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, Oct 05, 2015
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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.
    British Journal of Cancer 01/2014; 110(6). DOI:10.1038/bjc.2014.7 · 4.84 Impact Factor
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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.
    Genetic Testing and Molecular Biomarkers 11/2013; 18(1). DOI:10.1089/gtmb.2013.0197 · 1.46 Impact Factor
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    • "For minimizing the exposure of potential toxic compounds to the cellular homeostasis, P-glycoprotein is expressed primarily in regions that act as epithelial barriers or perform excretory functions, including blood-tissue barrier, the gastrointestinal tract, liver and kidney. Therefore, P-glycoprotein can play the role of sweeper by extruding several exogenous and endogenous substances, using ATP-dependent efflux pump [1-4]. The alteration of the cellular defense mechanism mediated by P-gp has been speculated to be closely associated with the development of various cancers including hepatocarcinoma, colorectal carcinoma, acute lymphoblastic leukemia and gall bladder tumors [5-8]. "
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    ABSTRACT: Background: The multidrug resistance (MDR) 1 gene encodes a 170-kDa membrane transporter called P-glycoprotein, which plays an important role in protecting cells against lipophilic xenobiotics by the way of an ATP-dependent cellular efflux mechanism. Three polymorphisms of MDR1, 3435C > T located in exon 26, 1236C > T in exon 12 and 2677G > T/A in exon 21 were the most extensively studied and were identified functionally important and ethnically diverse mapping to the gene region. Considering the potential influence of altering MDR1 activity, it is plausible that MDR1 polymorphisms might play a role in the development of cancer. Although the effects of MDR1 polymorphisms on susceptibility to human cancer have been investigated in many studies, the results still remain conflicting. Methods: To resolve these conflicts, we performed a quantitative synthesis of the association between these three polymorphisms and cancer risk, including 52 studies (15789 cases and 20274 controls) for 3435C > T polymorphism, 10 studies (2101 cases and 2842 controls) for 1236C > T polymorphism and 18 studies (3585 cases and 4351 controls) for 2677G > T/A polymorphism. Results: The stratified analyses for 3435C > T polymorphism, individuals with T-allele in 3435C > T had significantly higher ALL risks (TT versus CC: OR =1.286, 95% CI =1.123-1.474); significantly elevated risks were observed among Caucasian populations (TT versus CC: OR =1.276, 95% CI =1.112-1.464). When restricting the analysis to the source of controls, we found that HB (hospital-based) genetic models had higher risks (TT versus CC: OR =1.307, 95% CI =1.046-1.632), as well as in PB (population-based) genetic models (TT versus CC: OR =1.294, 95% CI =1.079-1.55).The T/A-allele frequency of 2677G > T/A polymorphism was associated with higher risk of cancer (TT + TA + AA vs. GG: OR =1.348, 95% CI =1.031-1.762), significantly elevated risks were observed among Asian populations (TT + TA + AA vs. GG: OR =1.642, 95% CI =1.340-2.012), and elevated risks could be associated with PB models (TT + TA + AA vs. GG: OR =1.641, 95% CI =1.018-2.646). Conclusions: Our meta-analysis suggested that 3435C > T polymorphism and 2677G > T/A polymorphism were associated with cancer risk when all studies were pooled together, while 1236C > T polymorphism not.
    Cancer Cell International 05/2013; 13(1):46. DOI:10.1186/1475-2867-13-46 · 2.77 Impact Factor
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