ABCC2 p.Ser185Thr
| Predicted by SNAP2: | A: N (97%), C: N (72%), D: N (72%), E: N (72%), F: N (53%), G: N (82%), H: N (53%), I: N (61%), K: N (82%), L: N (72%), M: D (53%), N: N (87%), P: N (82%), Q: N (87%), R: N (78%), T: N (93%), V: N (87%), W: D (53%), Y: D (59%), |
| Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: D, G: N, H: D, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, R: N, T: N, V: D, W: D, Y: D, |
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[hide] Single nucleotide polymorphism in ABCG2 is associa... J Hum Genet. 2009 Oct;54(10):572-80. Epub 2009 Aug 21. Cha PC, Mushiroda T, Zembutsu H, Harada H, Shinoda N, Kawamoto S, Shimoyama R, Nishidate T, Furuhata T, Sasaki K, Hirata K, Nakamura Y
Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression.
J Hum Genet. 2009 Oct;54(10):572-80. Epub 2009 Aug 21., [PMID:19696792]
Abstract [show]
Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case-control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (P(Fisher)<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed P(Fisher)=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (P(Fisher)=0.000237; P(Corrected)=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression.
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No. Sentence Comment
48 In addition to this SNP, rs7977213 in SLCO1B3 as well as the UGT1A7*3 variant Table 1 Demographical characteristic of patients First study Second study Combined study Case (N¼23) Control (N¼58) Case (N¼7) Control (N¼20) Case (N¼30) Control (N¼78) Age 62.04 (37-77) 60.29 (34-77) 60.29 (40-81) 67.60 (50-84) 61.63 (37-81) 62.21 (34-84) % of men 61 71 57 42 60 65 Types of cancers Lung 12 52% 10 17% 2 29% 4 17% 14 47% 14 18% Cervical 6 26% 2 3% 0 0% 0 0% 6 20% 2 3% Colorectal 3 13% 35 60% 3 43% 13 57% 6 20% 48 62% Gastric 1 4% 4 7% 1 14% 2 9% 2 7% 6 8% Ovarian 0 0% 2 3% 1 14% 1 4% 1 3% 3 4% Breast+cervical 1 4% 0 0% 0 0% 0 0% 1 3% 0 0% Pancreatic 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% Esophageal 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% Breast 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% No information 0 0% 2 0% 0 0% 0 0% 0 0% 2 3% Types of regimens CPT-11 1 4% 11 19% 1 14% 2 9% 2 6% 13 17% Other drug combinations 22 96% 47 81% 6 86% 18 91% 28 94% 65 83% Associations of 170 SNPs with severe myelosuppression in subjects who received irinotecan therapy Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio UGT1A9 rs3832043 UGT1A9*1b or *22 9T 10T 0.63 0.63 1.00E+00 8.05EÀ01 7.33EÀ01 0.76 UGT1A7 rs17868323 Exon 1 (Lys 129 Asn) T G 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 1A7_R131Kaa Exon 1 (R131K) (UGT1A7*2) C A 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 1A7_R131Kba Exon 1 (R131K) (UGT1A7*2) G A 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 rs11692021 Exon 1 (Arg 208 Trp) (UGT1A7*3) T C 0.65 0.76 1.71EÀ01 1.00E+00 6.72EÀ03 15.56 UGT1A1 rs887829 Intron (tagged UGT1A1*28, promoter indel) G A 0.96 0.90 3.53EÀ01 1.64EÀ01 1.00E+00 5.15 UGT1A1 rs4148323 Exon 1 (Arg 71 Gly) (UGT1A1*6) G A 0.76 0.78 8.34EÀ01 4.51EÀ01 2.14EÀ02 12.00 UGT1A1 rs35350960 Exon 1 (Gln 229 Pro) (UGT1A1*27) C A 1.00 0.99 1.00E+00 1.00E+00 1.00E+00 NA BCHE rs697356 3' near gene G C 0.30 0.40 2.74EÀ01 4.95EÀ01 4.46EÀ01 1.64 BCHE rs1007845 3' near gene G A 0.83 0.78 6.67EÀ01 6.13EÀ01 1.00E+00 1.40 BCHE rs2048493 Intron 2 C G 0.78 0.62 6.41EÀ02 5.08EÀ02 4.29EÀ01 2.74 BCHE rs4639017 Intron 1 C G 0.72 0.60 2.07EÀ01 2.07EÀ01 7.17EÀ01 2.07 ABCC5 rs6810123 3' near gene A G 0.33 0.41 3.72EÀ01 1.00E+00 2.07EÀ01 2.07 ABCC5 rs12638772 3' near gene A G 0.36 0.32 7.07EÀ01 2.50EÀ01 1.00E+00 2.36 ABCC5 rs7613247 3' near gene A G 0.93 0.94 1.00E+00 1.00E+00 1.00E+00 1.15 ABCC5 rs2176825 3' near gene A G 0.25 0.37 1.81EÀ01 5.07EÀ01 2.07EÀ01 1.98 ABCC5 rs13066518 3' near gene T A 0.33 0.39 4.78EÀ01 1.00E+00 4.50EÀ01 1.62 ABCC5 rs3749443 3' near gene A G 0.20 0.18 1.00E+00 1.00E+00 7.90EÀ01 1.29 ABCC5 rs1402001 3' near gene A G 0.52 0.57 6.03EÀ01 7.95EÀ01 2.30EÀ01 2.10 ABCC5 rs6790814 3' near gene C G 0.66 0.76 2.33EÀ01 4.63EÀ01 1.25EÀ01 4.42 ABCC5 rs9838667 3' near gene T G 0.34 0.46 2.12EÀ01 5.64EÀ01 3.05EÀ01 1.85 ABCC5 rs2280392 3' near gene G A 0.25 0.23 8.35EÀ01 3.40EÀ01 8.02EÀ01 2.84 ABCC5 rs1879257 3' near gene A G 0.43 0.32 2.02EÀ01 3.07EÀ01 3.27EÀ01 2.02 ABCC5 rs3817403 3' near gene A G 0.87 0.90 7.82EÀ01 1.00E+00 1.00E+00 1.19 ABCC5 rs3805111 3' near gene T C 0.09 0.10 7.85EÀ01 1.00E+00 7.72EÀ01 1.24 ABCC5 rs3805108b 3' near gene A G 0.11 0.19 2.50EÀ01 6.69EÀ01 4.00EÀ01 1.97 ABCC5 rs2872247 3' near gene T G 0.76 0.70 4.49EÀ01 6.30EÀ01 6.67EÀ01 1.30 ABCC5 rs2293001 3' near gene T C 0.48 0.54 6.00EÀ01 7.79EÀ01 5.56EÀ01 1.44 ABCC5 rs4148572 Intron 2 C G 0.33 0.22 1.60EÀ01 1.36EÀ01 3.30EÀ01 4.20 ABCC5 rs4148568 Intron 2 A G 0.13 0.18 6.37EÀ01 5.85EÀ01 7.89EÀ01 NA ABCC5 rs4148564 Intron 2 A G 0.89 0.82 3.44EÀ01 3.00EÀ01 1.00E+00 1.89 ABCC5 rs4148560 Intron 2 A T 0.78 0.80 8.30EÀ01 7.96EÀ01 1.36EÀ01 4.20 ABCC5 rs7624838 Intron 2 T C 0.50 0.52 8.63EÀ01 7.82EÀ01 1.00E+00 1.26 ABCG2 rs2231164 Intron 14 C T 0.36 0.39 8.56EÀ01 5.57EÀ02 4.46EÀ01 NA ABCG2 rs2622611 Intron 10 T G 0.16 0.18 8.20EÀ01 3.29EÀ01 1.00E+00 NA ABCG2 rs1871744 Intron 6 T C 0.55 0.69 9.76EÀ02 3.22EÀ01 1.71EÀ01 2.73 ABCG2 rs2231142 Exon 5 (Gln 141 Lys) C A 0.78 0.78 1.00E+00 1.00E+00 1.00E+00 0.79 ABCG2 rs2231137 Exon 2 (Val 12 Met) G A 0.67 0.79 1.53EÀ01 3.19EÀ01 1.36EÀ01 4.20 ABCG2 rs1564481 Intron 1 C T 0.72 0.62 2.77EÀ01 3.15EÀ01 6.67EÀ01 1.74 ABCG2 rs2622624 Intron 1 A G 0.41 0.29 1.93EÀ01 2.78EÀ01 3.35EÀ01 2.41 ABCG2 rs2622604 Intron 1 T C 0.28 0.09 2.35EÀ03 7.81EÀ02 6.66EÀ03 4.40 ABCB1 rs1882478 Intron 27 C T 0.59 0.55 7.27EÀ01 4.31EÀ01 7.57EÀ01 1.57 ABCB1 rs6979885 Intron 27 G A 0.89 0.91 1.00E+00 1.00E+00 1.00E+00 1.19 ABCB1 rs2235047 Intron 27 T G 0.50 0.52 8.63EÀ01 7.82EÀ01 1.00E+00 1.26 ABCB1 rs1045642 Exon 27 (Ile 3 Ile) T C 0.37 0.44 4.80EÀ01 1.00E+00 4.34EÀ01 1.67 ABCB1 rs1002205 Intron 26 C G 0.52 0.60 3.75EÀ01 4.21EÀ01 7.14EÀ01 1.70 ABCB1 rs6949448 Intron 26 T C 0.35 0.40 5.91EÀ01 1.00E+00 6.09EÀ01 1.42 ABCB1 rs2235067 Intron 23 A G 0.07 0.11 5.60EÀ01 1.00E+00 5.36EÀ01 1.83 ABCB1 rs2373588 Intron 22 T C 0.43 0.39 5.98EÀ01 7.20EÀ01 7.99EÀ01 1.53 ABCB1 rs7787082 Intron 22 A G 0.50 0.50 1.00E+00 7.72EÀ01 7.72EÀ01 NA ABCB1 rs3789246 Intron 20 A G 0.09 0.19 1.50EÀ01 5.51EÀ01 2.69EÀ01 2.31 ABCB1 rs1922242b Intron 17 A T 0.78 0.68 2.45EÀ01 3.24EÀ01 4.90EÀ01 1.74 ABCB1 rs2235046 Intron 17 A G 0.72 0.59 1.51EÀ01 4.38EÀ02 1.00E+00 2.89 ABCB1 rs868755 Intron 9 C A 0.59 0.61 1.00E+00 1.00E+00 7.29EÀ01 1.36 ABCB1 rs4148734 Intron 8 C T 0.87 0.90 7.79EÀ01 5.42EÀ01 1.00E+00 1.55 ABCB1 rs2235018 Intron 6 A G 0.67 0.81 9.65EÀ02 2.09EÀ01 1.40EÀ01 4.13 ABCB1 rs10256836a Intron 5 C G 0.13 0.09 5.68EÀ01 1.00E+00 5.31EÀ01 1.73 ABCB1 rs10259849a Intron 5 C T 0.14 0.10 5.75EÀ01 1.00E+00 5.36EÀ01 1.65 ABCB1 rs1202172 Intron 5 T G 0.96 0.86 1.01EÀ01 8.01EÀ02 1.00E+00 4.00 Table 2 Continued Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio ABCB1 rs17327442 Intron 5 T A 0.89 0.94 5.12EÀ01 4.93EÀ01 1.00E+00 1.87 ABCB1 rs1202184 Intron 5 G A 0.24 0.33 3.44EÀ01 1.00E+00 2.25EÀ01 1.91 ABCB1 rs3789243 Intron 4 T C 0.50 0.31 2.81EÀ02 5.05EÀ02 1.38EÀ01 3.50 ABCB1 rs3213619 Exon 2 (5' UTR) C T 0.02 0.10 1.81EÀ01 1.00E+00 1.63EÀ01 5.02 ABCB1 rs4148732 Intron 1 A G 0.87 0.96 7.89EÀ02 6.87EÀ02 1.00E+00 3.67 ABCB1 rs13233308 Intron 1 T C 0.43 0.44 1.00E+00 7.60EÀ01 7.95EÀ01 0.82 ABCB1 rs1978095 Intron 1 T C 0.67 0.73 5.59EÀ01 6.21EÀ01 6.89EÀ01 1.36 ABCB1 rs2157929 Intron 1 T C 0.93 0.79 3.32EÀ02 5.60EÀ02 5.51EÀ01 3.81 ABCB1 rs10278483 Intron 1 T C 0.96 0.86 1.01EÀ01 1.36EÀ01 5.88EÀ01 3.34 CYP3A5 rs776746 Intron 3 (CYP3A5*3) A G 0.22 0.32 2.50EÀ01 6.67EÀ01 3.26EÀ01 1.79 CYP3A4 rs28371759c Exon 10 (Pro 293 Leu) (CYP3A4*18) 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CYP3A4 rs12721627b Exon 7 (Ser 185 Thr) (CYP3A4*16) C G 1.00 0.96 3.23EÀ01 3.22EÀ01 1.00E+00 NA ABCC2 rs12268782 5' near gene A G 0.22 0.13 2.26EÀ01 1.00E+00 1.81EÀ01 2.21 ABCC2 rs2804398 Intron 7 T A 0.83 0.84 8.14EÀ01 7.90EÀ01 1.00E+00 1.29 ABCC2 rs2756109 Intron 7 G T 0.63 0.65 8.55EÀ01 1.00E+00 1.00E+00 1.12 ABCC2 rs2273697 Exon 10 (Ile 417 Val) G A 0.83 0.92 8.91EÀ02 5.96EÀ02 1.00E+00 3.33 ABCC2 rs11190291a Intron 11 T C 0.17 0.08 8.91EÀ02 1.00E+00 5.96EÀ02 3.33 ABCC2 rs2002042 Intron 19 T C 0.33 0.39 4.78EÀ01 2.78EÀ01 1.00E+00 3.52 ABCC2 rs17222723c Exon 25 (Glu 1188 Val) T A 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA ABCC2 rs3740065b Intron 29 T C 0.65 0.60 5.96EÀ01 6.18EÀ01 9.90EÀ02 6.36 ABCC2 rs12762549 3' near gene C G 0.48 0.36 2.13EÀ01 1.00E+00 6.81EÀ02 3.35 ABCC2 rs2862691 3' near gene T C 0.19 0.25 5.26EÀ01 6.05EÀ01 6.11EÀ01 NA ABCC2 rs11598781 3' near gene T C 0.17 0.27 2.30EÀ01 1.00E+00 1.40EÀ01 2.29 ABCC2 rs11190303 3' near gene T C 0.24 0.33 2.62EÀ01 5.33EÀ02 1.00E+00 NA SLCO1B3 rs12228798 Intron 1 C T 0.82 0.83 1.00E+00 7.77EÀ01 2.27EÀ01 NA SLCO1B3 rs7977213 Intron 2 G C 0.43 0.18 1.29EÀ03 1.31EÀ03 2.55EÀ02 NA SLCO1B3 rs10841661 Intron 2 T C 0.48 0.23 2.73EÀ03 5.65EÀ03 4.79EÀ02 9.88 SLCO1B3 rs4149118 Intron 4 A G 0.59 0.48 3.31EÀ01 3.49EÀ01 5.40EÀ01 1.85 SLCO1B3 rs3764009a Intron 4 A G 0.68 0.69 1.00E+00 1.00E+00 1.00E+00 1.16 SLCO1B3 rs7311358 Exon 7 (Ile 233 Met) A G 0.68 0.69 1.00E+00 1.00E+00 1.00E+00 1.16 SLCO1B3 rs11045585b Intron 12 G A 0.13 0.21 2.76EÀ01 3.14EÀ01 6.06EÀ01 NA SLCO1B3 rs980084 Intron 12 G C 0.28 0.45 7.48EÀ02 3.80EÀ01 7.66EÀ02 2.67 SLCO1B3 rs3764006 Exon 14 (Gly 611 Gly) T C 0.87 0.70 2.74EÀ02 1.32EÀ01 9.75EÀ02 NA SLCO1B3 rs919840 3' near gene C G 0.97 0.90 2.99EÀ01 2.77EÀ01 1.00E+00 3.74 SLCO1B3 rs2117032 3' near gene T C 0.52 0.47 6.05EÀ01 7.68EÀ01 7.82EÀ01 1.35 SLCO1B3 rs7312051 3' near gene C T 1.00 0.91 1.26EÀ01 1.04EÀ01 1.00E+00 NA SLCO1B3 rs10841714 3' near gene C T 0.15 0.17 8.01EÀ01 1.00E+00 1.00E+00 NA SLCO1B3 rs2174012 3' near gene T C 0.62 0.63 1.00E+00 5.72EÀ01 4.55EÀ01 0.39 SLCO1B3 rs11045639a 3' near gene G A 0.65 0.72 4.46EÀ01 2.17EÀ01 7.25EÀ01 2.05 SLCO1B3 rs2900459 3' near gene G A 0.46 0.56 2.95EÀ01 1.43EÀ02 5.70EÀ01 5.96 SLCO1B3 rs4762693 3' near gene G A 0.65 0.72 4.46EÀ01 2.17EÀ01 7.25EÀ01 2.05 SLCO1B3 rs10734711 3' near gene A G 0.28 0.35 4.61EÀ01 2.78EÀ01 8.05EÀ01 3.52 SLCO1B1 rs12228427 5' near gene (LST-3TM12 Intron 9) A G 0.96 0.88 1.59EÀ01 1.36EÀ01 1.00E+00 3.34 SLCO1B1 rs1910163 5' near gene (LST-3TM12 Intron 12) A T 0.28 0.34 4.66EÀ01 7.25EÀ01 6.21EÀ01 1.44 SLCO1B1 rs6487207 5' near gene (LST-3TM12 Intron 11) T G 0.78 0.73 5.54EÀ01 8.11EÀ01 3.22EÀ01 NA SLCO1B1 rs1604539 5' near gene (LST-3TM12 Intron 12) T G 0.80 0.75 5.41EÀ01 6.18EÀ01 1.00E+00 1.42 SLCO1B1 rs7973691 5' near gene T C 0.80 0.83 8.21EÀ01 7.98EÀ01 1.00E+00 1.22 SLCO1B1 rs10743408 Intron 2 C G 0.24 0.18 4.97EÀ01 1.00E+00 3.06EÀ01 1.73 SLCO1B1 rs976754 Intron 2 T C 0.83 0.69 1.15EÀ01 8.67EÀ02 6.67EÀ01 2.54 SLCO1B1 rs2291073 Intron 3 T G 0.78 0.72 4.35EÀ01 8.11EÀ01 1.76EÀ01 NA SLCO1B1 rs4149037 Intron 4 A G 0.70 0.80 2.12EÀ01 2.07EÀ01 6.19EÀ01 2.07 SLCO1B1 rs4149056 Exon 5 (Ala 174 Val) T C 0.72 0.84 8.02EÀ02 2.04EÀ01 8.01EÀ02 NA SLCO1B1 rs2417967 Intron 11 A G 0.33 0.21 1.54EÀ01 1.00E+00 8.68EÀ02 2.41 SLCO1B1 rs7969341b Intron 14 T C 0.50 0.46 7.24EÀ01 1.58EÀ01 5.60EÀ02 3.80 SLCO1B1 rs4149085 3' UTR T C 0.74 0.66 4.53EÀ01 8.05EÀ01 1.76EÀ01 NA SLCO1B1 rs12372067 3' near gene C A 0.21 0.33 2.06EÀ01 1.00E+00 1.68EÀ01 2.42 SLCO1B1 rs12310063 3' near gene A C 0.67 0.76 3.21EÀ01 2.13EÀ01 1.00E+00 2.07 ABCC1 rs8050881 5' near gene A G 0.33 0.23 2.37EÀ01 1.00E+00 1.44EÀ01 2.13 ABCC1 rs4148330 5' near gene G A 0.48 0.34 1.46EÀ01 2.95EÀ01 2.13EÀ01 2.02 Continued Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio ABCC1 rs7190484 Intron 1 T C 0.43 0.34 3.67EÀ01 5.03EÀ01 4.62EÀ01 1.52 ABCC1 rs215098 Intron 1 C A 0.41 0.34 4.63EÀ01 1.96EÀ01 1.00E+00 2.30 ABCC1 rs215096 Intron 1 T C 0.89 0.87 1.00E+00 5.63EÀ01 2.89EÀ01 0.00 ABCC1 rs152023 Intron 1 G A 0.48 0.41 4.75EÀ01 3.79EÀ01 8.05EÀ01 1.79 ABCC1 rs6498595 Intron 1 G C 0.41 0.31 2.70EÀ01 2.73EÀ02 1.00E+00 4.76 ABCC1 rs7196970 Intron 1 C G 0.70 0.63 4.71EÀ01 3.25EÀ01 1.00E+00 1.73 ABCC1 rs12935283 Intron 1 A G 0.67 0.61 4.78EÀ01 3.19EÀ01 1.00E+00 1.79 ABCC1 rs246240 Intron 5 A G 0.60 0.58 1.00E+00 1.00E+00 1.00E+00 1.06 ABCC1 rs924138b Intron 5 T C 0.68 0.63 5.84EÀ01 6.17EÀ01 1.00E+00 1.38 ABCC1 rs2062541 Intron 6 C T 0.71 0.64 4.46EÀ01 4.45EÀ01 7.51EÀ01 1.60 ABCC1 rs11647513 Intron 6 C T 0.78 0.70 3.34EÀ01 2.14EÀ01 1.00E+00 2.13 ABCC1 rs35593 Intron 11 T C 0.71 0.75 8.37EÀ01 1.00E+00 1.00E+00 2.70 ABCC1 rs3765129 Intron 11 C T 0.98 0.84 2.69EÀ02 1.75EÀ02 1.00E+00 9.90 ABCC1 rs17287570 Intron 12 A C 0.73 0.91 6.32EÀ03 1.03EÀ02 2.75EÀ01 4.27 ABCC1 rs35597 Intron 12 A G 0.59 0.55 7.19EÀ01 5.85EÀ01 1.00E+00 1.45 ABCC1 rs35598a Intron 12 A G 0.82 0.86 6.21EÀ01 7.86EÀ01 2.78EÀ01 NA ABCC1 rs9932506 Intron 12 G A 0.72 0.75 6.94EÀ01 6.21EÀ01 1.00E+00 1.44 ABCC1 rs35604 Intron 12 G A 0.24 0.25 1.00E+00 1.00E+00 1.00E+00 1.63 ABCC1 rs35606 Intron 13 C T 0.82 0.86 6.17EÀ01 7.82EÀ01 2.86EÀ01 NA ABCC1 rs35620 Intron 14 G C 0.26 0.23 8.39EÀ01 1.00E+00 6.19EÀ01 1.39 ABCC1 rs35625 Intron 14 C T 0.41 0.34 4.70EÀ01 7.52EÀ01 4.72EÀ01 1.45 ABCC1 rs35626 Intron 15 T G 0.43 0.40 7.21EÀ01 5.08EÀ01 2.96EÀ01 1.93 ABCC1 rs4148353 Intron 15 T G 0.20 0.07 2.42EÀ02 1.00E+00 1.69EÀ02 4.02 ABCC1 rs35629 Intron 15 C T 0.80 0.76 5.46EÀ01 6.24EÀ01 1.00E+00 1.32 ABCC1 rs2269800 Intron 20 A G 0.74 0.66 4.53EÀ01 8.06EÀ01 2.78EÀ01 3.52 ABCC1 rs11864374 Intron 21 G A 0.78 0.77 8.41EÀ01 1.00E+00 1.00E+00 1.63 ABCC1 rs3887893 Intron 22 A G 0.48 0.46 8.62EÀ01 2.30EÀ01 5.85EÀ01 2.10 ABCC1 rs4148376 Intron 23 A G 0.93 0.95 1.00E+00 1.00E+00 1.00E+00 1.30 ABCC1 rs2238475 Intron 23 C A 0.11 0.18 3.45EÀ01 1.00E+00 4.21EÀ01 1.80 ABCC1 rs212079 Intron 26 G A 0.76 0.83 3.77EÀ01 1.00E+00 6.71EÀ02 8.55 ABCC1 rs2283512 Intron 26 G T 0.48 0.46 1.00E+00 7.68EÀ01 1.00E+00 1.32 ABCC1 rs212081 Intron 27 T C 0.20 0.22 8.34EÀ01 5.73EÀ01 4.61EÀ01 1.50 ABCC1 rs212084 Intron 28 G A 0.68 0.77 2.90EÀ01 3.02EÀ01 6.00EÀ01 1.81 ABCC1 rs212087 Intron 28 C T 0.57 0.70 1.41EÀ01 1.38EÀ01 3.45EÀ01 2.30 ABCC1 rs4148380 3' UTR G A 0.87 0.89 7.88EÀ01 7.75EÀ01 1.00E+00 1.22 ABCC1 rs212091 3' UTR G A 0.22 0.34 1.84EÀ01 2.68EÀ01 3.35EÀ01 4.04 ABCC1 rs12448760 3' near gene G A 0.82 0.89 2.95EÀ01 3.79EÀ01 1.00E+00 1.79 ABCC1 rs9932935 3' near gene (ABCC6 Intron 29) A T 0.96 0.91 5.12EÀ01 5.00EÀ01 1.00E+00 1.93 ABCC1 rs2066738 3' near gene (ABCC6 Intron 28) C T 0.74 0.90 1.50EÀ02 5.28EÀ02 7.81EÀ02 2.95 ABCC1 rs169845 3' near gene (ABCC6 Intron 27) G C 0.26 0.40 1.04EÀ01 3.28EÀ01 2.13EÀ01 2.07 ABCC1 rs2238471 3' near gene (ABCC6 Intron 26) A C 0.93 0.81 5.49EÀ02 5.79EÀ02 1.00E+00 3.78 ABCC1 rs3213471 3' near gene (ABCC6 Intron 24) A G 0.91 0.92 1.00E+00 7.33EÀ01 1.00E+00 1.32 ABCC1 rs3213473 3' near gene (ABCC6 Intron 24) T G 0.16 0.13 7.98EÀ01 1.00E+00 7.71EÀ01 1.27 CES2 rs3843712 5' near gene G A 0.18 0.12 4.41EÀ01 1.00E+00 4.00EÀ01 1.80 CES2 rs8062110 5' near gene G C 0.61 0.65 7.16EÀ01 1.00E+00 7.28EÀ01 1.39 CES2 rs4783744 5' near gene G A 0.66 0.62 8.37EÀ01 7.76EÀ01 1.00E+00 1.24 CES2 rs7194513 5' near gene G A 0.26 0.27 1.00E+00 3.14EÀ01 6.29EÀ01 NA CES2 rs28382812c Exon 1 (Ile 37 Ile) C T 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CES2 rs2241410 Intron 2 T G 0.10 0.11 7.85EÀ01 1.00E+00 7.71EÀ01 1.26 CES2 rs2303218 Intron 2 G A 0.09 0.21 1.03EÀ01 5.55EÀ01 1.15EÀ01 2.70 CES2 rs8192924c Exon 5 (His 270 Arg) G A 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CES2 rs28382827c Exon 12 (Leu 613 Leu) C T 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA Abbreviations: Chrom, chromosome; HWE, Hardy-Weinberg equilibrium; NA, not available; SNP, single nucleotide polymorphism.
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ABCC2 p.Ser185Thr 19696792:48:7499
status: NEW[hide] Association study of genetic polymorphism in ABCC4... J Hum Genet. 2009 Oct;54(10):564-71. Epub 2009 Aug 21. Low SK, Kiyotani K, Mushiroda T, Daigo Y, Nakamura Y, Zembutsu H
Association study of genetic polymorphism in ABCC4 with cyclophosphamide-induced adverse drug reactions in breast cancer patients.
J Hum Genet. 2009 Oct;54(10):564-71. Epub 2009 Aug 21., [PMID:19696793]
Abstract [show]
Cyclophosphamide (CPA)-based combination treatment has known to be effective for breast cancer, but often causes adverse drug reactions (ADRs). Hence, the identification of patients at risk for toxicity by CPA is clinically significant. In this study, a stepwise case-control association study was conducted using 403 patients with breast cancer who received the CPA combination therapy. A total of 143 genetic polymorphisms in 13 candidate genes (CYP2B6, CYP2C9, CYP2C19, CYP3A4, CYP3A5, ALDH1A1, ALDH3A1, GSTA1, GSTM1, GSTP1, GSTT1, ABCC2 and ABCC4), possibly involved in the activation, metabolism and transport of CPA, were genotyped using 184 cases who developed either > or =grade 3 leukopenia/neutropenia or > or =grade 2 gastrointestinal toxicity and 219 controls who did not show any ADRs throughout the treatment. The association study revealed that one SNP, rs9561778 in ABCC4, showed a significant association with CPA-induced ADRs (Cochran-Armitage trend's P-value=0.00031; odds ratio (OR)=2.06). Subgroup analysis also indicated that the SNP rs9561778 was significantly associated with two major ADR subgroups; gastrointestinal toxicity and leukopenia/neutropenia (Cochran-Armitage trend's P-value=0.00019 and 0.014; OR=2.31 and 1.83). Furthermore, the SNP rs9561778 showed an association with breast cancer patients who were treated with CA(F) drug regimen-induced ADR (Cochran-Armitage trend's P-value=0.00028; OR=3.13). The SNPs in ABCC4 might be applicable in predicting the risk of ADRs in patients receiving CPA combination chemotherapy.
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53 This subgroup analysis revealed that the SNP rs9561778 in ABCC4 Table 1 Patients` characteristics Case (ADR) Control (non-ADR) The number of samples First set 76 140 Second set 108 79 Total 184 219 Mean age at diagnosis 57.7 52.0 Types of adverse drug reaction ^Grade 3 leucopenia or neutropenia 91 219 ^Grade 2 gastrointestinal toxicity 118 219 Table 2 Relationship between single nucleotide polymorphisms (SNPs) in candidate genes and ADR risk induced by CPA combination therapy MAF Cochran-Armitage HWE CHR Gene SNP Allele1 Allele2 Position/effect ADR Non-ADR trend P-value ADR Non-ADR 6 GSTA rs9367495 C T 3' UTR GSTA1 0.16 0.09 0.059 0.38 1.00 6 rs9395826 G A 3' UTR GSTA5 0.34 0.29 0.26 0.61 0.53 6 rs7739421 A G Intron 6 of GSTA5 0.18 0.20 0.68 0.71 0.79 6 rs9370155 G C Intron 5 of GSTA5 0.16 0.19 0.44 0.68 0.41 7 CYP3A5 rs776746 T C Intron_3 0.24 0.22 0.64 1.00 0.62 7 CYP3A4 rs28371759 C T Pro293Leu 0.03 0.01 0.22 1.00 1.00 7 rs12721627 G C Ser185Thr 0.02 0.00 0.092 1.00 1.00 9 ALDH1A1 rs4646548 G A 3' UTR 0.46 0.40 0.20 0.47 0.72 9 rs348471 G A Intron 12 0.48 0.42 0.26 0.36 0.86 9 rs1330291 T C Intron 11 0.08 0.10 0.66 1.00 0.62 9 rs4646544 C A Intron 7 0.09 0.10 0.65 0.08 1.00 9 rs8187929 A T Phe177Ile 0.03 0.04 0.72 1.00 1.00 9 rs13959 T C Exon 3 syn. 0.45 0.43 0.61 0.50 0.22 9 rs647880 A G Intron 1 0.46 0.49 0.60 0.16 0.50 9 rs10156653 T C Intergenic 0.46 0.50 0.47 0.64 0.24 9 rs3003989 C T Intergenic 0.05 0.03 0.47 0.14 1.00 9 rs7853400 G A Intergenic 0.38 0.42 0.41 0.81 0.49 10 CYP2C9 rs1074145 A G Intergenic 0.29 0.25 0.35 0.26 0.021 10 rs10509679 A G Intron 4 0.32 0.28 0.42 0.19 0.10 10 rs4918766 A G Intron 5 0.54 0.44 0.045 0.25 0.50 10 rs1057910 C A Tyr358Leu 0.05 0.05 0.99 1.00 1.00 10 rs1934968 T C Intron 7 0.22 0.30 0.057 0.74 1.00 10 rs11188133 G A 5' UTR 0.44 0.51 0.15 0.82 0.31 10 CYP2C19 rs4986893 A G Ter212Trp 0.18 0.13 0.20 1.00 1.00 10 rs4244285 A G Exon 5 syn. 0.31 0.26 0.26 0.29 0.045 10 ABCC2 rs2804398 T A Intron 7 0.14 0.12 0.59 0.62 0.41 10 rs2756109 T G Intron 7 0.36 0.34 0.80 0.13 0.19 10 rs11190291 T C Intron 11 0.14 0.14 0.99 0.34 0.14 10 rs2002042 T C Intron 19 0.31 0.32 0.92 0.03 0.17 10 rs3740065 G A Intron 29 0.35 0.36 0.91 0.80 0.14 10 rs12762549 C G Intergenic 0.42 0.44 0.76 0.35 0.010 10 rs2862691 T C Intergenic 0.23 0.21 0.65 1.00 0.44 11 GSTP1 rs612020 T C Intergenic 0.20 0.20 0.86 0.47 1.00 11 rs614080 G A 5' UTR 0.38 0.35 0.55 0.47 0.57 11 rs1695 G A Val105Ile 0.17 0.14 0.35 0.44 0.72 13 ABCC4 rs4148542 G A Intron 30 0.50 0.48 0.67 0.06 0.50 13 rs9561765 A G Intron 30 0.27 0.27 0.99 0.39 0.28 13 rs6492763 T C Intron 30 0.46 0.51 0.35 0.37 0.31 13 rs2182262 T C Intron 29 0.26 0.23 0.43 0.37 1.00 13 rs4148540 T C Intron 29 0.24 0.28 0.41 0.76 0.30 13 rs1614102 A G Intron 26 0.30 0.21 0.037 0.42 0.44 13 rs1751031 G A Intron 26 0.28 0.33 0.28 0.39 0.08 13 rs9561778 T G Intron 26 0.24 0.13 0.0086 0.75 0.71 13 rs931110 G A Intron 26 0.53 0.47 0.29 0.65 0.12 13 rs4148532 T A Intron 21 0.22 0.14 0.032 1.00 0.73 13 rs17234998 T C Intron 20 0.16 0.21 0.22 0.19 0.015 13 rs1751055 T C Intron 20 0.28 0.34 0.23 0.78 0.19 13 rs2698243 C T Intron 20 0.47 0.51 0.39 0.36 0.17 13 rs1729775 A G Intron 20 0.28 0.18 0.027 1.00 1.00 2 Continued MAF Cochran-Armitage HWE CHR Gene SNP Allele1 Allele2 Position/effect ADR Non-ADR trend P-value ADR Non-ADR 13 rs9561784 G A Intron 20 0.19 0.21 0.64 0.45 0.19 13 rs1729741 G A Intron 19 0.13 0.18 0.23 1.00 0.57 13 rs1751070 G C Intron 19 0.23 0.15 0.029 0.33 0.31 13 rs2619313 T C Intron 19 0.24 0.23 0.78 0.03 0.46 13 rs997777 T A Intron 19 0.38 0.39 0.85 0.15 0.48 13 rs4148508 T A Intron 19 0.16 0.15 0.64 0.68 0.17 13 rs1479390 A C Intron 19 0.27 0.31 0.34 1.00 0.84 13 rs7988595 C A Intron 19 0.19 0.27 0.057 1.00 0.83 13 rs7988271 T C Intron 19 0.10 0.16 0.10 0.54 0.75 13 rs3765534 T C Lys757Glu 0.11 0.17 0.14 1.00 0.54 13 rs1729764 G A Intron 16 0.33 0.32 0.93 1.00 0.85 13 rs4148500 T C Intron 15 0.21 0.19 0.57 0.30 0.41 13 rs9561797 G A Intron 14 0.28 0.36 0.080 0.57 0.26 13 rs12429339 A T Intron 14 0.16 0.17 0.70 0.38 1.00 13 rs1729786 A G Intron 13 0.30 0.23 0.12 0.42 0.34 13 rs1189458 C T Intron 13 0.31 0.37 0.24 0.79 0.46 13 rs6492768 G A Intron 13 0.48 0.46 0.69 0.50 1.00 13 rs1751003 A G Intron 13 0.15 0.16 0.88 0.67 0.74 13 rs1887162 T G Intron 13 0.22 0.27 0.31 0.51 0.67 13 rs10161985 T C Intron 11 0.45 0.43 0.66 0.16 0.39 13 rs1564352 T G Intron 11 0.33 0.35 0.80 1.00 0.71 13 rs10162199 T C Intron 11 0.33 0.30 0.61 1.00 0.69 13 rs3843689 G A Intron 11 0.29 0.30 0.81 0.58 0.84 13 rs2766474 A G Intron 11 0.15 0.16 0.76 0.65 0.75 13 rs1557069 G A Intron 10 0.24 0.22 0.76 1.00 0.47 13 rs4773843 T C Intron 10 0.13 0.15 0.59 1.00 1.00 13 rs9561802 A G Intron 10 0.17 0.15 0.61 1.00 0.74 13 rs1678374 T C Intron 9 0.41 0.40 0.96 1.00 0.28 13 rs4148486 T C Intron 9 0.33 0.33 0.95 0.43 0.70 13 rs7319330 C T Intron 9 0.47 0.50 0.65 1.00 0.73 13 rs4148481 C T Intron 9 0.40 0.41 0.88 1.00 0.59 13 rs1678384 A G Intron 8 0.05 0.07 0.63 1.00 0.012 13 rs4148478 C T Intron 8 0.29 0.31 0.67 0.58 0.55 13 rs1751022 T C Intron 8 0.24 0.21 0.52 0.11 0.61 13 rs1751025 G C Intron 8 0.30 0.29 0.78 1.00 0.83 13 rs4773844 T C Intron 8 0.27 0.29 0.79 0.24 0.53 13 rs17268170 T C Intron 8 0.07 0.07 0.81 1.00 1.00 13 rs9556465 T G Intron 8 0.07 0.09 0.41 1.00 0.60 13 rs1751029 A G Intron 8 0.19 0.18 0.78 0.06 0.25 13 rs2274408 T C Intron 7 0.45 0.42 0.54 0.65 0.22 13 rs9524827 C T Intron 6 0.38 0.37 0.87 0.32 0.71 13 rs873706 T C Intron 5 0.37 0.37 0.95 0.63 0.35 13 rs11568658 T G Trp187Gly 0.07 0.10 0.43 0.33 0.61 13 rs9524831 C A Intron 4 0.26 0.28 0.75 0.37 0.52 13 rs7330519 T C Intron 4 0.49 0.50 0.84 0.35 0.49 13 rs4773856 A G Intron 4 0.22 0.22 0.98 0.75 1.00 13 rs9561814 C T Intron 4 0.17 0.18 0.82 0.03 0.77 13 rs7333234 A G Intron 4 0.32 0.34 0.79 0.43 0.70 13 rs4148456 G A Intron 3 0.09 0.09 0.94 1.00 1.00 13 rs9561817 T C Intron 3 0.37 0.38 0.89 0.32 0.58 13 rs4258481 C G Intron 3 0.51 0.49 0.69 0.10 0.86 13 rs12427972 A G Intron 3 0.28 0.32 0.42 0.24 0.69 13 rs2892715 A G Intron 3 0.16 0.11 0.14 0.0022 1.00 13 rs4148450 G A Intron 3 0.28 0.32 0.39 0.26 0.84 13 rs10508019 T C Intron 3 0.22 0.28 0.23 0.33 0.67 13 rs4148440 A G Intron 3 0.45 0.47 0.71 0.35 0.12 13 rs4148436 C T Intron 2 0.27 0.22 0.30 0.37 0.80 13 rs4148434 A G Intron 1 0.20 0.16 0.33 0.06 0.34 showed a significant association with a higher odds ratio (Cochran-Armitage trend`s P-value¼0.00028; OR¼3.13; 95% CI¼1.68-5.83) with patients treated with the CA(F) regimen (Table 5).
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ABCC2 p.Ser185Thr 19696793:53:954
status: NEW