ABCMdb

ABCC1 p.Ala893Ser

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Publications

PMID: 12960109 [PubMed] Mathijssen RH et al: "Irinotecan pathway genotype analysis to predict pharmacokinetics."

No. Sentence Comment

136 Table 4 Genotype and Allele frequencies for the studied genes Polymorphisma Nomenclature Descriptionb Genotype frequenciesc Allele frequencies (95% CI)d Wt Het Var p q r ABCB1 1236 CϾT n/ae G411G 23 15 8 0.66 (0.52-0.78) 0.34 (0.22-0.48) ABCB1 3435 CϾT n/a E1143E 16 35 8 0.57 (0.44-0.69) 0.43 (0.31-0.56) ABCB1 2677 GϾT/A n/a A893S or T 12 23/4 13/1 0.48 (0.35-0.61) 0.47 (0.34-0.60) 0.05 (0.02-0.14) ABCC1 14008 GϾA n/a intron 27 32 27 5 0.71 (0.59-0.81) 0.29 (0.19-0.41) ABCC1 462 CϾT n/a P154P 65 0 0 1.00 0.00 ABCC1 34215 CϾG n/a intron 18 0 20 40 0.17 (0.1-0.28) 0.83 (0.72-0.90) ABCC2 156231 AϾG n/a intron 3 65 0 0 1.00 0.00 ABCG2 623TϾC n/a F208S 63 0 0 1.00 0.00 CES1 1440 AϾT n/a L480F 64 0 0 1.00 0.00 CES1 1525 AϾC n/a N509H 60 1 0 0.99 (0.92-1) 0.01 (0-0.08) CES2 1647 CϾT n/a L549L 56 1 0 0.99 (0.92-1) 0.01 (0-0.08) CYP3A4 -392 AϾG CYP3A4*1B Promoter 46 3 0 0.97 (0.88-0.99) 0.03 (0.01-0.12) CYP3A4 15713 TϾC CYP3A4*2 S222P 39 0 0 1.00 0.00 CYP3A4 23172 TϾC CYP3A4*3 M445T 62 2 0 0.98 (0.91-1) 0.02 (0-0.09) CYP3A5 22893 GϾA CYP3A5*3C Splice variant 56 8 0 0.94 (0.85-0.98) 0.06 (0.02-0.15) CYP3A5 30597 GϾA CYP3A5*6 Splice variant 63 0 0 1.00 0.00 UGT1A1 (TA)n f UGT1A1*28 Promoter 34 22 2 0.78 (0.66-0.87) 0.22 (0.13-0.34) UGT1A1 1456 TϾG UGT1A1*7 Y486D 62 0 0 1.00 0.00 XRCC1 26304 CϾT n/a R194W 35 8 0 0.91 (0.79-0.96) 0.09 (0.04-0.21) XRCC1 27466 GϾA n/a R280H 60 2 0 0.98 (0.91-1) 0.02 (0-0.09) XRCC1 28152 GϾA n/a R399Q 25 27 5 0.68 (0.55-0.79) 0.32 (0.21-0.45) a Number represents position in nucleotide sequence. Login to comment

PMID: 15229462 [PubMed] Sparreboom A et al: "Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype."

No. Sentence Comment

56 Frequencies for studied variant genes and genotype-phenotype relationships Polymorphism and nomenclature Effect Allele frequencies Ratio (q/p) for intravenous AUC Ratio (q/p) for oral AUC p q Value† P value Value† P value ABCG2 421CϾA Q141K 0.88 0.12 2.98 .015 1.15 .74 ABCC2-24CϾT 5'-UTR 0.89 0.11 0.868 .82 0.890 .78 ABCC2 1249GϾA V417I 0.86 0.14 1.06 .92 2.10 .063 ABCC2 156231AϾG Intron 3 1.00 0.00 NA NA NA NA ABCB1 1236CϾT‡ (ABCB1*8§) G411G 0.40 0.60 0.877 .82 0.585 .31 ABCB1 2677GϾA/T࿣ (ABCB1*7§) A893S/T 0.63 0.34/0.03 0.784 .61 1.27 .55 ABCB1 3435CϾT‡ (ABCB1*6§) I1145I 0.45 0.55 0.978 .97 0.955 .93 CYP3A4 -392AϾG (CYP3A4*1B) Promotor 0.91 0.09 0.731 .63 0.834 .75 CYP3A4 15713TϾC‡ (CYP3A4*2) S222P 1.00 0.00 NA NA NA NA CYP3A4 23172TϾC (CYP3A4*3) M445T 1.00 0.00 NA NA NA NA CYP3A5 22893GϾA‡ (CYP3A5*3) Splice Variant 0.86 0.14 0.808 .77 0.813 .76 CYP3A5 30597GϾA (CYP3A5*6) Splice Variant 1.00 0.00 NA NA NA NA AUC, Area under plasma concentration-time curve normalized to dose (ie, observed AUC/dose in milligrams); NA, not available. Login to comment

PMID: 15882131 [PubMed] Lepper ER et al: "Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2."

No. Sentence Comment

90 A detailed analysis of the potential functional consequences of different ABCB1 variants has not yet been performed, except for the five most common non-synonymous coding SNPs (i.e., Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser/Thr, and Ala998Thr) as assessed by a vaccinia virus-based transient expression system [74]. Login to comment
126 In addition to the possible decrease in expression levels, ATPase activity in the ABCG2 +24 Intron 20 G A +40 Intron 20 C T 2547 Exon 21 A G 849 Ile to Met 2650 Exon 21 C T 884 Syn 2677 Exon 21 G T 893 Ala to Ser 2677# Exon 21 G A 893 Ala to Thr +31 Intron 22 G A 2956 Exon 24 A G 986 Met to Val 2995 Exon 24 G A 999 Ala to Thr 3151 Exon 25 C G 1051 Pro to Ala 3320 Exon 26 A C 1107 Gln to Pro 3322 Exon 26 T C 1108 Trp to Arg 3396 Exon 26 C T 1132 Syn 3421 Exon 26 T A 1141 Ser to Thr 3435** Exon 26 C T 1145 Syn 3751 Exon 28 G A 1251 Val to Ile 3767 Exon 28 C A 1256 Thr to Lys 4030 Exon 28 G C Non-coding 4036 Exon 28 A G Non-coding +21 Intron 28 T C Table 2. Summary of common genetic variants in the ABCB1 gene (continued) *cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number M14758 with an A as the reference at position 43. Login to comment
93 One of the tested SNPs, the ABCB1 G2677T/A [75], contains a tri-allelic polymorphism (with G at nucleotide 2677 found in the wild-type sequence, and with A or T at that position being the two possible variants), which results in an amino acid change in exon 21 (Ala893Ser/Thr). Login to comment

PMID: 16766035 [PubMed] Cascorbi I et al: "Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs."

No. Sentence Comment

706 Mickley et al. (1998) discovered 2 non-synonymous SNP, a 2677G>T transversion in exon 21 and a 2995G>A transition in exon 24 of ABCB1 leading to an A893S and A999T exchanges, respectively. Login to comment
732 Since 3435C>T is linked with 2677G>T/A, leading to an A893S/T amino acid exchange, it was speculated whether this SNP could be causal for P-gp activity. Login to comment
737 Very recently, significantly differences of A893S/T- overexpressing membrane vesicles from Sf9 insect cells for vincristin could be observed. Login to comment
761 0.09d c. 61 A>G N21D 0.11d IVS 5-35 G>C intronic 0.006c IVS 5-25 G>T intronic 0.16c IVS 6+139 C>T intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T synonymous 0.41d IVS 12+44 C>T intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17-76 T>A intronic 0.46d IVS 17+137 A>G intronic 0.006c c. 2650 C>T synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T synonymous 0.54e c. 4030 G >C synonymous 0.005b c. 4036 A>G synonymous 0.30b a Taniguchi et al. (2003). Login to comment
821 In essence, further studies on ABCB1 polymorphisms confirmed these associations for 2677G>T/A (Ala893Ser/ Thr) or special ABCB1 haplotype constellations (Brant et al., 2003; Potocnik et al., 2004; Ho et al., 2006). Login to comment

PMID: 17323126 [PubMed] Huang Y et al: "Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy."

No. Sentence Comment

124 Moreover, Letourneau et al. examined 10 non-synonymous ABCC1 SNPs to determine Table 2 Summary of genetic variants in ABC transporters ABCB1, ABCC1, ABCC2 and ABCG2 involved in cancer chemotherapy Variants (location, effect) Phenotype Drug Sample Reference ABCB1 +103T>C (5'flanking, non-coding) Increased transcription Doxorubicin vincristine osteosarcoma Stein et al., 1994 [19] +8T>C (5'flanking, non-coding) Unknown Leukemia Rund et al., 1999 [21] 1236C>T (exon12, synonymous) Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Higher exposure Irinotecan, SN-38 Cancer patients Mathijssen et al., 2003 [45] 2677G>T/A (exon21, A893S/T) Lower expression placenta Tanabe et al., 2001 [42] Lower expression placenta Hitzl et al., 2004 [37] Higher expression AML blasts Illmer et al., 2002 [47] Allele specific expression Cell lines, lymphoma Mickley et al., 1998 [22] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Survival leukemia Illmer et al., 2002 [47] Survival leukemia van den Heuvel-Eibrink et al., 2001 [48] Worse survival AML blasts Kim et al., 2006 [10] Higher efficacy Paclitaxel Ovarian cancer Green et al., 2006 [50] 2995G>A (exon24, A999T) None Cell lines, lymphoma Mickley et al., 1998 [22] 3435C>T (exon26, synonymous) Lower expression Duodenal protein Hoffmeyer et al., 2000 [26] Lower expression placenta Hitzl et al., 2004 [37] Higher expression Intestine mRNA Nakamura et al., 2002 [32] Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Lower efflux Digoxin CD56+ NK cells Hitzl et al., 2001 [27] Higher plasma level Digoxin Healthy volunteers Hoffmeyer et al., 2000 [26] Higher AUC Cyclosporin transplant patients Bonhomme-Faivre et al., 2004 [36] Lower CNS relapse Cancer patients Stanulla et al., 2005 [46] Better survival leukemia Illmer et al., 2002 [47] Higher efficacy Breast cancer Kafka et al., 2003 [49] Higher activity, worse survival AML Kim et al., 2006 [10] Better survival Platinums Esophageal cancer Wu et al., 2006 [43] No difference Docetaxel patients Puisset et al., 2004 [41] No difference Irinotecan Cancer patients Mathijssen et al., 2004 [39] No difference Vincristine patients Plasschaert et al., 2004 [40] No difference colon Taniguchi et al., 2003 [24] ABCC1 -260G>C (5'flanking, non-coding) Higher activity Transfected cell line Wang et al., 2005 [62] Table 2 (Continued) Variants (location, effect) Phenotype Drug Sample Reference 128G>C (exon2, C43S) Reduced resistance Vincristine, arsenite Transfected cell line Leslie et al., 2003 [60] 1299G>T (exon10, R433S) Reduced transport of LTC4, increased resistance to doxorubicin Leukotriene C4, doxorubicin Transfected cell line Conrad et al., 2002 [59] 2012G>T (exon16, G671V) No change in activityLeukotriene C4 Transfected cell line Conrad et al., 2001 [58] Heart toxicity Doxorubicin nLon-Hodgkin lymphoma Wojnowski et al., 2005 [63] 2965G>A (exon22, A989T) Reduced transport Estradiol 17β-glucuronide Transfected cell line Letourneau et al., 2005 [61] ABCC2 1271A>G (exon10, R421G) Reduced drug elimination, increased nephrotoxicity Methotrexate One lymphoma patient Hulot et al., 2005 [79] 3972C>T (exon28, nonsynonymous) Reduced drug clearance Irinotecan Cancer patients Innocenti et al., 2004 [80] ABCG2 376C>T (exon4, Q126stop) Reduced transport Porphyrin Trensfected cell Tamura et al., 2006 [104] 421C>A (exon5, Q141K) Lower expression Transfected cell lines Imai et al., 2002 [94] Lower expression Transfected cell lines Kondo et al., 2004 [95] Lower expression Placenta Kobayashi et al., 2005 [98] Reduced ATPase activity Trensfected cell lines Mizuarai et al., 2004 [97] Higher plasma levels Diflomotecan patients Sparreboom et al., 2004 [100] Increased bioavailability Topotecan patients Sparreboom et al., 2005 [101] Increased bioavailability 9-Aminocamptothecin patients Zamboni et al., 2006 [81] Increased drug accumulation Imatinib Transfected cell lines Gardner et al., 2006 [96] Increased drug accumulation Topotecan Trensfected cell lines Imai et al., 2002 [94] No difference Imatinib patients Gardner et al., 2006 [96] No difference intestine Zamber et al., 2003 [99] No difference MTX Trensfected cell lines Kondo et al., 2004 [95] the effects on expression and function of this transporter in transfected HEK293T cells [61]. Login to comment
57 2677G>T in exon 21 and 2995G>A/T in exon 24 were reported by Mickley et al. [22], leading to amino acid changes of A893S and A999T, respectively. Login to comment

PMID: 18154452 [PubMed] Sharom FJ et al: "ABC multidrug transporters: structure, function and role in chemoresistance."

No. Sentence Comment

300 The first SNP reported for human Pgp was the G2677T variant, which is a nonsynonymous SNP resulting in a change in the coding sequence, A893S. Login to comment
303 One common haplotype includes the SNPs C1236T (exon 12, synonymous), G2677T (exon 21, nonsynonymous, A893S) and C3435T (exon 26, synonymous), and is found frequently in European Americans, whereas C1236C-G2677T-C3435C haplotype is common in Africans [135]. Login to comment
312 However, the nonsynonymous mutations of G2677T/A/C, which result in the amino acid changes A893S, A893T and A893P, gave changes in both substrate specificity and ATPase kinetic properties as measured with 41 different test compounds [139]. Login to comment

PMID: 19200005 [PubMed] Porcelli L et al: "Intracellular trafficking of MDR transporters and relevance of SNPs."

No. Sentence Comment

227 [112] reported that the C3435T, as well as the synonymous C1236T (G411G) and the nonsynonymous G2677T (A893S) polymorphisms were expressed at equivalent levels at the cell surface. Login to comment
228 Similar results for the A893S SNP were reported by Kimchi-Sarfaty et al. Login to comment
229 [113], who showed that HeLa cells transfected with either the wild-type or the ABCB1 polymorphisms A61G (N21D), T307C (F103L), G1199A (S400N), G2677T (A893S) and G2995A (A998T) expressed the transporter at the cell surface. Login to comment
230 Additionally, cells transfected with double mutants (N21D-S400N, N21D-A893S, and S400N-A893S) revealed similar ABCB1 cell surface expression [113]. Login to comment

PMID: 19949922 [PubMed] Cascorbi I et al: "Pharmacogenetics of ATP-binding cassette transporters and clinical implications."

No. Sentence Comment

52 Functional Significance of ABCB1 SNPs Table6.3 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies (134) Position Amino acid or effect Frequency of the variant allele 5'-Flanking -2903 T>C 0.02a 5'-Flanking -2410 T>C 0.10a 5'-Flanking -2352 G>A 0.28a 5'-Flanking -1910 T>C 0.10a 5'-Flanking -1717 T>C 0.02a 5'-Flanking -1325 A>G 0.02a 5'-Flanking -934 A>G 0.10a 5'-Flanking -692 T>C 0.10a 5'-Flanking -41 A>G 0.09b IVS 1a -145 C>G 0.02b IVS 1b -129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 -1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 -35 G>C Intronic 0.006c IVS 5 -25 G>T Intronic 0.16c IVS 6 +139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T Synonymous 0.41d IVS 12 +44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 -76 T>A Intronic 0.46d IVS 17 +137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d c. 4030 Synonymous 0.005b c. 4036 Synonymous 0.30b References: a [42], b [26], c [25], d [28], e [23] with lower activity or expression in Caucasians. Login to comment
76 Table6.4 Functional significance of ABCB1 genetic variants and relevance for clinical outcome Position Amino acid exchange Effect of variant 5'-Flanking -2410 T>C Decreased mRNAa 5'-Flanking -692 T>C Decreased mRNAa c. 571 G>A G191R Reduced chemotherapy resistanceb c. 1199 G>A S400N Elevated activityc c. 1236 C>T Synonymous Increased imatinib disposition and therapy responsed c. 2677 G>T/A A893S/T In vitro increased vmax ,q no effect on vincristine,e increased imatinib response in CMLd c. 3435 C>T Synonymous Decreased mRNA and protein expression,f, g decreased invitro transport,h no effect on expression and bioavailability of talinolol,i no effect on invitro transport,j, k decreased digoxin bioavailability,l increased etoposid disposition,m no effect on AML or ALL outcome,k better prognosis of multiple myeloma,n better chemotherapy response in breast cancer,o no effect in colon cancerp References: a [42], b [69], c [38], d [53], e [51], f [23], g [64], h [31], i [39], j [135], k [65-67], l [40, 41], m [52], n [68], o [74], p [70, 71], q [36] As mentioned earlier, the first systematic study on ABCB1 genetic variability and its association to expression and bioavailability was the first one, showing an association of 3435C>T with digoxin plasma levels. Login to comment
59 The missense variant 2677G>T/A coding for the three different amino acids A893S/T exhibits altered transport properties in membrane vesicles from Sf9 insect cells, overexpressing human ABCB1. Login to comment

PMID: 19950006 [PubMed] Sissung TM et al: "Pharmacogenetics of membrane transporters: an update on current approaches."

No. Sentence Comment

45 There are three single-nucleotide polymorphisms (SNPs) that are common in most ethnic groups and demonstrate strong linkage disequilibrium: the synonymous transition at nucleotide 1236C[T (Gly411Gly) in exon 12, the non-synonymous tri-allelic transition 2677G[T/A (Ala893Ser/ Thr) in exon 21, and the synonymous transition 3435C[T (Ile1145Ile) in exon 26. Login to comment
46 Of these SNPs, only the 2677G[T/ A (Ala893Ser/Thr) transition causes an amino acid change within a structurally important transmembrane domain of the translated protein, and the effects of this transition are controversial and drug-specific [15, 22, 28-30]. Login to comment
82 Many of the recent publications regarding transporter genotyping have utilized restriction fragment length polymorphism (RFLP) analysis or direct sequencing, although several other methods of genotyping are available such as resequencing, allele-specific PCR, TaqMan PCR, Fluorescence Resonance Energy Transfer (FRET), etc. Table 2 includes polymerase chain reaction (PCR) and direct Table 2 Primers used to amplify selected polymorphisms in the ABCB1, ABCG2, OATP1B1, and OATP1B3 genes Transporter polymorphism Forward primer Reverse primer Ref. ABCB1 1236C[T PCR amplification 50 -GGCACAAACCAGATAATATTAAGG-30 50 -TATCCTGTCCATCAACACTGACC-30 # Nested PCR 50 -GTTCACTTCAGTTACCCATCTCG-30 50 -TCCTGTCCATCAACACTGACCTG-30 # Sequencing PCR 50 -GTCAGTTCCTATATCCTGTGTCTG-30 50 -TCGCATGGGTCATCTCACCATC-30 # ABCB1 2677G[T/A (A893S/T) PCR amplification 50 -AGGCTATAGGTTCCAGGCTTGC-30 50 -AGAACAGTGTGAAGACAATGGCC-30 # Nested PCR 50 -CCCATCATTCGAATAGCAGGAG-30 50 -GAACAGTGTGAAGACAATGGCCT-30 # Sequencing PCR 50 -ATCCTTCATCTATGGTTGGCAAC-30 50 -TGAGTCCAAGAACTGGCTTTGC-30 # ABCB1 3435C[T PCR amplification 50 -ATCTCACAGTAACTTGGCAGTTTC-30 50 -AACCCAAACAGGAAGTGTGGCC-30 # Sequencing PCR 50 -GCTGGTCCTGAAGTTGATCTGTG-30 50 -AAACAGGAAGTGTGGCCAGATGC-30 # ABCG2 421C[T PCR amplification 50 -TGGCAAATCCTTGTATGAAGCAG-30 50 -TTCACGTACAACACCACATTGCC-30 # Sequencing PCR 50 -GCAGGTTCATCATTAGCTAGAAC-30 50 -CCTACTTATGCTGATCATGAGC-30 # OATP1B1*1b PCR amplification 50 -GCAAATAAAGGGGAATATTTCTC-30 50 -AGAGATGTAATTAAATGTATAC-30 [45] RFLP enzyme ClaI OATP1B1*5 PCR amplification 50 -GTTAAATTTGTAATAGAAATGC-30 50 -GTAGACAAAGGGAAAGTGATCATA-30 [45] Allele specific PCR primers WT 50 -CATACATGTGGATATATGT-30 N/A [45] MT 50 -CATACATGTGGATATATGC-30 D OATP1B3 334T[G (S112A) PCR amplification 50 -CCTTCACAGTTAAATTACATGGTC-30 50 -TATTCATTTCATATAAAACTGTATACC-30 # Sequencing PCR 50 -GGGCATATTTGCATTCATTTGGG-30 50 -CATGATAAATAAAGAAATACATGATG-30 # OATP1B3 699G[A (M233I) PCR amplification 50 -TCCTTGTATTTAGGTAACGTACAG-30 50 -TCAAGTTTGGTTATTTTGGATCAAG-30 # Sequencing PCR 50 -GATCTACCCTTGAAATAATAATGTC-30 50 GTAAAAGCAAAGTATAAATAGGAGC-30 # OATP1B3 1564G[T (G522C) PCR amplification 50 -ATATACAGAATTTCATACACTAATTTC-30 50 -AATTCTAAGAAAATGCATTCTCAAAG-30 # Sequencing PCR 50 -TATTTTGCCTTCACTATTAAGCAAC-30 50 -AATATGAATTTGAGCTCAAAATACAG-30 # Primers are used for direct sequencing following amplification from genomic DNA, unless otherwise indicated # Denotes previously unpublished primer sequencing PCR primers that are currently used in the field to amplify polymorphic regions of DNA. Login to comment

PMID: 11258197 [PubMed] Kerb R et al: "ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2."

No. Sentence Comment

97 SNP Region N Frequency of SNPs (%) Effect Heterozygous Homozygous Observed Estimated T-12C E1 85 11.8 0 0.4 Non-coding G-1A E2 188 11.2 0 0.4 TL initiation A61G E2 188 17.6 0.5 0.81 Asn21Asp G-25T I4 85 26 3.5 2.3 G-35C I4 85 1.2 0 0.01 # T307C E5 85 1.2 0 0.01 Phe103Leu C+139T I5 85 48.2 16.5 16.8 C+145T I5 85 2.4 0 0.01 G1199A E11 85 12.9 0 0.4 Ser400Asn C1236T E12 188 48.9 13.3 14.4 Gly412Gly # C+44T I12 188 11.7 0 0.4 T-76A I16 85 45.9 22.4 20.3 A+137G I17 85 1.2 0 0.01 G2677T E21 83b 43.4 42.2 38.4 Ala893Ser G2995A E24 36b 11.1 38.4 Ala999Thr C3435T E26 537 47.7 26.4 24.1 Ile1145Ile C3396T E26 188 0.53 0 0.01 Wobble § MDR1 sequences gb:AC002457 and AC005068 are defined as 'wild type`. Login to comment

PMID: 12392094 [PubMed] Moriya Y et al: "Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects."

No. Sentence Comment

46 These results suggested that the higher MDR1 expression in the duodenum was associated with the lower plasma concentration of fexofenadine and serum concentration of digoxin after single oral administration in subjects with the mutant T-allele at position 3435.9,10) The silent mutation C3435T has been suggested to be linked with the missense G2677(A,T) producing Ala893Thr and Ala893Ser, respectively.9,11) In the present study, the mutations T-129C, G2677(A,T) and C3435T of the MDR1 gene were found at allele frequencies of 2/26, 16/26 and 12/26, respectively, and 3 of 5 subjects with C/C3435 were accompanied with G/G2677 , and 3 of 4 subjects with T/T3435 were accompanied with T/T2677 , probably due to linkage between positions 3435 and 2677 in the MDR1 gene (Table 1). Login to comment

PMID: 16041239 [PubMed] Colombo S et al: "Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo."

No. Sentence Comment

101 or Ref sequence; locus Frequencies Fold-increase of nelfinavir AUCintracell Significance AA Aa aa Aa2 AA Aa aa Aa2 chi-squared P-value ABCB1 IVS 1 - 80delG rs3214119 27 1 1 1.0 0.03 0.85 c.61A > G (N21D) rs9282564 26 2 1 2.5 3.85 0.05 TAG1 rs3789243 7 17 3 1 0.8 0.6 1.23 0.54 c.1199G > A (S400N) rs2229109 24 2 1 0.9 0.62 0.43 TAG5 rs1128503 4 18 5 1 0.8 1.3 3.33 0.19 TAG6 rs2235046 6 18 3 1 0.6 0.7 4.43 0.11 c.2677G > T (A893S) rs2032582 4 17 5 1 1 1.0 1.7 1.2 6.42 0.09 IVS 21 + 49T > C rs2032583 19 8 1 0.6 3.45 0.06 TAG8, 3435C > T rs1045642 4 18 6 1 1.4 2.1 6.35 0.04 IVS 26 + 59T > G rs2235047 24 2 1 1.0 0.02 0.89 IVS 26 + 80T > C rs2235048 3 17 6 1 1.3 2.4 7.09 0.03 TAG11 rs1186746 16 10 1 1 1.1 0.3 2.46 0.29 TAG12 rs1186745 17 9 1 1 0.7 1.0 0.33 0.85 ABCC1 c.816G > A NM_004996; c.1012G > A 27 1 1 1.5 1.05 0.30 c.825T > C rs246221 13 11 3 1 1.5 0.7 3.99 0.14 c.1062T > C rs35587 13 11 3 1 1.5 0.7 3.02 0.22 IVS 9 + 8A > G rs35588 13 11 3 1 1.5 0.7 3.02 0.22 IVS 10 + 64C > T NC_000016; g.98791C > T 23 3 1 0.4 1.97 0.16 ABCC2 g. Login to comment
70 2650C > T exon 21 synonymous (p.L884L) Kim et al., 2001 md-v-110 rs9282563 c.2677G > T exon 21 p.A893S Kim et al., 2001 md-v-031 rs2032582 c.2677G > A exon 21 p.A893T Kim et al., 2001 md-v-109 IVS 21 + 14 - 17 delAATA intron 21 Epidauros md-v-092 IVS 21 + 49 T > C intron 21 Epidauros md-v-042 rs2032583 IVS 21 + 66 T > C intron 21 Epidauros md-v-108 IVS 26 - 156 T > C intron 25 Epidauros md-v-095 IVS 26 - 68 A > G intron 25 Epidauros md-v-164 c.3320A > C exon 26 p.Q1107P Cascorbi et al., 2002 md-v-033 c.3322T > C exon 26 p.W1108R Kroetz et al., 2003 md-v-225 c.3325C > T exon 26 p.L1109F Epidauros md-v-165 c 3364C > T exon 26 synonymous (p.A1132A) Hoffmeyer et al., 2000 md-v-034 c.3321T > A exon 26 p.S1141T Kim et al., 2001 md-v-035 c.3435C > T (Tag8) exon 26 synonymous (p.I1145I) Hoffmeyer et al., 2000 md-v-036 rs1045642 IVS 26 + 59 T > G intron 26 Epidauros md-v-097 rs2235047 IVS 26 + 80 T > C intron 26 Epidauros md-v-040 rs2235048 IVS 26 + 123_24 insCATG intron 26 Epidauros md-v-096 Tag 11 intron 27 Soranzo et al., 2004 rs1186746 Tag 12 intron 27 Soranzo et al., 2004 rs1186745 MRP1 (ABCC1) c.816G > A exon 8 synonymous (p.P272P) Epidauros mr-v-014 c.825T > C exon 8 synonymous (p.V275V) Saito et al., 2002 mr-v-015 rs246221 c.1062T > C exon 9 synonymous (p.N354N) Saito et al., 2002 mr-v-016 rs35587 c.1068G > A exon 9 synonymous (p.T356T) Epidauros mr-v-057 rs8187852 IVS 9 + 8 A > G intron 9 Saito et al., 2002 mr-v-017 rs35588 c.1303G > T exon 10 p.R433S Conrad et al., 2002 mr-v-018 IVS 10 + 64 C > T intron 10 Epidauros mr-v-019 MRP2 (ABCC2) g. Login to comment

PMID: 18851956 [PubMed] Rebecchi IM et al: "ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment."

No. Sentence Comment

26 The G2677T/A/C (rs2032582) is a non-synonymous polymorphism in the exon 21 with three distinct amino acid changes (Ala893Ser, Ala893Thr, and Ala893Pro, respectively) that is located at the transmembrane domain of the protein and it has a great impact on both the activity and the substrate specificity of ABCB1 toward different test compounds [10]. Login to comment

PMID: 20368717 [PubMed] Bergmann TK et al: "Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer."

No. Sentence Comment

135 This effect on clearance of a 'non-fixed` variable provides a competing and dynamic biological explanation for clearance that certainly should be Table 4 Clearance of unbound paclitaxel as function of observed genotypes Gene/allelea Effectb Reference homozygote Heterozygote Variant homozygote P-valuee SNP IDf Nc CLd (10th-90th) Nc CLd (10th-90th) Nc CLd (10th-90th) Candidate SNPs for confirmative analysis CYP2C8 1196A4G(*3) K399R 74 395 (297-490) 19 350 (238-458) 0.03* (0.04) rs10509681 ABCB1 1236C4T G412G 29 391 (270-569) 45 393 (299-490) 19 359 (291-437) 0.25 (0.25) rs1128503 2677G4T/Ag A893S/T 26 387 (270-490) 42(GT) 396 (299-490) 20(TT) 356 (294-437) 0.20 (0.26) rs2032582 3435C4T I1145I 11 403 (326-548) 44 387 (282-490) 38 378 (297-468) 0.83 (0.43) rs1045642 Candidate SNPs for exploratory analysis CYP2C8 792C4G(*4) I264M 86 391 (297-490) 7 321 (270-374) 0.04* (0.03) rs1058930 15577956G4T (*1B) - 49 395 (298-552) 43 373 (291-478) 1 461 0.75 (0.36) rs7909236 15578055A4C (*1C) - 69 382 (291-478) 24 393 (300-552) 0.48 (0.62) rs17110453 ABCB1 À1A4G - 1 458 29 396 (270-592) 63 379 (297-477) 0.56 (0.3) rs2214102 61A4G N21D 63 384 (282-490) 29 386 (298-478) 1 437 0.52 (0.77) rs9282564 1199G4A S400N 83 385 (291-490) 10 386 (322-461) 0.74 (0.99) rs2229109 CYP3A4 24616372T4C (*1B) - 85 383 (296-490) 7 397 (270-641) 0.67 (0.72) rs2740574 CYP3A5 219-237G4A Frameshift 84 388 (297-490) 9 360 (176-726) 0.30 (0.36) rs776746 SLCO1B3 699G4A M233I 1 326 19 377 (299-481) 73 388 (291-490) 0.99 (0.46) rs7311358 767G4C G256A 67 386 (298-481) 26 383 (291-490) 0.63 (0.89) rs60140950 CYP1B1 1294C4G (*3) V432L 30 389 (270-530) 36 401 (298-490) 27 361 (300-470) 0.77 (0.24) rs1056836 ABCC1 7356253C4G - 65 394 (297-548) 27 368 (291-470) 1 332 0.04* (0.15) rs504348 ABCC2 1249G4A V417I 67 381 (291-490) 24 396 (297-552) 2 415 (368-468) 0.21 (0.39) rs2273697 3563T4A V1188E 87 386 (296-490) 5 370 (176-569) 0.7 (0.7) rs17222723 4544G4A C1515Y 75 389 (296-490) 3 355 (176-569) 0.72 (0.52) rs8187710 ABCG2 421C4A Q141K 61 374 (291-478) 32 408 (315-548) 0.4 (0.09) rs2231142 34G4A V12M 87 385 (291-490) 4 395 (296-726) 0.68 (0.83) rs2231137 ABCC10 2759T4C I920T 46 386 (297-478) 43 386 (291-548) 4 373 (326-467) 0.88 (0.89) rs2125739 Abbreviations: CL, clearance of unbound paclitaxel; SNP, single-nucleotide polymorphism. Login to comment

PMID: 12357145 [PubMed] Lotsch J et al: "Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?"

No. Sentence Comment

106 33 T/T T/T MDR1 2 A61G Asn21Asp 11.2 20.6 9 A/G A/G Forward: 5Ј-AGG AGC AAA GAA GAA GAA CTT TTT TAA ACT GAT C-3Ј 9.3 17.6 8 Reverse: 5Ј-GAT TCC AAA GGC TAG CTT GC-3Ј 5 T307C Phe103Leu 0.6 1.2 9 T/T T/T Forward: 5Ј-GTG GTT GCA CAC AGT CAG CA-3Ј Reverse: 5Ј-GGA GGA TGT CTA ATT ACC TGG TCA-3Ј 11 G1199A Ser400Asn 5.5 11.1 9 G/G G/G Forward: 5Ј-CAG CTA TTC GAA GAG TGG GC-3Ј 6.5 12.9 8 Reverse: 5Ј-CCG TGA GAA AAA AAC TTC AAG G-3Ј 21 G2677T Ala893Ser 41.6 49.2 9 T/T T/T Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј 63.9 43.4 8 Reverse: 5Ј-GTT TGA CTC ACC TTC CCA G-3Ј 21 G2677A Ala893Thr 0.9 2 9 NA NA Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј Reverse: 5Ј-TTT AGT TTG ACT CAC CTT CCC G-3Ј 26 A3320C Gln1107Pro 0.2 0.4 9 A/A A/A 26 C3396T Ala1132Ala 0.3 0.5 8 C/C C/C Forward: 5Ј-ATC TGT GAA CTC TTG TTT TCA GC-3Ј 26 C3435T Ile1145Ile 50.3 47.7 8 T/T T/T Reverse: 5Ј-TCG ATG AAG GCA TGT ATG TTG-3Ј 53.9 50.5 9 - - MRP2 10 G1249A Val417Ile 12.5 20.8 34 G/G G/G Forward: 5Ј-GGG TCC TAA TTT CAA TCC TTA-3Ј Reverse: 5Ј-TAT TCT TCT GGG TGA CTT TTT-3Ј 18 C2302T Arg768Trp 1 2.1 34 C/C C/C Forward: 5Ј-GGA GTA GTG CTT AAT ATG AAT-3Ј 18 C2366T Ser789Phe 1 2.1 34 C/C C/C Reverse: 5Ј-CCC ACC CCA CCT TTA TAT CTT-3Ј 28 C3972T Ile132Ile 21.9 35.4 34 C/T C/T Forward: 5Ј-TGC TAC CCT TCT CCT GTT CTA-3Ј Reverse: 5Ј-ATC CAG GCC TTC CTT CAC TCC-3Ј 31 G4348A Ala1450Thr 1 2.1 34 G/G G/G Forward: 5Ј-AGG AGC TAA CAC ATG GTT GCT-3Ј Reverse: 5Ј-GGG TTA AGC CAT CCG TGT CAA-3Ј † Sequence is not translated. Login to comment

PMID: 12359865 [PubMed] Schwab M et al: "Genetic polymorphisms of the human MDR1 drug transporter."

No. Sentence Comment

60 In a Northern Italian population, the extent of linkage disequilibrium TABLE 2 Summary of MDR1 genetic variants in different ethnic groups Location Position Allele Effect Reference promotor 5 flanking/-41a A (28) G exon 1a exon 1a/-145 C (28) G exon 1b exon 1b/-129 T (25, 33) C intron 1 exon 2/-4 C (29) T intron 1 exon 2/-1 G initiation of translation (25, 27, 29) A exon 2 exon 2/61 A Asn21Asp (25-27, 29) G intron 4 exon 5/-35 G (25) C intron 4 exon 5/-25 G (25) T exon 5 exon 5/307 T Phe103Leu (25) C intron 6 exon 6/+139 C (25, 27) T intron 6 exon 6/+145 C (25) T exon 7 exon 7/548 A Asn183Ser (29) G exon 11 exon 11/1199 G Ser400Asn (25, 27, 29) A exon 12 exon 12/1236 C wobble (23, 25, 27, 29) T (Gly412Gly) intron 12 exon 12/+44 C (25, 27) T exon 13 exon 13/1474 C Arg492Cys (29) T intron 16 exon 17/-76 T (25, 27) A intron 17 exon 17/137 A (25) G exon 21 exon 21/2650 C wobble (29) T (Leu884Leu) (Continued ) TABLE 2 (Continued) Location Position Allele Effect Reference exon 21 exon 21/2677 G (22, 23, 27, 29) T Ala893Ser A Ala893Thr exon 24 exon 24/2956 A Met986Val (33) G exon 24 exon 24/2995 G Ala999Thr (22) A exon 26 exon 26/3320 A Gln1107Pro (27) C exon 26 exon 26/3396 C wobble (25) T exon 26 exon 26/3421 T Ser1141Thr (29, 30) A exon 26 exon 26/3435 C wobble (23, 25, 29) T (Ile1145Ile) exon 28 exon 28/4030 G (33) C exon 28 exon 28/4036 A (23, 33) G The positions of the polymorphisms correspond to positions of MDR1 cDNA with the first base of the ATG start codon set to 1 (GenBank accession # M14758). Login to comment
73 Both polymorphisms, G2677T/A and G2995A, resulting in amino acid exchanges in exon 21 (Ala893Ser/Thr) and exon 24 (Ala999Thr), respectively, are located in the second transmembrane domain, the exon G2995A polymorphism closer to the ABC domain. Login to comment
86 However, a recent publication characterized the functional consequences of five coding SNPs (Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system (40a). Login to comment

PMID: 14586389 [PubMed] Pauli-Magnus C et al: "No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects."

No. Sentence Comment

168 In the MDR1 3435CC group, 2 individuals had haplotypes encoding P-glycoprotein variants (Ala893Thr and Asn21Asp), and all subjects in the MDR1 3435TT group were at least heterozygous for a haplotype encoding for the P-glycoprotein Ala893Ser variant. Login to comment
164 Importantly, the MDR1*13 haplotype encodes the Ala893Ser change in P-glycoprotein. Login to comment

PMID: 15379652 [PubMed] Sakaeda T et al: "Pharmacogenetics of drug transporters and its impact on the pharmacotherapy."

No. Sentence Comment

84 Two amino acid substitutions, Gly185Val and Ala893Ser, were detected in MDR1 isolated from normal human adrenal glands, and the latter was suggested to reflect a genetic polymorphism. Login to comment
127 Position Location Effect A1a/-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G G5/-25T G5/-35C exon 2 intron intron Asn21Asp T307C C6/+139T exon 5 intron Phe103Leu A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T C12/+44T exon 12 intron silent C1474T T17/-76A A17/+137G exon 13 intron intron Arg492Cys C2650T exon 21 silent G2677(A,T) exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent The list was based on the reports [67,68,71-74]. Login to comment
99 It has been confirmed that C3435T is in significant linkage disequilibrium (LD) with C1236T and G2677T, the latter resulting in Ala893Ser [73,74,84-88]. Login to comment

PMID: 17001288 [PubMed] Owen A et al: "Pharmacogenetics of HIV therapy."

No. Sentence Comment

171 Pharmacogenetics of HIV therapy Owen et al. 699 Table 1 Polymorphisms that have been studied within the context of metabolism, transport and toxicity (but not progression and response) along with the reference ID (where available), the genotypic consequence and the observed phenotype for antiretroviral drugs Gene SNP (haplotype) Reference SNP Genotypic consequence Phenotypic consequence Confirmation CYP3A4 A - 392G (CYP3A4*1B) rs2740574 Promoter; altered expression No effect on nelfinavir or efavirenz Yes for nelfinavir; controversial for efavirenz T878C (CYP3A4*18) rs4986909 L293P; altered activity No effect on efavirenz No CYP3A5 A6986G (CYP3A5*3) rs776746 Splice defect No effect on nelfinavir, saquinavir or efavirenz AUC but altered urinary metabolic ratio of saquinavir Yes for efavirenz G14690A (CYP3A5*6) rs10264272 Splice defect No effect on nelfinavir or efavirenz Yes CYP2C19 G681A (CYP2C19*2) rs4244285 Truncated protein Higher nelfinavir AUC and trend toward decreased virological failure; no effect on efavirenz Yes for efavirenz; controversial for nelfinavir CYP2D6 A2549del (CYP2D6*3) NT21914757 Frameshift Trend to higher plasma levels of nelfinavir and efavirenz No G1846A (CYP2D6*4) rs3892097 Splice defect Trend to higher plasma levels of nelfinavir and efavirenz No T1707del (CYP2D6*6) rs5030655 Frameshift Higher plasma nelfinavir concentrations No CYP2B6 G516 T (CYP2B6*6, *7, *9, *13, *19 and *20) rs3745274 Q172H Higher plasma and intracellular efavirenz AUCs and increased neurotoxicity Yes, numerous studies C1459T (CYP2B6*5 and *7) rs3211371 R487C No effect on nelfinavir or efavirenz No ABCB1 IVS1 - 80delG rs3214119 N/A No influence on cellular nelfinavir No A61G rs9282564 N21D No influence on cellular nelfinavir No TAG1 rs3789243 N/A No influence on cellular nelfinavir No G1199A rs2229109 S400N No influence on cellular nelfinavir No TAG5 rs1128503 N/A No influence on cellular nelfinavir No TAG6 rs2235046 N/A No influence on cellular nelfinavir No IVS21 + T49C rs2032583 N/A No influence on cellular nelfinavir No C3435T rs1045642 Synonymous Some evidence of an influence on plasma and intracellular nelfinavir; decreased efavirenz plasma concentrations; currently under debate; increase in HDL cholesterol with efavirenz Controversial G2677T rs2032582 Ala893Ser No effect on efavirenz, ritonavir, nelfinavir, indinavir or viral decay and CD4 count Yes IVS26 + T59G rs2235047 N/A No influence on cellular nelfinavir No IVS26 + T80C rs2235048 N/A Increased intracellular nelfinavir concentrations No TAG11 rs1186746 N/A No influence on cellular nelfinavir No TAG12 rs1186745 N/A No influence on cellular nelfinavir No ABCC1 G816A P272P No influence on cellular nelfinavir No T825C rs246221 V275V No influence on cellular nelfinavir No T1062C rs35587 Synonymous No influence on cellular nelfinavir No IVS9 + A8G rs35588 N/A No influence on cellular nelfinavir No IVS10 + C64T N/A No influence on cellular nelfinavir No ABCC2 C - 24T rs717620 N/A No influence on cellular nelfinavir No G1249A rs2273697 V417I No influence on cellular nelfinavir No C1436G Synonymous No influence on cellular nelfinavir No IVS16 - G47A N/A No influence on cellular nelfinavir No T3563A rs8187694 V1188E No influence on cellular nelfinavir No C4488T rs8187707 Synonymous No influence on cellular nelfinavir No IVS31 + G12A rs8187708 N/A No influence on cellular nelfinavir No IVS31 + C74T N/A No influence on cellular nelfinavir No G4544A rs8187710 C1515Y No influence on cellular nelfinavir No G + 259T N/A No influence on cellular nelfinavir No ABCG2 - 19571_ - 19568delT- CAC rs4148162 Deletion No influence on cellular nelfinavir No A-19541G N/A No influence on cellular nelfinavir No G34A rs2231137 V12M No influence on cellular nelfinavir No IVS2 + 35G rs4148152 N/A No influence on cellular nelfinavir No C421A rs2231142 Q141K No influence on cellular nelfinavir No APOCIII C-482T Pending Promoter Hyperlipidaemia in presence of ritonavir Yes T-455C Pending Promoter Hyperlipidaemia in presence of ritonavir Yes C3238G rs5128 30 UTR variant Hyperlipidaemia in presence of ritonavir Yes APOE 2060T/2198T (APOEe2) rs429358 R112C/R158C Hyperlipidaemia in presence of ritonavir Yes 2060T/2198C (APOEe3) rs7412 R112C/R158R Hyperlipidaemia in presence of ritonavir Yes TNFa G - 238A rs361525 Promoter Rapid development of lipoatrophy Controversial SPINK-1 C112T rs17107315 N34S Associated with risk of pancreatitis Yes, in general population CFTR G1717 - 1A Splice defect Associated with risk of pancreatitis Yes, in general population IVS8 5T Splice defect Associated with risk of pancreatitis Yes, in general population HLA-B HLA-B*57.1 N/A Abacavir hypersensitivity Yes, but not in all populations HLA-DR HLA-DRB1*0101 N/A Nevirapine hypersensitivity No HSPA1L C2437T rs2227956 M493T Abacavir hypersensitivity No UGT1A1 A(TA)7TAA, - 43_ - 42in- sTA (UGT1A1*28) rs8175347 Promoter; insertion at TATA box Gilberts syndrome, hyperbilirubinaemia in presence of atazanavir and indinavir but not saquinavir Yes MT-CO1 C7028T Synonymous Haplogroup T associated with greater incidence of peripheral neuropathy No 700 Pharmacogenetics and Genomics 2006, Vol 16 No The NNRTI nevirapine can also cause a hypersensitivity syndrome characterized by a rash with systemic symptoms; occasionally liver injury may be part of the clinical picture, or alternatively, may actually be the only manifestation. 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PMID: 18058331 [PubMed] Wang JS et al: "The emerging importance of transporter proteins in the psychopharmacological treatment of the pregnant patient."

No. Sentence Comment

84 Other SNPs at exon 21 (G2677T/A) change encoded amino acids (Ala893Ser and Ala893Thr), and at exon 1b, T129C, was associated with altered P-gp expression (Hitzl et al., 2004; Nakamura et al., 2002; Tanabe et al., 2001). Login to comment

PMID: 21103972 [PubMed] Cascorbi I et al: "P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations."

No. Sentence Comment

60 These SNPs caused an Ala893Ser and Ala999Thr exchange, respectively. Login to comment
81 Table 2 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies [according to Cascorbi (2006) and Cascorbi and Haenisch (2010)] Position Amino acid or effect Frequency of the variant allele Association to expression, kinetics or drug response 50 -flanking À2903 T>C 0.02a 50 -flanking À2410 T>C 0.10a Decreased mRNAa 50 -flanking À2352 G>A 0.28a 50 -flanking À1910 T>C 0.10a 50 -flanking À1717 T>C 0.02a 50 -flanking À1325 A>G 0.02a 50 -flanking À934 A>G 0.10a 50 -flanking À692 T>C 0.10a Decreased mRNAa 50 -flanking À41 A>G 0.09b IVS 1a À145 C>G 0.02b IVS 1b À129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 À1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 À35 G>C Intronic 0.006c IVS 5 À25 G>T Intronic 0.16c IVS 6 þ139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 571 G>A G191R 0.07f Reduced chemotherapy resistancef c. 1199 G>A S400N 0.05d c. 1199 C>T S400I 0.02g Elevated activityg c. 1236 C>T Synonymous 0.41d Increased imatinib disposition and therapy responseh IVS 12 þ44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 À76 T>A Intronic 0.46d IVS 17 þ137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d In vitro increased vmax,i increased imatinib response in CMLh c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d Decreased mRNA and protein expression,e, k decreased in vitro transport,l no effect on expression and bioavailability of talinolol,m no effect on in vitro transport,n, o decreased digoxin (continued) 4.2.1 Digoxin The heart glycoside digoxin is widely accepted as typical P-glycoprotein substrate. Login to comment
75 The missense variant 2677G>T/A coding for the three different amino acids A893S/T exhibits altered transport properties in membrane vesicles from Sf9 insect cells, overexpressing human ABCB1. Login to comment

PMID: 21619426 [PubMed] Stieger B et al: "Pharmacogenetics of drug transporters in the enterohepatic circulation."

No. Sentence Comment

721 209 Schaefer M, Roots I, Gerloff T: In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms. Login to comment

PMID: 20103563 [PubMed] Klaassen CD et al: "Xenobiotic, bile acid, and cholesterol transporters: function and regulation."

No. Sentence Comment

6832 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ↔ N.D. T307C F103L N.D. N.D. G1199A S400N 1↔ Normal C2005T R669C ↔ N.D. G2677T A893S 21↔ Normal G2677A A893T 1↔ Notmal T3421A S1141T 2↔ N.D. C3435T I1145I 2↔ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. Login to comment
6892 Consistent with enhanced in vitro transport activity, the Ala893Ser ABCB1 (MDR1) variant is associated with reduced plasma fexofenadine concentrations (Table 19) (Kim et al., 2001). Login to comment
6829 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ࢒ N.D. T307C F103L N.D. N.D. G1199A S400N 1࢒ Normal C2005T R669C ࢒ N.D. G2677T A893S 21࢒ Normal G2677A A893T 1࢒ Notmal T3421A S1141T 2࢒ N.D. C3435T I1145I 2࢒ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ࢒, no change in function; N.D. not determined. Login to comment
6889 Consistent with enhanced in vitro transport activity, the Ala893Ser ABCB1 (MDR1) variant is associated with reduced plasma fexofenadine concentrations (Table 19) (Kim et al., 2001). Login to comment

PMID: 22112610 [PubMed] Tian C et al: "Common variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes among women with advanced stage ovarian cancer treated with platinum and taxane-based chemotherapy: a Gynecologic Oncology Group study."

No. Sentence Comment

124 Of the more than 50 SNPs identified in the ABCB1 gene, G2677T/A is a non-synonymous polymorphism (encoding Ala893Ser/Thr), and C3435T is a synonymous polymorphism (encoding Ile1145Ile) associated with reduced ABCB1 mRNA expression [44]. Login to comment

PMID: 17083032 [PubMed] Izzedine H et al: "Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy."

No. Sentence Comment

85 (%) P Group 1 (n p 13) Group 2 (n p 17) Exon 28, 3609 GrA (rs11568695) Ala1203Ala Genotype .43 GG 12 (92) 17 (100) GA 1 (8) 0 AA 0 0 Allele G 25 (96.2) 34 (100) A 1 (3.8) 0 ABCB1 Exon 12, 1236CrT (rs1128503) Gly412Gly Genotype .66 CC 7 (54) 6 (35.2) CT 5 (38) 9 (52.9) TT 1 (8) 2 (11.9) Allele C 19 (73.0) 21 (62.8) T 7 (27.0) 13 (38.2) Exon 21, 2677GrT/A (rs2032582) Ala893Ser/Thr Genotype .82 GG 5 (38) 8 (47) GT 5 (38) 7 (41) TT 1 (8) 1 (6) GA 1 (8) 0 AA 0 1 (6) TA 1 (8) 0 Allele G 16 (61.5) 23 (67.8) T 8 (30.8) 9 (26.4) A 2 (7.7) 2 (5.8) Exon 26, 3435CrT (rs1045642) Ile1145Ile Genotype .25 CC 7 (54) 5 (29.4) CT 3 (23) 9 (52.9) TT 3 (23) 3 (17.7) Allele C 17 (65.4) 19 (55.9) T 9 (34.6) 15 (44.1) NOTE. Login to comment

PMID: 16209890 [PubMed] Takano M et al: "Expression and function of efflux drug transporters in the intestine."

No. Sentence Comment

1100 Siegmund et al. (2002b) investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21, as well as the influence of 7 frequent or putative functional single nucleotide polymorphisms (SNPs) on duodenum MDR1 mRNA and P-gp expression and on talinolol disposition after intravenous and oral administration. Login to comment

PMID: 12729805 [PubMed] Sparreboom A et al: "Pharmacogenomics of ABC transporters and its role in cancer chemotherapy."

No. Sentence Comment

105 One of the tested SNPs, the ABCB1 2677G>T/A (Mickley et al., 1998), contains a tri-allelic polymorphism (with G at nucleotide 2677 found in the wild-type sequence, and with A or T at that position being the two possible variants), which results in an amino acid change in exon 21 (Ala893Ser/Thr). Login to comment

PMID: 12406647 [PubMed] Suzuki H et al: "Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition."

No. Sentence Comment

32 Moreover, Ala893Ser rabbit and human MRP2 [21,38,40,42-61], as sum- mutation in MDR1 gene results in the reduced oral marized in Refs. [7,23,25,26]. Login to comment

PMID: 11956513 [PubMed] Nakamura T et al: "Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects."

No. Sentence Comment

81 The C3435T mutation is a silent mutation that does not cause amino acid substitution and is suggested to be linked with a mutation at exon 21, position 2677 [G2677(A,T)], producing Ala893Thr and Ala893Ser, respectively.6,11 The effect of the C3435T mutation may reflect that of G2677(A,T), and there may be racial differences in the relation between C3435T and G2677(A,T). Login to comment

PMID: 22139683 [PubMed] Yoo HD et al: "Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes."

No. Sentence Comment

43 The silent 3435C > T (exon 26) and the 2677G > T/A (exon 21), which leads to an amino acid exchange (Ala893Ser/Thr), are common ABCB1 polymorphisms. Login to comment

PMID: 20504109 [PubMed] Choong E et al: "The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution."

No. Sentence Comment

209 Different SNPs were associated with the phenotype of remission, and carriers of the C allele for the rs2032583 genotype had higher odds ratio for remission (7.72, 95% CI 2.8 -- 21.3) at 4 weeks Exon 7 Exon 13 Exon 11Exon 2 Exon 8 Exon 6 Exon 3 Exon 4 Exon 9 Exon 17 Exon 10 Exon 14 Exon 12 Exon 15 Exon 16 Exon 19 Exon 21 Exon 18 Exon 23 Exon 24 Exon 28 Exon 27 Exon 20 Exon 22 A893S Exon 25 Exon 26 Exon 5 N21D N183S N400S Variant (548G, Ser183) MDR1*1 (548A, Asn183) Variant (2677T, Ser893) S1141T ATP-binding domain ATP-binding domain MDR1*1 (2677g, Ala893) R492C A. B. Figure 2. Login to comment

PMID: 20138191 [PubMed] Ishikawa T et al: "Emerging new technologies in Pharmacogenomics: rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1)."

No. Sentence Comment

361 (A) The allele frequencies of WT (Ala893), A893S (Ser893), and A893T (Thr893) among different ethnic populations. Login to comment
413 To understand the molecular mechanisms underlying the observed differences in the ATPase activity among ABCB1 WT, A893P, A893S, and A893T (Sakurai et al., 2007), we performed MD simulation based on the homology model of ABCB1. Login to comment
441 The initial three-dimensional structure of each variant protein (A893S, A893T, or A893P) was deduced from the ABCB1 structure template by using the LEAP module in the AMBER (Assisted model building and energy refinement) simulation package. Login to comment
452 Thus, MD calculation was performed to simulate the movement of the intracellular loop located between TM10 and TM11 for each variant protein (A893S, A893T, or A893P) as well as the WT. Login to comment
453 Fig. 4B demonstrates the loop structures of WT, A893S, A893T, or A893P calculated from the trajectory data of MD simulations at 310 K (37˚C) for 3 ns. Login to comment
455 The RMSF value of alpha carbon of each amino acid residue was calculated from the trajectory data for the intracellular loop of WT, A893S, A893T, and A893P. Login to comment
478 To functionally validate the non-synonymous polymorphisms of ABCB1 (P-glycoprotein/MDR1) in vitro, we generated SNP variant forms (i.e., S400N, R492C, R669C, I849M, A893P, A893S, A893T, M986V, A999T, P1051A, and G1063A; refer to Fig. 6) and expressed them in Sf9 cells. Login to comment
480 The effect of test compounds on the ATPase activity of ABCB1 WT, A893P, A893S, and A893T. Login to comment
500 SNP Km Vmax Vmax / Km (µM) (nmol/min/mg protein) WT 5.8±2.3 62.4±7.8 10.8 S400N 5.8±2.8 46.7±5.3⁎⁎ 8.0 R492C 5.6±1.9 49.6±10.0⁎ 8.9 R669C 3.2±1.6⁎ 64.7±6.9 20.1 I849M 1.5±0.7⁎⁎ 80.3±9.5⁎⁎ 51.8 A893P 1.5±0.5⁎⁎ 405.2±16.5⁎⁎ 274.6 A893S 11.1±5.4 43.1±7.1⁎⁎ 3.9 A893T 4.3±1.4 98.9±9.5⁎⁎ 22.9 M986V 5.1±1.1 114.9±13.6⁎⁎ 22.5 A999T 2.0±0.8⁎⁎ 143.1±21.2⁎⁎ 70.9 P1051A 6.2±3.0 52.1±13.6 8.4 G1063A 6.2±3.7 117.9±16.4⁎⁎ 19.0 Data are expressed as mean±S.D., n=6. Login to comment
519 As to the most common nonsynonymous SNP 2677GNT (A893S), there are relatively minor effects on predicted ATPase activity, which is consistent with the clinical association data for this SNP. Login to comment

PMID: 19949926 [PubMed] Staud F et al: "Expression and function of p-glycoprotein in normal tissues: effect on pharmacokinetics."

No. Sentence Comment

189 An association between synonymous SNP in exon 26 (C3435T) and nonsynonymous SNP in exon 21 (G2677A,T, Ala893Ser) was observed. Login to comment

PMID: 19710077 [PubMed] Anderson PL et al: "Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors."

No. Sentence Comment

224 However, the T variant in 2677 encodes an Ala893Ser in exon 21, which was associated with increased activity in one in vitro study.41 Another study showed that the T variant in 2677 is associated with higher basal CYP3A4 expression and activity.42 Finally, some investigators raise the possibility that protein folding differences with the variant haplotype (1236T, 2677T, 3435T) could lead to enhanced P-glycoprotein function, depending on the substrate.17 These investigations are consistent with the findings in the present study. Login to comment

PMID: 19285158 [PubMed] Fung KL et al: "A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function."

No. Sentence Comment

152 A study in our lab showed that common polymorphisms of MDR1 at 61ANG (N21D), 307TNC (F103L), 1199GNA (S400N), 2677GNT (A893S) and 2995GNA (A999T) do not change the transport of four MDR1 substrates when expressed at high levels in human cells [66]. Login to comment
153 A recent study by Gow et al. suggested that all of the SNPs they tested (N21D, S400N, R669C, A893S, A893T, S1141T, V1251I) produced small changes which in most cases are not statistically significant [59]. Login to comment
154 Another study using a yeast host to express human MDR1 SNPs (M89T, L662R, R669C, A893S, W1108R, S1141T) showed increased resistance to anthracyclines, actinomycin D and valinomycin. Login to comment
185 The occurrence of 2677GNT (A893S) is far more frequent than G2677A (A893T). Login to comment

PMID: 19571437 [PubMed] Vahab SA et al: "Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population."

No. Sentence Comment

30 These three coding region SNPs- synonymous c.1236CÀT (p.Gly412Gly) and c.3435CÀT (p.Ile1145Ile), as well as the non-synonymous c.2677GÀT/A (p.Ala893Ser/Thr) are in significant linkage disequilibrium and a few of their haplotypes have shown association to phenotypes with over-expression of the protein.7-10) However, for these three SNPs, ethnic differences have been reported in the pattern of linkage disequilibrium with an allele frequency of 45-55% in Whites and 5-10% in African Americans. Login to comment

PMID: 18627414 [PubMed] Loscher W et al: "The clinical impact of pharmacogenetics on the treatment of epilepsy."

No. Sentence Comment

60 The synonymous 3435C>T polymorphism is in linkage disequilibrium with a synonymous SNP in exon 13 (1236C>T) and a nonsynonymous SNP in exon 22 (2677G>TA), suggesting that the observed functional differences in Pgp, initially attributed to the exon 27 synonymous SNP, may be the result of the associated nonsynonymous polymorphism in exon 22, which results in amino acid exchanges (Ala893Ser or Ala893Thr) (Marzolini et al., 2004). Login to comment

PMID: 19093297 [PubMed] Sharma S et al: "Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians."

No. Sentence Comment

70 Gene polymorphisms and MTX response in RA Sharma et al. 1043 published single nucleotide polymorphisms One commonly investigated SNP rs1051266 (80 G > A, Arg27His, exon 3) of RFC gene; a total of eight SNPs from MDR1 gene including one promoter SNP rs3213619 ( - 129T > C); three commonly analysed exonic SNPs rs1128503 (1236C > T, Gly411Gly, exon 12); triallelic SNP rs2032582 (2677G> T, G > A, Ala893Ser, Ala893Thr, exon 21); and rs1045642 (3435C > T, Ile1145Ile, exon 26); and four splice variants rs28381943, rs2235064, rs2235044 and rs2235032; three SNPs from GGH gene including one promoter SNP rs3758149 ( - 401C > T); two exonic SNPs rs1800909 (16T > C, Cys6Arg, exon 1); and rs11545078 (452C > T, Thr151Ile, exon 5) and one tag SNP rs1544105 G > A through hapmap database (release #21) in the vicinity of FPGS gene were genotyped in the sample set. Login to comment

PMID: 17621683 [PubMed] Edafiogho IO et al: "Enaminones: Exploring additional therapeutic activities."

No. Sentence Comment

92 The most commonly identified linked MDR1 SNPs (linkage disequilibrium) in P-gp are the synonymous 1236 (exon 12, C > T, Glu 412 Glu) and 3435 (exon 26, C > T, Ile 1145 Ile) and the nonsynonymous 2677 (exon 21, G > T/A, Ala 893 Ser/Thr [less frequent]113 ) plymorphisms.102,114-118 To date, discrepancies in the outcomes of genotype-phenotype studies are attributed to the emphasis on studying single SNPs rather than haplotypes, racial variation in allele fre- quencies119 and the number of haplotype combinations,120 the use of P-gp substrates which are affected by other transporters or metabolizing enzymes, and other interfering factors (route of administration and applied dose, steady state versus single-dose kinetics, environmental and experimental factors). Login to comment

PMID: 17652833 [PubMed] Bartnicka L et al: "Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T polymorphisms and P-glycoprotein inhibitors on salivary digoxin secretion in congestive heart failure patients."

No. Sentence Comment

24 The 3435C >T SNP is a silent mutation that does not cause amino acid substitution and is suggested to be linked, in a majority of subjects, with the mutation in exon 21, position 2677 (2677G >T,A), producing Ala893Thr and Ala893Ser, respectively [16]. Login to comment

PMID: 16563694 [PubMed] Ceckova-Novotna M et al: "P-glycoprotein in the placenta: expression, localization, regulation and function."

No. Sentence Comment

1527 Kim et al. subsequently demonstrated linkage disequilibrium (though not complete) between the synonymous SNP in exon 26 (C3435T) and nonsynonymous SNP in exon 21 (G2677T, Ala893Ser), which can be associated with altered transporter expression or function [110]. Login to comment

PMID: 16895999 [PubMed] Kroetz DL et al: "Role for drug transporters beyond tumor resistance: hepatic functional imaging and genotyping of multidrug resistance transporters for the prediction of irinotecan toxicity."

No. Sentence Comment

27 The current study reported by Michael et al suggests that UGT1A1 genotype alone may not be sufficient to identify patients who would benefit from a lower starting dose of irinotecan.16 They also genotyped for three common coding region variants of ABCB1, two synonymous changes, and a nonsynonymous change resulting in the Ala893Ser variant of Pgp. Login to comment

PMID: 17025270 [PubMed] Wang D et al: "Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1)."

No. Sentence Comment

48 Indeed, C3435T is in linkage disequilibrium with G2677T (Ala893Ser). Login to comment

PMID: 16504381 [PubMed] Kerb R et al: "Implications of genetic polymorphisms in drug transporters for pharmacotherapy."

No. Sentence Comment

64 R. Kerb / Cancer Letters 234 (2006) 4-338 naturally-occurring polymorphisms in the human ABCB1 gene reported was the amino acid substitution Gly185Val [89], and more recently Ala893Ser and Met986Val [90]. Login to comment
76 Table 3 Overview of the 15 most common ABCB1 (MDR1) genetic variants Position Location Effect Allelic frequency (%) CA AS AA K129TOC 50 UTR Non-coding 5 4 7 K1GOA 50 UTR Non-coding 8 5 0 61AOG Exon 2 Asn21Asp 8 2 2.5 Exon 5-25GOT Intron 4 16 7 30 Exon 10-44AOG Exon 10 Intron 9 45 69 26 1199GOA Exon 11 Ser400Asn 2.5 0 !1 1236COT Exon 12 Synonymous 46 69 21 Exon 11C44COT Intron 12 5 0 17 Exon 12C24COT Intron 13 52 54 54 Exon 13C38AOG Intron 14 50 68 54 Exon 19C24GOA Intron 20 12 7 15 2677GOT/A Exon 21 Ala893Ser/Thr 46/2 45/7 O1 3421TOA Exon 26 Ser1141Thr 0 0 10 3435COT Exon 26 Synonymous 56 40 10 IVSC21TOC Intron 28 0 8 0 AA, African American; AS, Asian; CA, Caucasian. Login to comment
78 Clinical investigations of genotype-related function of MDR1 have been performed mainly focusing on the silent 3435COT and a non-synonymous variant, the transversion 2677GOT (Ala893Ser) and 2677GOA (Ala893Thr). Login to comment
169 It should be noted that, in the majority of subjects, this synonymous 3435COT polymorphism is linked to the nonsynonymous exon 21 2677GOT/A polymorphism, which results in Ala893Ser/Thr, as well as another conservative SNP, 1236COT [47]. Login to comment

PMID: 15720288 [PubMed] Fischer V et al: "Efflux transporters and their clinical relevance."

No. Sentence Comment

149 The C3435T polymorphism is highly linked with the SNP at exon 21, position 2677 (G2677T/A), which results in amino acid changes Ala893Thr and Ala893Ser, respectively, and with C1236T in exon 12 [70, 83]. Login to comment

PMID: 15931768 [PubMed] Chowbay B et al: "An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore."

No. Sentence Comment

427 Kim et al. (2001) indicated that cells transduced with a variant MDR1 containing Ser893 showed reduced intracellular accumulation of [3 H]-digoxin compared with cells with the wild-type Ala893 , suggesting enhanced efflux by the polymorphism of Ala893Ser (G2677T). Login to comment

PMID: 15276711 [PubMed] Fromm MF et al: "Importance of P-glycoprotein at blood-tissue barriers."

No. Sentence Comment

112 The C3435T polymorphism is in linkage disequilibrium with the G2677T/A polymorphism, which results in amino acid exchanges (Ala893Ser or Ala893Thr) [59,60]. Login to comment

PMID: 12869659 [PubMed] Mizuno N et al: "Impact of drug transporter studies on drug discovery and development."

No. Sentence Comment

1866 The G2677T transversion in exon 21 resulted in an alteration in the encoded protein (Ala893Ser). Login to comment

PMID: 12235446 [PubMed] Siegmund W et al: "Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition."

No. Sentence Comment

111 However, there was a significant trend toward higher intestinal MDR1 mRNA but not protein levels in subjects with the polymorphism G2677T (Ala893Ser) in exon 21, which has been shown to have an allelic frequency of 41.6% in German white subjects. Login to comment

PMID: 20367109 [PubMed] Giraud C et al: "ABC transporters in human lymphocytes: expression, activity and role, modulating factors and consequences for antiretroviral therapies."

No. Sentence Comment

158 Two polymorphisms have been abundantly studied: one polymorphism at the 2677 position of exon 21 that may result in two distinct amino-acid changes, Ala893Ser (G2677T) and Ala893Thr (G2677A), and one synonymous polymorphism in exon 26 (C3435T). Login to comment

PMID: 23396606 [PubMed] Vulsteke C et al: "Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC)."

No. Sentence Comment

114 Overview of 33 additional SNPs located in genes involved in the pharmacokinetics (PK) or pharmacodynamics (PD) of the 5-fluorouracil (5-FU), epirubicin and cyclophosphamide (FEC) regimen Genes Name Function of the gene product Variant allele (rs number, position, amino acid change) PK or PD effect ABCBI/ MDR1 Multidrug resistance 1 Drug transporter implicated in energy-dependent transport of cytotoxic agents out of the cell rs2032582 c.2677G>T/A Ala893Ser/Thr Selected because missense mutations are likely to affect gene function. Login to comment