ABCC2 p.Val471Ile
| Predicted by SNAP2: | A: D (53%), C: N (66%), D: D (80%), E: D (80%), F: D (63%), G: D (75%), H: D (80%), I: N (93%), K: D (85%), L: N (66%), M: D (59%), N: D (75%), P: D (80%), Q: D (80%), R: D (85%), S: D (71%), T: D (59%), W: D (80%), Y: D (75%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D, |
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[hide] Signatures of recent positive selection at the ATP... Hum Mol Genet. 2007 Jun 1;16(11):1367-80. Epub 2007 Apr 5. Wang Z, Wang J, Tantoso E, Wang B, Tai AY, Ooi LL, Chong SS, Lee CG
Signatures of recent positive selection at the ATP-binding cassette drug transporter superfamily gene loci.
Hum Mol Genet. 2007 Jun 1;16(11):1367-80. Epub 2007 Apr 5., [PMID:17412754]
Abstract [show]
Members of the ATP-binding cassette (ABC) superfamily of transporters have been implicated as major players in drug response. Single nucleotide polymorphisms (SNPs) in the ABC transporter genes may account for variation in drug response between individuals. Given the abundance of SNPs within the human genome, identification of functionally important SNPs is difficult. Here, we utilized signatures of recent positive selection (RPS) to identify SNPs in ABC genes that have potential functional significance by using the long-range-haplotype test to search for signatures of RPS at 18 ABC genes involved in drug transport. From the genotype data of these 18 ABC genes in four populations extracted from the HapMap database, at least one SNP in each of these genes displayed genomic signatures of RPS in at least one population. However, only 13 SNPs in 10 ABC genes from three populations retained statistical significance after Type I error reduction. The functional significance of six of these RPS SNPs, including those that failed multiple testing correction (MTC), has been reported previously. We experimentally confirmed a functional effect for two SNPs, including one that failed to show evidence of RPS after MTC. These observations suggest that Type I error reduction may inadvertently increase Type II error. Although the remaining positively selected SNPs have yet to be functionally validated, our study illustrates the feasibility of using this strategy to identify SNPs within 'adaptive' genes that may confer functional effect, prior to testing their roles in individual/population drug response variation or in complex disease susceptibility.
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196 The exonic SNP e10/G1249A, which involves a conservative amino acid change (V471I), was reported to result in decreased ABCC2 mRNA expression in preterm babies (56).
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ABCC2 p.Val471Ile 17412754:196:76
status: NEW195 The exonic SNP e10/G1249A, which involves a conservative amino acid change (V471I), was reported to result in decreased ABCC2 mRNA expression in preterm babies (56).
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ABCC2 p.Val471Ile 17412754:195:76
status: NEW[hide] Implications of genetic polymorphisms in drug tran... Cancer Lett. 2006 Mar 8;234(1):4-33. Epub 2006 Feb 28. Kerb R
Implications of genetic polymorphisms in drug transporters for pharmacotherapy.
Cancer Lett. 2006 Mar 8;234(1):4-33. Epub 2006 Feb 28., [PMID:16504381]
Abstract [show]
Drug transporters are increasingly recognized as a key determinant of drug disposition and response. It is now widely appreciated that expression of the ATP-dependent efflux transporter, MDR1 (ABCB1, P-glycoprotein), in organs such as the gastrointestinal tract, liver and kidney significantly alters the extent of drug absorption and excretion. Moreover, expression of MDR1 at the level of the blood-brain barrier limits the entry of many drugs into the central nervous system. Given such an important role of MDR1 in the drug disposition process, it is not surprising to see increasing focus on the role of single nucleotide polymorphisms (SNPs) in this transporter as a potential determinant of interindividual variability in drug disposition and pharmacological response. However, drug transport is often the result of the concerted action of efflux and uptake pumps located both in the basolateral and apical membranes of epithelial cells. A growing list of membrane-spanning proteins involved in the in- or outward transport of a large variety of drugs has been recognized and characterized over the past few years in almost all tissues, including organic anion and cation transporters (OAT, OCT, solute carrier family SLC22A), organic anion transport proteins (OATP, solute carrier family SLCO, formerly SLC21A), and MRPs (ABCCs), other members of the ATP-binding cassette family. We are just beginning to appreciate their role for drug delivery and disposition and the contribution of genetic polymorphisms in these transport proteins to interindividual variability in the efficacy and safety for pharmacotherapy. This review summarizes the consequences of inherited differences in drug transport for pharmacotherapy. With the main focus on ABCB1, an update of recent advances is given and clinically relevant examples are used to illustrate how heritable differential drug transport can help to explain individual variability in drug response. The pharmacogenetics of other transporters is briefly introduced.
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209 Nonsynonymous SNPs that occur with a frequency of clearly more than 1% have only reported for ABCC2: Val471Ile (1249GOA; 14% in African American,13% in Asian,and 24% in Caucasian), Phe981Leu (2943COG; 4% in Caucasian), and Cys1515Tyr (4544GOA; 2% in Caucasian), as well as for ABCC3, His68Tyr (202COT; 2% in Caucasian) and Arg1297His (3890GOA, 5% in Caucasian).
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ABCC2 p.Val471Ile 16504381:209:101
status: NEW[hide] ABC transporters in human lymphocytes: expression,... Expert Opin Drug Metab Toxicol. 2010 May;6(5):571-89. Giraud C, Manceau S, Treluyer JM
ABC transporters in human lymphocytes: expression, activity and role, modulating factors and consequences for antiretroviral therapies.
Expert Opin Drug Metab Toxicol. 2010 May;6(5):571-89., [PMID:20367109]
Abstract [show]
IMPORTANCE OF THE FIELD: ATP-binding cassette (ABC) transporters are a superfamily of efflux pumps that transport numerous compounds across cell membranes. These transporters are located in various human tissues including peripheral blood cells, in particular lymphocytes, and present a high variability of expression and activity. This variability may affect the intracellular concentrations and efficacy of drugs acting within lymphocytes, such as antiretroviral drugs. AREAS COVERED IN THIS REVIEW: This review focuses on the current knowledge about the expression, activity, roles and variability of ABC drug transporters in human lymphocytes. The identified modulating factors and their impact on the intracellular pharmacokinetics and efficacy of antiretroviral drugs are also detailed. WHAT THE READER WILL GAIN: Controversial data regarding the expression, activity and sources of variability of ABC transporters in lymphocytes are discussed. The modulating factors and their pharmacological consequences regarding antiretroviral therapies are also provided. TAKE HOME MESSAGE: Numerous studies have reported conflicting results regarding the expression and activity of ABC drug transporters in lymphocytes. Despite these discrepancies, which may partly result from heterogeneous analytical methods, ABCC1 appears to have the highest expression in lymphocytes and may thus play a predominant role in the resistance to antiretroviral drugs, particularly to protease inhibitors.
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192 The most frequent, considered as 'common`, are the -24C > T polymorphism in the 5'-UTR region (allelic frequency: 18% of Caucasians), the non-synonymous 1249 G > A polymorphism (V471I, 21% of Caucasians) and the silent polymorphism 3972C > T (34% of Caucasians) [94].
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ABCC2 p.Val471Ile 20367109:192:178
status: NEW193 The V471I polymorphism did not modify the in vitro activity of the transporter [95].
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ABCC2 p.Val471Ile 20367109:193:4
status: NEW[hide] Genetic Variations of ABCC2 Gene Associated with A... Genomics Inform. 2013 Dec;11(4):254-62. doi: 10.5808/GI.2013.11.4.254. Epub 2013 Dec 31. Yi JH, Cho YJ, Kim WJ, Lee MG, Lee JH
Genetic Variations of ABCC2 Gene Associated with Adverse Drug Reactions to Valproic Acid in Korean Epileptic Patients.
Genomics Inform. 2013 Dec;11(4):254-62. doi: 10.5808/GI.2013.11.4.254. Epub 2013 Dec 31., [PMID:24465238]
Abstract [show]
The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p = 0.0057) and the GG genotype (61.0% vs. 39.7%, p = 0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p = 0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs.
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95 The frequency of haplotype 3 was higher in ID ߜ1774 Gdel ߜ1549 G/A ߜ24C/T ߜ23G/A V471I T486I 2620+ 3A/G 2934 G/A 3972C/ T 4147&#ff0d; 35G/A 4508+ 12G/A Group Control CNS ADR -Yes CNS ADR -No 1 del G C G V C A G C G G 69 (31.3) 13 (15.8) 82 (32.3)** 2 G G C G V C A G C G G 54 (24.4) 24 (29.0) 65 (25.7) 3 G A T G V C A G T G G 31 (14.2) 18 (22.3)* 29 (11.4) 4 G G C G I C A G C G G 19 (8.7) 8 (9.3) 17 (6.7) 5 G G T G V C A G T G G 4 (1.7) 9 (10.6) 25 (9.8) ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; ľd; Total 220 82 254 Values are presented as number (%).
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ABCC2 p.Val471Ile 24465238:95:107
status: NEW