A "Silent" Polymorphism in the MDR1 Gene Changes Substrate Specificity

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 02/2007; 315(5811):525-8. DOI: 10.1126/science.1135308
Source: PubMed


Synonymous single-nucleotide polymorphisms (SNPs) do not produce altered coding sequences, and therefore they are not expected to change the function of the protein in which they occur. We report that a synonymous SNP in the Multidrug Resistance 1 (MDR1) gene, part of a haplotype previously linked to altered function of the MDR1 gene product P-glycoprotein (P-gp), nonetheless results in P-gp with altered drug and inhibitor interactions. Similar mRNA and protein levels, but altered conformations, were found for wild-type and polymorphic P-gp. We hypothesize that the presence of a rare codon, marked by the synonymous polymorphism, affects the timing of cotranslational folding and insertion of P-gp into the membrane, thereby altering the structure of substrate and inhibitor interaction sites.

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    • "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]. Homozygotes for the variant allele T have higher risk of cardiovascular events and less platelet inhibition[14], even though there were studies with the opposite results[15]. "
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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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    • "Since it is a synonymous SNP, no change in amino acid of the protein occurs. For a long time, it was assumed that synonymous SNPs were inconsequential , but the assumption has been questioned in a number of studies [25] [26]. It is now believed that synonymous SNPs can result "
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    ABSTRACT: Epidermal growth factor receptor (EGFR) mutations are important predictors of treatment response to tyrosine kinase inhibitors (TKIs) in patients with non−small cell lung cancer (NSCLC). However, some patients with mutations do not respond and some patients without mutations show response. We therefore need additional biomarkers to improve the selection of these patients for treatment. A promising candidate could be germline genetic variations in the EGFR gene that can alter protein expression or function and may influence the response to TKIs. Thus, the aim of this study was to evaluate the predictive role of genetic variations in the EGFR gene in advanced NSCLC patients treated with a TKI.
    Full-text · Article · Sep 2015 · Lung cancer (Amsterdam, Netherlands)
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    • "To confirm reproducibility, genotyping was repeated for 10% of the samples yielding 100% identity. ABCB1/rs1045652 [45] [46] [47] [48], ABCB1/rs1128503 [49], ABCG2/rs2231142 [50] [51] [52], ABCG2/rs2231137 [53],ABCG2/rs2622604 [53], ABCC2/rs2273697[54], ABCC2/17222723 [55] and ABCC2/rs717620 [54] were all selected based on their documented functionality from a literature search; and ABCG2/rs3789243 was chosen based on its association with inflammatory bowel disease [56], CRC [29] and low mRNA levels in morphologically normal intestinal tissue from patients with adenoma [24]. "
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    ABSTRACT: The ATP-binding cassette (ABC) transporter family transports various molecules across the enterocytes in the gut protecting the intestine against potentially harmful substances. Moreover, ABC transporters are involved in mucosal immune defence through interaction with cytokines. The study aimed to assess whether polymorphisms in ABCB1, ABCC2 and ABCG2 were associated with risk of colorectal cancer (CRC) and to investigate gene-environment (dietary factors, smoking and use of non-steroidal anti-inflammatory drugs) and gene-gene interactions between previously studied polymorphisms in IL1B and IL10 and ABC transporter genes in relation to CRC risk. We used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort. Incidence rate ratios were calculated based on Cox' proportional hazards model. None of the polymorphisms were associated with CRC, but ABCB1 and ABCG2 haplotypes were associated with risk of CRC. ABCB1/rs1045642 interacted with intake of cereals and fiber (p-Value for interaction (Pint) = 0.001 and 0.01, respectively). In a three-way analysis, both ABCB1/rs1045642 and ABCG2/rs2231137 in combination with IL10/rs3024505 interacted with fiber intake in relation to risk of CRC (Pint = 0.0007 and 0.009). Our results suggest that the ABC transporters P-glycoprotein/multidrug resistance 1 and BRCP, in cooperation with IL-10, are involved in the biological mechanism underlying the protective effect of fiber intake in relation to CRC. These results should be replicated in other cohorts to rule out chance findings.
    Full-text · Article · Jun 2015 · Scandinavian Journal of Gastroenterology
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