ABCB1 p.Glu448Lys
| Predicted by SNAP2: | A: N (53%), C: D (53%), D: N (82%), F: D (63%), G: N (66%), H: D (63%), I: D (66%), K: N (61%), L: D (66%), M: D (59%), N: N (66%), P: D (85%), Q: N (78%), R: D (71%), S: N (87%), T: D (63%), V: N (66%), W: D (66%), Y: D (66%), |
| Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: N, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Additive effects of drug transporter genetic polym... Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22. Sai K, Saito Y, Maekawa K, Kim SR, Kaniwa N, Nishimaki-Mogami T, Sawada J, Shirao K, Hamaguchi T, Yamamoto N, Kunitoh H, Ohe Y, Yamada Y, Tamura T, Yoshida T, Matsumura Y, Ohtsu A, Saijo N, Minami H
Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients.
Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22., [PMID:19771428]
Abstract [show]
PURPOSE: Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated. METHODS: Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients). RESULTS: Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ((#) IIB) and SLCO1B1 521T>C (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory. CONCLUSIONS: Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.
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No. Sentence Comment
124 patients who experienced grade 4 neutropenia ID Gene Genetic variation Nucleotide change (amino acid substitution) Haplotypea b1 ABCB1 304G[C (G102R) Block 1 *3 b2(B)b 1804G[A (D602N) Block 2 *12 b3(B)b 1342G[A (E448K) Block 2 *14 b4 3043A[G (T1015A) Block 2 *16 b5 3751G[A (V1251I) Block 3 *2 c1 ABCC2 1177C[T (R393W) *7 g1 ABCG2 376C[T (Q126X) Block 1 *4 g2 1465T[C (F489L) Block 2 *2 g3 1723C[T (R575X) Block 2 *5 s1(S)c SLCO1B1 1007C[G (P336R) s2 311T[A (M104K) u1 UGT1A1 -3279T[G, 1941C[G # 60-# IB (?/?)
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ABCB1 p.Glu448Lys 19771428:124:212
status: NEW55 Since the SN-38 AUC/dose level of one patient with haplotypes ABCB1*2 [2677G[T (A893S)] and *14 [2677G[T (A893S) and 1345G[A (E448K)] showed an outlying value (indicated as ''a`` in Fig. 1), this patient was excluded from the statistical analysis.
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ABCB1 p.Glu448Lys 19771428:55:126
status: NEW[hide] Genetic variations and haplotype structures of the... Ann Hum Genet. 2006 Sep;70(Pt 5):605-22. Sai K, Itoda M, Saito Y, Kurose K, Katori N, Kaniwa N, Komamura K, Kotake T, Morishita H, Tomoike H, Kamakura S, Kitakaze M, Tamura T, Yamamoto N, Kunitoh H, Yamada Y, Ohe Y, Shimada Y, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kamatani N, Ozawa S, Sawada J
Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences.
Ann Hum Genet. 2006 Sep;70(Pt 5):605-22., [PMID:16907707]
Abstract [show]
As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks -1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms -1,789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re-assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally-important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease-association studies carried out using Asian subjects.
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No. Sentence Comment
67 Novel variations included 8 nonsynonymous substitutions: 49T>C(F17L), 144G>T(K48N), 304G>C(G102R), 1342G>A(E448K), 1804G>A(D602N), 2359C>T (R787W), 2719G>A(V907I) and 3043A>G(T1015A); and 2 synonymous substitutions: 354C>T (Y118Y) and 447A>G(K149K); with frequencies ranging from 0.001 to 0.005.
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ABCB1 p.Glu448Lys 16907707:67:107
status: NEW117 Novel haplotype groups bearing amino acid substitutions were assigned as * 12 [1804G>A (D602N)], * 13 [2719G>A (V907I)], * 14 [1342G>A (E448K)], * 15 [2956A>G (M986V)], * 16 [3043A>G (T1015A)], and * 17 [2359C>T(R787W)], xE6.Int.6In.t7Itn8.Iin.t9Itn1.0nI.t12Int.14Ex.15xE1.9nI.t19Ex.22nI.t42 VI5S 2+32 VI5S +422 447 I6SV 1-90 VI7S 1+4 I8SV 601- I9SV 44- I1SV0 4-1 32161342 I1SV2 1+7 VI1S3 2+4 VI31S 18+ I1SV4 3+8 0814 VI51S 59- I1SV5 6-9 VI1S6 5+2 VI61S 37+ I1SV6 7-6 VI1S8 8+7 VI81S 53- 2953 VI1S9 8-8 VI02S 42+ I2SV0 -351 76272677 I2SV1 4+9 VI2S1 7-3__ 7-6 729126594033 VI42S 1+6 3534 VI2S6 5+9 VI62S 8+0 A>TG>TAG>>GTG>AA>G>GATG>C>TGA>>GATC>C>TG>AG>AAG>>TCAC>A>GTA>C>TG>CC>TC>TGA>>AGGA>>GTT>C edl CTGT G>AA>GAG>C>TC>T>TGTC> 941KK214GGEK844D206NR787WAT3988AS39I709VM9V68T1A510I1I541FNreqcneuy 1*e711011.0 1*f74440.0 1*g72520.0 1*L01900.0 1*h60600.
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ABCB1 p.Glu448Lys 16907707:117:136
status: NEW