Article

Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein)

Department of Genetics, Stanford University Medical Center, Stanford, California 94305-5120, USA.
Pharmacogenetics and Genomics (Impact Factor: 3.48). 03/2011; 21(3):152-61. DOI: 10.1097/FPC.0b013e3283385a1c
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Available from: Laura Hodges
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    • "One of the most common polymorphisms of ABCB1 gene, related to impaired transport mediated by this protein, is a synonymous mutation C3435T (rs1045642) in exon 26. Polymorphic T allele is associated with more than two times lower P-gp intestinal expression and increased in vivo activity[8,11,12]. Not only its expression, but the affinity of the transporter for various drugs may also be altered[13]. "
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    ABSTRACT: Background/aims: One of the most common polymorphisms of ABCB1 gene, a synonymous mutation C3435T (rs1045642), is associated with increased in vivo activity. The main goal of this study was to determine the association of C3435T polymorphism with clopidogrel and 2-oxo-clopidogrel concentrations in plasma. Methods: The patients were recruited upon acute myocardial infarction diagnosis. They were all tested for ABCB1 C3435T polymorphism. In plasma, drawn 1 h after the drug administration, concentrations of clopidogrel and 2-oxo-clopidogrel were measured using UHPLC-DAD-MS analysis. Results: Due to differences in the maintenance doses, we have calculated the dose-adjusted concentrations of clopidogrel (0.2 ng/ml/mg (0.1-0.4)) and 2-oxo-clopidogrel (2.1 ng/ml/mg (0.5-4.6)). Patients carrying at least one C allele achieved significantly higher serum concentration of clopidogrel (p < 0.001), as well as dose-adjusted clopidogrel (p < 0.001) and 2-oxo-clopidogrel concentrations (p < 0.05). Conclusion: The ABCB1 3435CC genotype is associated with increased clopidogrel and 2-oxo-clopidogrel dose-adjusted concentrations. Therefore, the ABCB1 C3435T genotyping should be one of the parameters taken into account when deciding about the dosing regimen of clopidogrel.
    Full-text · Article · Dec 2015 · Pharmacology
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    • "The manner that ABCB1 variants affect the P-gp expression on the apical villi of enterocytes remains unresolved (Lin and Yamazaki, 2003; Leschziner et al, 2007; Hodges et al, 2011; Wolf et al, 2011). Nakamura et al (2002) reported that healthy Japanese subjects with 3435T/T had significantly higher duodenal ABCB1 mRNA expression and lower digoxin plasma level compared with C/C or C/T genotype carriers, while Hoffmeyer et al (2000) and Efferth et al (2003) disagreed with such a correlation. "
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    ABSTRACT: Background: Host germline variations and their potential prognostic importance is an emerging area of interest in paediatric ALL. Methods: We investigated the associations between 20 germline variations and various clinical end points in 463 children with ALL. Results: After adjusting for known prognostic factors, variants in two genes were found to be independently associated with poorer EFS: ABCB1 T/T at either 2677 (rs2032582) or 3435 (rs1045642) position (P=0.003) and IL15 67276493G/G (rs17015014; P=0.022). These variants showed a strong additive effect affecting outcome (P<0.001), whereby patients with both risk genotypes had the worst EFS (P=0.001), even after adjusting for MRD levels at the end of remission induction. The adverse effect of ABCB1 T/T genotypes was most pronounced in patients with favourable cytogenetics (P=0.011) while the IL15 67276493G/G genotype mainly affected patients without common chromosomal abnormalities (P=0.022). In both cytogenetic subgroups, increasing number of such risk genotypes still predicted worsening outcome (P<0.001 and=0.009, respectively). Conclusion: These results point to the prognostic importance of host genetic variants, although the specific mechanisms remain unclarified. Inclusion of ABCB1 and IL15 variants may help improve risk assignment strategies in paediatric ALL.
    Full-text · Article · Jan 2014 · British Journal of Cancer
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    • "Tri-allelic G2677TA nonsynonymous polymorphism has been also widely reported, since its variants are known to induce amino acid modification (Ala893 to Ser/ Thr893) (Leschziner et al., 2007). This polymorphism is also known to affect P-GP functionality (Hodges et al., 2011). Despite functional studies, investigations focusing on the influence of P-GP polymorphisms and the risk of depression are scarce and have only been conducted in Asian (Qian et al., 2006; Fujii et al., 2012) and Mexican American patients (Dong et al., 2009). "
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    ABSTRACT: Major depressive disorder (MDD) is a highly prevalent disorder, which has been associated with an abnormal response of the hypothalamus-pituitary-adrenal (HPA) axis. Reports have argued that an abnormal HPA axis response can be due to an altered P-Glycoprotein (P-GP) function. This argument suggests that genetic polymorphisms in ABCB1 may have an effect on the HPA axis activity; however, it is still not clear if this influences the risk of MDD. Our study aims to evaluate the effect of ABCB1 C1236T, G2677TA and C3435T genetic polymorphisms on MDD risk in a subset of Portuguese patients. DNA samples from 80 MDD patients and 160 control subjects were genotyped using TaqMan(®) SNP Genotyping assays. A significant protection for MDD males carrying the T allele was observed (C1236T: odds ratio (OR)=0.360, 95% confidence interval [CI]: [0.140-0.950], p=0.022; C3435T: OR=0.306, 95% CI: [0.096-0.980], p=0.042; and G2677TA: OR=0.300, 95% CI: [0.100-0.870], p=0.013). Male Portuguese individuals carrying the 1236T/2677T/3435T haplotype had nearly 70% less risk of developing MDD (OR=0.313, 95% CI: [0.118-0.832], p=0.016, FDR p=0.032). No significant differences were observed regarding the overall subjects. Our results suggest that genetic variability of the ABCB1 is associated with MDD development in male Portuguese patients. To the best of our knowledge, this is the first report in Caucasian samples to analyze the effect of these ABCB1 genetic polymorphisms on MDD risk.
    Full-text · Article · Nov 2013 · Genetic Testing and Molecular Biomarkers
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