation in UTRs on ABCB1 mRNA levels.

Genetic variation in ABCB1 influences paclitaxel pharmacokinetics in Japanese patients with ovarian cancer

Paclitaxel, an antineoplastic agent used for the treatment of ovarian cancer, is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8 and is excreted from cells by ATP-binding cassette (ABCB1) (multi-drug resistance [MDR1], P-glycoprotein). Expression of these proteins is regulated by pregnane X receptor (PXR). Although there are common genetic polymorphisms in the genes encoding these proteins, their effect on the clinical efficacy of paclitaxel is unclear. We therefore examined the relationship of the paclitaxel pharmacokinetics in 13 patients with ovarian cancer to polymorphisms in CYP2C8, CYP3A5, ABCB1, and PXR. We found high interindividual variability in the plasma concentrations of two metabolites, 6alpha-hydroxypaclitaxel and p-3'-hydroxypaclitaxel. All the patients were genotyped as CYP2C8*1/*1. Neither the CYP3A5 A6986G (CYP3A5*3) nor the PXR C-25385T alleles were associated with altered plasma concentrations of paclitaxel and its metabolites. ABCB1 T-129C, T1236C, and G2677(A,T), however, was associated with lower area under the plasma concentration-time curve (AUC) of paclitaxel. We also observed a significant correlation between the AUC (r=-0.721) or the total clearance of paclitaxel (CL(tot)) (r= 0.673) and the ABCB1 mutant allele dosage in each patient. Taken together, our findings suggest that interindividual variability in paclitaxel pharmacokinetics could be predicted by ABCB1 genotyping.

0121 Haplotype analysis in ABC transporter genes and association of genetic variation in ABCB1, ABCC1, ABCC2, ABCC5 and ABCB4 with epilepsy outcome

0121 Haplotype analysis in ABC transporter genes and association of genetic variation in ABCB1, ABCC1, ABCC2, ABCC5 and ABCB4 with epilepsy outcome