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.

X

ABCB1 p.Val1251Ile 15882131:126:531

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106 Position Allele Amino acid Allele frequency in Caucasian populations Allele frequency in Japanese populatins Allele frequency in African populations n % n % n % 61 A G 21 Asn 21 Asp 799 89.7 10.3 193 100 0 100 97.5 2.5 266 T C 89 Met 89 Thr 100 99.5 0.5 145 100 0 100 100 0 307 T C 103 Phe 103 Leu 546 99.9 0.1 48 100 0 ND ND ND 325 G A 108 Glu 108 Lys ND ND ND 37 95.9 4.1 ND ND ND 781 A G 261 Ile 261 Val 100 100 0 145 100 0 100 98.5 1.5 1199 G A 400 Ser 400 Asn 696 95.0 5.0 193 100 0 100 99 1 1985 T G 662 Leu 662 Arg 100 99.5 0.5 145 100 0 100 100 0 2005 C T 669 Arg 669 Cys 100 100 0 145 100 0 100 99 1 2485 A G 829 Ile 829 Val 185 99.2 0.8 ND ND ND ND ND ND 2547 A G 849 Ile 849 Met 100 99.5 0.5 145 100 0 100 100 0 2677 G T A 893 Ala 893 Ser 893 Thr 611 55.1 42.1 2.8 241 40.0 41.1 18.9 100 90 10 0.5 2956 A G 986 Met 986 Val ND ND ND 100 99.5 0.5 ND ND ND 3151 C G 1051 Pro 1051 Ala 100 100 0 145 100 0 100 99.5 0.5 3320 A C 1107 Gln 1107 Pro 461 99.8 0.2 ND ND ND ND ND ND 3322 T C 1108 Trp 1108 Arg 100 100 0 145 100 0 100 99.5 0.5 3421 T A 1141 Ser 1141 Thr 100 100 0 145 100 0 100 88.9 11.1 3751 G A 1251 Val 1251 Ile 100 100 0 145 99 1 100 100 0 3767 C A 1256 Thr 1256 Lys 100 99.5 0.5 145 100 0 100 100 0 Data from [31-38, 203].

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ABCB1 p.Val1251Ile 16259577:106:1118

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129 N21D M89T N44S H2N F103L E108K N183S G185V I261V S400N R492C A599T L662R R669C V801M A893S/T I829V I849M M986V A999T G1063A P1051A Q1107P W1108R I1145M S1141T V1251I T1256K COOH ATP-binding site ATP-binding site EXTRACELLULAR INTRACELLULAR A80E Figure 2.

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ABCB1 p.Val1251Ile 16259577:129:159

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532 Nucleotide change rs number Amino acid change 49T>C rs28381804 F17L 61A>G rs61615398; rs9282564 N21D 131A>G rs1202183 N44S 178A>C rs41315618 I60L 239C>A rs9282565 A80E 266T>C Rs35810889 M89T 431T>C rs61607171 I144T 502G>A rs61122623 V168I 548A>G rs60419673 N183S 554G>T rs1128501 G185V 781A>G rs36008564 I261V 1199G>A rs2229109 S400N 1696G>A rs28381902 E566K 1777C>T rs28381914 R593C 1778G>A rs56107566 R593H 1795G>A rs2235036 A599T 1837G>T rs57001392 D613Y 1985T>G rs61762047 L662R 2005C>T rs35023033 R669C 2207A>T rs41316450 I736K 2398G>A rs41305517 D800N 2401G>A rs2235039 V801M 2485A>G rs2032581 I829V 2506A>G rs28381967 I836V 2547A>G rs36105130 I849M 2677T>A/G rs2032582 S893A/T 2975G>A rs56849127 S992N 3151C>G rs28401798 P1051A 3188G>C rs2707944 G1063A 3262G>A rs57521326 D1088N 3295A>G rs41309225 K1099E 3320A>C rs55852620 Q1107P 3322T>C rs35730308 W1108R 3410G>T rs41309228 S1137I 3421T>A rs2229107 S1141T 3502A>G rs59241388 K1168E 3669A>T rs41309231 E1223D 3751G>A rs28364274 V1251I 3767C>A r35721439 T1256K Data are from NCBI dbSNP (access date: 2 August 2008).

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ABCB1 p.Val1251Ile 18855611:532:986

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86 = UGT1A1*6 or *28. a BJL contains -1789G[A, *2 (block 1) = 325G[A (E109K), *3 (block 1) = 304G[A (G102R); b *2 (block 2) contains 2677G[T (A893S); c *1b (block 3) = IVS27-182G[T, *2 (block 3) = 3751G[ A (V1251I); d *1A contains -1774delG; e IIB contains 421C[A (Q141K) and IVS12 ?

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ABCB1 p.Val1251Ile 19771428:86:204

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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.Val1251Ile 19771428:124:275

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103 A total of 30 segregating sites have not been previously described, including eight non-synonymous changes coding for the following amino acid changes: Met89Thr, Leu662Arg, Arg669Cys, Ile849Met, Pro1051Ala, Trp1108Arg, Val1251Ile, and Thr1256Lys.

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ABCB1 p.Val1251Ile 12893986:103:219

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113 An additional five coding variants occurred at sites that were conserved in six of the seven species, including those resulting in the Arg669Cys, Ile849Met, Trp1108Arg, and Val1251Ile changes.

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ABCB1 p.Val1251Ile 12893986:113:173

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141 Unauthorized reproduction of this article is prohibited. Table 1 Genetic variation in ABCB1 Allele frequencyd Variant cDNA NT DNA/AA AA Total CA AA AS ME PA No.a positionb changec position change (n ¼ 494) (n ¼ 200) (n ¼ 200) (n ¼ 60) (n ¼ 20) (n ¼ 14) 1.1Ã (À274) G to A Intron À1 0.006 0 0.016 0 0 0 1.2Ã (À223) C to T Intron À1 0.002 0.005 0 0 0 0 1.3Ã (À146) T to C Intron À1 0.002 0 0.005 0 0 0 1.4Ã (À60) A to T Intron À1 0.004 0 0.010 0 0 0 1.5 (À41) A to G Intron À1 0.002 0 0 0.017 0 0 1.6Ã À241 G to A Non-coding 0.002 0 0 0.017 0 0 1.7 À145 C to G Non-coding 0.002 0 0 0.017 0 0 1.8 À129 T to C Non-coding 0.060 0.051 0.071 0.036 0.100 0.071 1.9 À43 A to G Non-coding 0.012 0 0.020 0.036 0 0 1.10Ã (+140) C to A Intron 1 0.013 0.005 0.021 0 0 0.071 1.11Ã (+237) G to A Intron 1 0.004 0 0.010 0 0 0 2.1 À4 C to T Non-coding 0.004 0 0.010 0 0 0 2.2 À1 G to A Non-coding 0.036 0.080 0.005 0 0.050 0 2.3 61 A to G 21 Asn to Asp 0.045 0.080 0.025 0.017 0 0 4.1Ã (À8) C to G Intron 3 0.002 0.005 0 0 0 0 4.2Ã 266 T to C 89 Met to Thr 0.002 0.005 0 0 0 0 5.1 (À25) G to T Intron 4 0.210 0.158 0.300 0.067 0.200 0.286 8.1 729 A to G 243 Syn 0.002 0.005 0 0 0 0 8.2Ã 781 A to G 261 Ile to Val 0.006 0 0.015 0 0 0 10.1Ã (À44) A to G Intron 9 0.400 0.450 0.255 0.685 0.450 0.571 11.1Ã (À41) T to G Intron 10 0.002 0 0 0.017 0 0 11.2 1199 G to A 400 Ser to Asn 0.014 0.025 0.010 0 0 0 12.1Ã (À4) G to A Intron 11 0.002 0 0.005 0 0 0 12.2 1236 C to T 412 Syn 0.385 0.459 0.209 0.685 0.450 0.571 12.3Ã 1308 A to G 436 Syn 0.002 0 0.005 0 0 0 12.4Ã (+17) G to A Intron 12 0.008 0 0.020 0 0 0 12.5 (+44) C to T Intron 12 0.088 0.046 0.168 0 0 0 13.1 (+24) C to T Intron 13 0.530 0.521 0.542 0.540 0.450 0.571 14.1 1617 C to T 539 Syn 0.002 0.005 0 0 0 0 14.2 (+38) A to G Intron 14 0.540 0.505 0.540 0.683 0.450 0.500 15.1 (+38) G to A Intron 15 0.004 0.005 0.005 0 0 0 16.1Ã 1985 T to G 662 Leu to Arg 0.002 0.005 0 0 0 0 16.2Ã 2005 C to T 669 Arg to Cys 0.004 0 0.010 0 0 0 18.1Ã (À27) A to G Intron 17 0.008 0.010 0.005 0 0.050 0 20.1Ã (+8) C to G Intron 20 0.002 0 0.005 0 0 0 20.2 (+24) G to A Intron 20 0.126 0.121 0.150 0.067 0.200 0 20.3Ã (+40) C to T Intron 20 0.014 0 0.035 0 0 0 21.1Ã 2547 A to G 849 Ile to Met 0.002 0.005 0 0 0 0 21.2 2650 C to T 884 Syn 0.004 0.005 0.005 0 0 0 21.3a 2677 G to T 893 Ala to Ser 0.308 0.464 0.100 0.450 0.400 0.357 21.3b 2677 G to A 893 Ala to Thr 0.035 0.036 0.005 0.067 0 0.357 22.1 (+31) G to A Intron 22 0.002 0 0.005 0 0 0 25.1Ã 3151 C to G 1051 Pro to Ala 0.002 0 0.005 0 0 0 26.1Ã 3322 T to C 1108 Trp to Arg 0.002 0 0.005 0 0 0 26.2 3421 T to A 1141 Ser toThr 0.047 0 0.111 0 0.050 0 26.3 3435 C to T 1145 Syn 0.392 0.561 0.202 0.400 0.500 0.500 28.1 3751 G to A 1251 Val to Ile 0.002 0 0 0 0.050 0 28.2 3767 C to A 1256 Thr to Lys 0.002 0.005 0 0 0 0 28.3 (+21) T to C Intron 28 0.031 0 0.077 0 0 0 a Variants are numbered sequentially by exon.

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ABCB1 p.Val1251Ile 12893986:141:2967

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164 M89T I849M V1251I T1256K S1141TW1108R P1052AR669C A893S/T L662R Cytoplasm S400N I261V N21D Extracellular Fig. 1.

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ABCB1 p.Val1251Ile 12893986:164:11

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102 Unauthorized reproduction of this article is prohibited. Copyright(c)LippincottWilliams&Wilkins.Unauthorizedreproductionofthisarticleisprohibited. Table 2 List of SNPs and deletion/insertion of the ABCB1 gene found in a Japanese population SNP IDÃ Position Nucleotide Effect on Block Site Our SNP ID NCBI IMS-JST NT_007933.10 cDNA-based change protein Frequency Block À1 59-Flanking MPJ6_AB1057 12472341 À8104 T.C 0.003 59-Flanking MPJ6_AB1059 12472207 À7970 C.T 0.007 Block 1 59-Flanking MPJ6_AB1002 rs2188524 ssj0000008 12464608 À371 A.G 0.128 Exon 1 (59-UTR) MPJ6_AB1003 12464382 À145 C.G 0.024 Exon 1 (59-UTR) MPJ6_AB1004 rs3213619 ssj0000009 12464366 À129 T.C 0.093 Intron 1 MPJ6_AB1005 rs3214119 ssj0000010 12463753 IVS1-74 delG 0.121 Intron 3 MPJ6_AB1008 rs2235074 12459219 IVS3+36 C.T 0.093 Intron 4 MPJ6_AB1010 rs2235014 12433788 IVS4-76 T.C 0.017 Intron 4 MPJ6_AB1011 rs2235015 12433737 IVS4-25 G.T 0.086 Exon 5 MPJ6_AB1012 12433674 325 G.A E109K 0.010 Intron 5 MPJ6_AB1013 rs2235016 12433585 IVS5+76 T.G 0.055 Block 2 Intron 5 MPJ6_AB1014 rs2235018 12433538 IVS5+123 A.G 0.141 Intron 5 MPJ6_AB1015 rs2235020 12433438 IVS5+223 A.T 0.548 Intron 5 MPJ6_AB1016 rs2235021 12433437 IVS5+224 G.T 0.548 Intron 6 MPJ6_AB1017 12429839 IVS6-109 G.T 0.007 Intron 7 MPJ6_AB1018 12429545 IVS7+14 G.A 0.010 Intron 8 MPJ6_AB1020 rs1922240 ssj0000016 12417527 IVS8-106 A.G 0.348 Intron 9 MPJ6_AB1021 12414371 IVS9-44 G.A 0.445 Intron 10 MPJ6_AB1023 rs2235029 12414108 IVS10-41 T.G 0.017 Exon 12 MPJ6_AB1025 rs1128503 12413774 1236 C.T G412G (silent) 0.555 Intron 12 MPJ6_AB1052 12413643 IVS12+17 G.A 0.010 Intron 13 MPJ6_AB1026 rs2235033 ssj0000018 12413316 IVS13+24 T.C 0.445 Intron 13 MPJ6_AB1027 rs2235035 ssj0000019 12413259 IVS13+81 C.T 0.348 Intron 14 MPJ6_AB1028 rs2235013 ssj0000020 12412799 IVS14+38 G.A 0.445 Intron 15 MPJ6_AB1029 12408557 IVS15-69 T.C 0.014 Intron 16 MPJ6_AB1030 rs2235046 12408239 IVS16+73 A.G 0.452 Intron 16 MPJ6_AB1031 rs1922242 12407840 IVS16-76 T.A 0.369 Intron 18 MPJ6_AB1034 12402869 IVS18-35 G.C 0.003 Intron 20 MPJ6_AB1035 rs2235040 ssj0000027 12399923 IVS20+24 G.A 0.090 Exon 21 MPJ6_AB1036 12394791 2677 G.A A893T 0.200 Exon 21 MPJ6_AB1037 rs2032582 12394791 2677 G.T A893S 0.403 Intron 21 MPJ6_AB1038 rs2032583 ssj0000031 12394734 IVS21+49 T.C 0.090 Intron 24 MPJ6_AB1040 12379982 IVS24+16 C.T 0.031 Exon 26 MPJ6_AB1041 rs1045642 ssj0000040 12372818 3435 C.T I1145I (silent) 0.441 Intron 26 MPJ6_AB1042 rs2235047 ssj0000048 12372705 IVS26+59 T.G 0.403 Intron 26 MPJ6_AB1043 rs2235048 ssj0000049 12372684 IVS26+80 T.C 0.448 Block 3 Exon 27 MPJ6_AB1068 12369435 3587 T.G I1196S 0.003 Intron 27 MPJ6_AB1044 12369323 IVS27+63 C.G 0.003 Intron 27 MPJ6_AB1053 12368127 IVS27-189 A.G 0.007 Intron 27 MPJ6_AB1045 rs1186745 ssj0000051 12368120 IVS27-182 G.T 0.200 Intron 27 MPJ6_AB1054 12368110 IVS27-172 G.A 0.010 Intron 27 MPJ6_AB1047 rs1186744 12368106 IVS27-168 T.C 0.010 Intron 27 MPJ6_AB1048 12368105 IVS27-167 A.G 0.014 Intron 27 MPJ6_AB1055 12368090 IVS27-152 A.G 0.003 Intron 27 MPJ6_AB1049 12368057 IVS27-119 C.T 0.021 Intron 27 MPJ6_AB1056 rs2235049 12368025 IVS27-87 A.G 0.007 Intron 27 MPJ6_AB1070 12368024 IVS27-86 T.C 0.003 Intron 27 MPJ6_AB1071 12368018 IVS27-80 ins C 0.003 Exon 28 MPJ6_AB1051 12367824 3751 G.A V1251I 0.010 ÃSNP ID assigned by our project team (MPJ-6).

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ABCB1 p.Val1251Ile 14646693:102:3291

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103 746Pharmacogenetics2003,Vol13No12 Copyright(c)LippincottWilliams&Wilkins.Unauthorizedreproductionofthisarticleisprohibited. Table 3 Classification of major ABCB1 haplotypes Site Exon 2 Exon 5 Exon 7 Exon 11 Exon 12 Exon 13 Exon 21 Exon 21 Exon 21 Exon 26 Exon 26 Exon 27 Exon 28 Positionà Exon 1 Exon 1 61A.G 325G.A 548A.G 1199G.A 1236C.T 1474C.T 2650C.T 2677G.T 2677G.A 3421T.A 3435C.T 3587T.G 3751G.A Effect on protein À4C.T À1G.A N21D E109K N183S S400N G412G R492C L884L A893S A893T S1141T I1145I I1196S V1251I Classification by Kim et al. [12] Ã1 - - - - - - - - - - - Ã1A - - - - A - - - - - - Ã1B T - - - - - - - - - - Ã1C - - - - - - - - - A - Ã1D - - - G - - - - - - - Ã2 - - - - - T - - T - T Ã2A - - G - - T - - T - T Ã2B - - - - - T - T T - T Ã2C - - - - - T T - T - T Ã3 - - - - - - - - T - T Ã4 - - - - - T - - - - T Ã5 - A - - - - - - - - T Ã6 - - - - - - - - - - T Ã7 - - - - - - - - T - - Ã8 - - - - - T - - - - - Classification of haplotype group detected in this paperÃà Block 1 Ã1 - - - - Ã2 - - G - Block 2 Ã1 - - - - - - - - - Ã2 - - T - - T - - T Ã4 - - T - - - - - T Ã6 - - - - - - - - T Ã8 - - T - - - - - - Ã9 - - - - - - - - - Ã10 - - - - - - A - - Ã11 - - T - - - A - - Block 3 Ã1 - - Ã2 - A Ã3 G - ÃAdenine of the initiation codon ATG in exon 2 was numbered +1.

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ABCB1 p.Val1251Ile 14646693:103:523

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154 The Ã2 and Ã3 haplotypes had a nonsynonymous SNP of 3751G.A (V1251I) and 3587T.G (I1196S), respectively.

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ABCB1 p.Val1251Ile 14646693:154:71

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162 *1b Block 3 Site Position Nucleotide change Effect on protein Exon 27 3587 TϾG I1196S Diplotype *1a/*1a Intron 27 Intron 27 IVS27 ϩ63 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Exon 28 IVS27 -189 IVS27 -182 IVS27 -172 IVS27 -168 IVS27 -167 IVS27 -152 IVS27 -119 IVS27 -87 IVS27 -86 IVS27 -80 3751 CϾG AϾG GϾT GϾA TϾC AϾG AϾG CϾT AϾG TϾC ins C GϾA V1251I *1a/*1b *1a/*1c *1a/*1d *1a/*1e *1a/*1f *1a/*1g *1a/*1h *1a/*1i *1a/*1j *1a/*1k *1a/*1m *1a/*1n *1a/*1p *1a/*1q ?

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ABCB1 p.Val1251Ile 14646693:162:472

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28 6, June 2004 ((c) 2004) 9040724-8741/04/0600-0904/0 (c) 2004 Plenum Publishing Corporation Table I. MDR1 Coding Variants cDNA positiona NT change DNA/AA position AA change Allele frequencyb Total (n ‫ס‬ 494) CA (n ‫ס‬ 200) AA (n ‫ס‬ 200) AS (n ‫ס‬ 60) ME (n ‫ס‬ 20) PA (n ‫ס‬ 14) 61 A to G 21 Asn to Asp 0.045 0.080 0.025 0.017 0 0 266 T to C 89 Met to Thr 0.002 0.005 0 0 0 0 729 A to G 243 Syn 0.002 0.005 0 0 0 0 781 A to G 261 Ile to Val 0.006 0 0.015 0 0 0 1199 G to A 400 Ser to Asn 0.014 0.025 0.010 0 0 0 1236 C to T 412 Syn 0.385 0.459 0.209 0.685 0.450 0.571 1308 A to G 436 Syn 0.002 0 0.005 0 0 0 1617 C to T 539 Syn 0.002 0.005 0 0 0 0 1985 T to G 662 Leu to Arg 0.002 0.005 0 0 0 0 2005 C to T 669 Arg to Cys 0.004 0 0.010 0 0 0 2547 A to G 849 Ile to Met 0.002 0.005 0 0 0 0 2650 C to T 884 Syn 0.004 0.005 0.005 0 0 0 2677 G to T 893 Ala to Ser 0.308 0.464 0.100 0.450 0.400 0.357 2677 G to A 893 Ala to Thr 0.035 0.036 0.005 0.067 0 0.357 3151 C to G 1051 Pro to Ala 0.002 0 0.005 0 0 0 3322 T to C 1108 Trp to Arg 0.002 0 0.005 0 0 0 3421 T to A 1141 Ser to Thr 0.047 0 0.111 0 0.050 0 3435 C to T 1145 Syn 0.392 0.561 0.202 0.400 0.500 0.500 3751 G to A 1251 Val to Ile 0.002 0 0 0 0.050 0 3767 C to A 1256 Thr to Lys 0.002 0.005 0 0 0 0 a cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number M14758.

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ABCB1 p.Val1251Ile 15212152:28:1294

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85 Ethnic diŠerences in nonsynonymous SNPs of ABCB1W MDR1 cDNA positiona Position and amino acid change C AA AS J 61AÀG N21D 0.080 0.025 0.017 0 266TÀC M89T 0.005 0 0 0 781AÀG I261V 0 0.015 0 0 1199GÀA S400N 0.025 0.010 0 0 1985TÀG L662R 0.005 0 0 0 2005CÀT R669C 0 0.010 0 0 2547AÀG I849M 0.005 0 0 0 2677GÀT A893S 0.464 0.100 0.450 0.403 2677GÀA A893T 0.036 0.005 0.067 0.200 3151CÀG P1051A 0 0.005 0 0 3322TÀC W1108R 0 0.005 0 0 3421TÀA S1141T 0 0.111 0 0 3751GÀA V1251I 0 0 0 0.010 3767CÀA T1256K 0.005 0 0 0 C, 100 Caucasians; AA, 100 African-Americans; AS, 30 Asians; J, 145 Japanese (our study 116) ).

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ABCB1 p.Val1251Ile 15499174:85:534

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11 Among these SNPs, only MPJ6äAB1051 resulted in an amino acid alteration, V1251I.

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ABCB1 p.Val1251Ile 15618713:11:78

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37 Novel SNPs in the ABCB1 gene found in Japanese individuals SNP name AB1017 AB1018 AB1021 AB1052 AB1029 AB1040 AB1053 AB1054 AB1048 AB1055 AB1049 AB1051 Intron 6 Intron 7 Intron 9 Intron 12 Intron 15 Intron 24 Intron 27 Intron 27 Intron 27 Intron 27 Intron 27 Exon 28 Position (NTä017168.9) 7251272 7251566 7266740 7267488 7272554 7301129 7312984 7313001 7313006 7313021 7313054 7313287 Position (cDNA) IVS6 „109a IVS7 +14b IVS9 „44 IVS12 +17 IVS15 „69 IVS24 +16 IVS27 „189 IVS27 „172 IVS27 „167 IVS27 „152 IVS27 „119 3751 Nucleotide change GÀT GÀA GÀA GÀA TÀC CÀT AÀG GÀA AÀG AÀG CÀT GÀA Amino acid change V1251I Frequency, z G: 99.2 G: 99.2 G:56.7 G: 98.3 T: 98.3 C: 99.2 A: 98.3 G: 97.5 A: 98.3 A: 99.2 C: 99.2 G: 98.3 T: 0.8 A: 0.8 A:43.3 A: 1.7 C: 1.7 T: 0.8 G: 1.7 A: 2.5 G: 1.7 G: 0.8 T: 0.8 A: 1.7 a Numbers following IVS (intervening sequence) represents number of the preceding exon.

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ABCB1 p.Val1251Ile 15618713:37:711

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74 Of these SNPs, only one SNP, MPJ6äAB1051 which was found in 2 subjects, introduced a nonsynonymous amino acid change (V1251I).

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ABCB1 p.Val1251Ile 15618713:74:123

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159 As observed previously, the rare haplotype groups * 2 [3751G>A (V1251I)] and * 3 [3587T>G (I1196S)] were observed at frequencies of 0.014 and 0.001, respectively.

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ABCB1 p.Val1251Ile 16907707:159:64

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4 The A893S, A893T, and V1251I variants and the N21D/ 1236CϾT/A893S/3435CϾT haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner.

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ABCB1 p.Val1251Ile 18287207:4:22

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55 The following variants were created from the reference ABCB1 plasmid in pCIneo: 61AϾG (N21D), 1199GϾA (S400T), 1596TϾG [a nonfunctional nucleotide-binding domain (NBD) mutant], 2005CϾT (R669C), 2677GϾA (A893T), 3421TϾA (S1141T), and 3751GϾA (V1251I).

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ABCB1 p.Val1251Ile 18287207:55:284

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103 There are six polymorphic residues that meet these criteria: N21D, S400T, R669C, A893S/T, S1141T, and V1251I.

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ABCB1 p.Val1251Ile 18287207:103:102

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111 Intra-and interexperimental replicates (n ϭ 3) for reference, NBD, and variant P-gp samples have TABLE 2 Allele frequencies, evolutionary conservation, and Grantham values for selected ABCB1 nonsynonymous polymorphisms and haplotypes Variant or Haplotype Allele Frequenciesa Amino Acid Conservationc Grantham Valued Nucleotide Change Amino Acid Change AA (n ϭ 200) CA (n ϭ 200) Reference Variant % 61AϾG N21D 2.5 8 23 1199GϾA S400T 1 2.5 d, ha, mk ms, r 46 2005CϾT R669C 1 0 d, ha, mk, r, s 180 2677GϾT A893S 10 46.4 ha, ms, r d, mk, s 99 2677GϾA A893T 0.5 3.6 ha, ms, r 58 3421TϾA S1141T 11.1 0 d, ha, mk, ms, r, s 58 3751GϾA V1251I 0b 0 d, ha, mk, ms, r s 29 1236CϾT/2677GϾT/3435CϾT A893S 6 34 N.A. N.A. N.A. 61AϾG/1236CϾT/2677GϾT/3435CϾT N21D/A893S 2.5 8 N.A. N.A. N.A. N.A., not applicable.

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ABCB1 p.Val1251Ile 18287207:111:687

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163 Six of 13 previously described nonsynonymous variants were chosen for study based on an allele frequency Ͼ2%: N21D, S400N, A893S, A893T, S1141T, and V1251I.

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ABCB1 p.Val1251Ile 18287207:163:155

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170 The data collected in the absence of cyclosporin A for empty vector (gray, dotted), P-gp reference (black), NBD mutant (gray), A893S (green), V1251I (blue), and haplotype N21D/1236CϾT/A893S/3534CϾT (red) are shown in a representative fluorescence histogram (a).

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ABCB1 p.Val1251Ile 18287207:170:142

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171 The effects of cyclosporin A on BODIPY-FL-paclitaxel accumulation are displayed in a representative histogram in b for P-gp reference (black, shaded), A893S (green), A893T (orange), S1141T (pink), V1251I (blue), and haplotype N21D/1236CϾT/A893S/3534CϾT (red).

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ABCB1 p.Val1251Ile 18287207:171:197

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189 The A893T and V1251I variants had lower intracellular levels of calcein, indicating increased efflux of calcein-AM by P-gp (Table 3).

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ABCB1 p.Val1251Ile 18287207:189:14

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199 Likewise, we found that the functional effects of A893S, A893T, V1251I, and N21N/1236CϾT/A893S/3435CϾT were substrate-dependent.

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ABCB1 p.Val1251Ile 18287207:199:64

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209 It should be noted that V1251I P-gp displays decreased function with BODIPY-FL-paclitaxel but increased function with calcein-AM.

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ABCB1 p.Val1251Ile 18287207:209:24

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211 There is no other data on the function of the V1251I variant, and testing additional substrates may elucidate the importance of this amino acid change.

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ABCB1 p.Val1251Ile 18287207:211:46

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214 There was increased function for A893S and S1141T depending on the substrate, TABLE 3 Substrateand inhibitor-dependent effects of P-gp variants on transport function Variant or Haplotype Calcein-AM BODIPY-FL-Paclitaxel -CsAa ϩCsAb -CsA ϩCsA N21D 1 S400T R669C 1 A893S 1 2 2 A893T 1 2 S1141T 2 V1251I 1 2 2 1236CϾT/A893S/3435CϾT N21D/1236CϾT/A893S/3435CϾT 2 2 a Arrows indicate statistically significant changes in P-gp function relative to reference in the absence of cyclosporin A (-CsA).

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ABCB1 p.Val1251Ile 18287207:214:305

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229 Intracellular accumulation of calcein-AM and/or BODIPY-FL-paclitaxel was altered by A893S, A893T, V1251I, and N21D/1236CϾT/A893S/3435CϾT.

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ABCB1 p.Val1251Ile 18287207:229:98

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48 Four of the 12 associated nsSNPs (E3/61A4G, E5/266C4T, E17/1985T4C and E17/2005C4T) cannot be mapped to the mouse crystal Table 1 Genetic conservation of amino acids corresponding to ABCB1 coding region SNPs 1 - rs28381804 E3/49T>C (F17L) F17 W16 S16 Y17 Y35 F39 - A42 - - G11 - - 2 - rs41304191 E3/55C>T (L19L) L19 M18 M18 I19 G37 P41 - E44 - - L13 - - 3 - rs76199854 E3/57G>A (L19L) L19 M18 M18 I19 G37 P41 - E44 - - L13 - - --51I--64H-34K93N12N02K02K12N)D12N(G>A16/3E4652829sr-4 7.832.8105P12A01K88D61D18T07T55S34G34N44N)S44N(G>A131/5E3812021sr1sn5 6 ns2 rs41315618 E5/178A>C (I60L) I60 I59 I59 A71 I86 A97 G32 G104 K26 N37 L66 27.3 46.6 1.924.6368N75G64N421Y25G711I601I19V97A97A08A)E08A(A>C932/5E5652829sr3sn7 8 - rs35810889 E5/266C>T (M89T) - M89 F89 S85 T96 I112 - - - - - - - - 9 ns4 rs61607171 E7/431T>C (I144T) TM2 I144 I145 I140 V152 N168 I176 A98 A172 L93 V97 L124 36.4 40.9 2.645.45841G121T711V691A221T002S291S671A461V961V861V)I861V(A>G205/7E32622116sr5sn01 11 s1 rs1128500 E8/540C>T (S180S) S180 S181 S176 S188 E204 S212 L136 N208 E129 E133 E160 27.3 42.0 12 ns6 rs60419673 E8/548A>G (N183S) N183 N184 N179 N191 K207 E215 Q139 Q211 K132 A136 S163 27.3 39.9 9.045.54561G831S431F312G141F712G902G391G181G681G581G)V581G(T>G455/8E1058211sr7sn31 14 s2 rs1128502 E8/555A>T (G185G) G185 G186 G181 G193 G209 G217 F141 G213 F134 S138 G165 45.5 40.9 15 s3 rs2235022 E9/729A>G (E243E) E243 E244 E239 E251 E267 E275 I199 Q271 R192 M196 S223 18.2 33.3 16 s4 rs28381867 E9/738G>A (A246A) A246 A247 A242 A254 R270 M278 E202 V274 A195 T199 Y226 9.1 34.5 17 ns8 rs36008564 E9/781A>G (I261V) C-NBD (Internal) I261 I262 I257 V267 I285 I293 V217 I289 I210 H214 I241 36.4 50.3 18 s5 rs80153317 E10/879T>C (I293I) TM5 I293 I294 I289 I301 L317 M325 L249 I321 R242 S246 F273 18.2 36.3 19 ns9 rs2229109 E12/1199G>A (S400N) N-NBD (Internal) S400 S401 S396 N408 T424 Q439 T355 V428 Q348 T350 H386 18.2 60.7 20 s6 rs1128503 E13/1236C>T (G412G) N-NBD (External) G412 G413 G408 G420 G436 K451 D367 N440 D359 N361 D398 27.3 55.9 21 s7 rs35068177 E13/1308A>G (T436T) T436 T437 T432 T44 I460 C475 V391 I464 L383 I385 I422 54.5 64.6 22 s8 rs41311775 E15/1326G>A (R442R) R442 R443 R438 R450 R466 R481 R397 R470 R389 R391 R428 100.0 54.5 23 s9 rs35633772 E15/1617C>T (I539I) I539 I540 I535 I547 I563 I578 I494 I576 L486 I489 I571 90.9 65.8 24 s10 rs60247941 E15/1632C>T (A544A) A544 A545 A540 A552 A568 A583 A499 A581 I491 A494 A576 63.6 65.1 25 s11 rs2235012 E15/1662G>C (L554L) L554 L555 L550 L562 L578 L593 L509 L591 L501 L504 L586 100.0 73.6 26 s12 rs56871767 E15/1674G>A (T558T) T558 T559 T554 T566 T582 T597 T513 T595 T505 T508 T590 100.0 78.7 27 s13 rs59697741 E15/1695C>T (S565S) S565 S566 S561 S573 S589 S604 S520 S602 S512 S515 S597 100.0 75.4 28 ns10 rs28381902 E15/1696G>A (E566K) E566 E567 E562 E574 E590 E605 E521 E603 E513 E516 E598 100.0 76.6 29 ns11 rs28381914 E16/1777C>T (R593C) R593 R594 R589 R601 R617 R632 R548 R630 T540 E543 R627 54.5 67.3 30 ns12 rs56107566 E16/1778G>A (R593H ) R593 R594 R589 R601 R617 R632 R548 R630 T540 E543 R627 54.5 67.3 31 s14 rs28381915 E16/1794C>T (I598I) I598 I599 I594 I606 I622 I637 I553 I635 I545 I548 I632 100.0 65.5 32 ns13 rs2235036 E16/1795G>A (A599T) A599 A600 A595 A607 I623 V638 C554 V636 V546 V549 F633 54.5 63.6 33 ns14 rs57001392 E16/1837G>T (D613Y) N-NBD (External) D613 D614 D609 S621 R637 Q652 E568 N650 R560 N563 D677 45.5 60.5 -0.0637E--807A516E896K496M176E856L366L266L)R266L(C>T5891/71E06975653sr-43 35 - rs35023033 E17/2005C>T (R669C) R669 R670 R665 R678 I702 D705 S662 T715 - - N743 0.0 - 36 - rs59340265 E17/2037C>T (D679D) D679 D680 D675 N688 D712 N715 S632 N725 - - E753 9.1 - 37 ns15 rs41316450 E18/2207T>A (I736K) TM7 I736 I737 V732 I745 M779 I771 V682 I820 I37 L48 V814 72.7 36.7 38 ns16 rs77144566 E19/2281A>C (A761S) TM8 A761 V763 I757 A769 V802 I796 G706 I844 I647 G655 L836 63.6 42.1 39 ns17 rs41305517 E21/2398G>A (D800N) C-NBD (Internal) D800 D801 D796 D808 H841 D835 E745 D883 S108 P112 E875 9.1 45.4 40 ns18 rs2235039 E21/2401G>A (V801M) C-NBD (External) V801 V802 V797 M809 I842 V836 V746 V884 A109 V113 M876 63.6 47.6 2.035.54409L931S531I219S447V468T078I738T528T038I928I)V928I(G>A5842/22E1852302sr91sn14 42 s15 rs28381966 E22/2505A>G (V835V) V835 V836 V831 L843 T876 T870 L780 T918 N141 T145 F911 45.5 33.0 43 ns20 rs28381967 E22/2506A>G (I836V) I836 I837 I832 I844 V877 I871 L781 V919 I142 V146 F911 63.6 28.5 7.448.18429M951M551I239L497I488D098I758I548I058I948I)M948I(G>A7452/22E03150163sr12sn44 45 s16 rs9282563 E22/2650C>T (L884L) L884 L885 L880 K892 V925 M919 R829 E967 R190 K194 I959 27.3 31.2 7.535.54289P302V991V679S838S829C439S109A988S498A398S)T/A398S(A/T>G7762/22E2852302sr22sn64 4.834.631801M203T892V5701F739G7201L5301T0001S889S399S299S)N299S(A>G5792/52E72194865sr32sn74 5.633.729801E903Q503T2801T449V4301Q2401A7001A599A0001A999A)T999A(A>G5992/52E48725527sr42sn84 49 s17 rs2235044 E26/3084G>A (P1028P) P1028 P1029 P1024 P1036 - P1063 P973 V1111 P332 V334 I1117 0.0 33.0 50 ns25 rs28401798 E26/3151C>G (P1051A) P1051 P1052 P1047 K1059 E1093 Q1086 I996 K1135 P355 P357 P1142 18.2 57.6 51 ns26 rs2707944 E26/3188G>C (G1063A) G1063 G1064 G1059 G1071 G1105 G1098 G1008 G1147 G367 G369 K1154 45.5 53.8 52 s18 rs2707943 E26/3189C>G (G1063G) G1063 G1064 G1059 G1071 G1105 G1098 G1008 G1147 G367 G369 K1154 45.5 53.8 53 ns27 rs74755520 E26/3222A>C (C1074W) C-NBD (Internal) C1074 C1075 C1070 C1082 C1116 C1109 S1019 C1158 G378 S380 S1165 63.6 67.8 54 ns28 rs57521326 E26/3262G>A (D1088N) D1088 D1089 D1084 D1096 D1130 D1123 D1033 D1172 D392 D394 D1179 100.0 53.9 55 ns29 rs41309225 E27/3295A>G (K1099E) K1099 K1100 K1095 I1107 S1141 C1134 R1044 V1183 H403 H405 I1237 18.2 38.5 56 ns30 rs55852620 E27/3320A>C (Q1107P) Q1107 Q1108 Q1103 Q1115 E1149 T1142 R1052 N1191 G411 A413 R1245 27.3 43.7 57 ns31 rs35730308 E27/3322T>C (W1108R) W1108 Q1109 W1104 Q1116 H1150 N1143 S1053 D1192 S412 S414 D1246 27.3 43.5 58 s19 rs34748655 E27/3396C>T (A1132A) C-NBD (Internal) A1132 A1133 A1128 A1140 I1174 S1167 M1077 V1216 L436 A438 K1270 27.3 56.8 59 ns32 rs41309228 E27/3410G>T (S1137I ) S1137 S1138 S1133 S1145 P1179 A1172 S1082 S1220 P440 E443 - 18.2 41.8 60 ns33 rs2229107 E27/3421T>A (S1141T) S1141 S1142 S1137 S1149 T1183 T1176 D1086 S1224 D444 R447 T1277 45.5 50.9 61 s20 rs1045642 E27/3435C>T (I1145I) C-NBD (Internal) I1145 I1146 I1141 I1153 V1187 I1180 I1090 M1228 V447 I450 V1281 72.7 57.6 62 ns34 rs59241388 E28/3502A>G (K1168E) K1168 R1169 R1164 R1176 R1210 R1203 C1113 L1251 E470 V473 N1304 27.3 61.9 63 ns35 rs41309231 E29/3669A>T (E1223D) E1223 E1224 E1219 E1231 E1265 E1258 V1168 Q1306 K525 K528 D1359 27.3 60.2 64 s21 rs2235051 E29/3747C>G (G1249G) C-NBD (Internal) G1249 G1250 G1245 G1257 G1291 G1284 G1194 G1332 G551 G554 T1392 63.6 63.0 65 ns36 rs45456698 E29/3751G>A (V1251I) V1251 V1252 V1247 V1259 I1293 V1286 V1196 I1334 I553 I556 V1394 81.8 59.2 4.957.279931T165T855T9331T1021N1921D8921T4621T2521T7521T6521T)K6521T(A>C7673/92E93412753sr73sn66 C-NBD (External) C-NBD (External) C-NBD (External) C-NBD (External) TM4 - TM9 TM10 - TM1 S. aureus TM12 N-NBD (Internal) N-NBD (External) N-NBD (Internal) C-NBD (External) TM3 C. elegans D. melanoga ster A. thaliana S. pombe # SNP (amino acid substitution) Mapped to Abcb1a domain (internal/external surface) rsNo Conservation (%)a H. Sapiens C. l. Familiaris M. Musculus G. gallus P. falciparum Amino acid residue housing SNP Individual Regional 3 structure E. coli a The conservation of residues corresponding to all coding regions SNPs was obtained following multiple sequence alignment of 11 confirmed ABCB1 homolog protein sequences.

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ABCB1 p.Val1251Ile 21625253:48:6743

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120 Majority of the other SNPs previously associated with drug pharmacokinetics that could be mapped to the crystal structure reside at the outer surface of the C-terminal NBD Of the eight remaining SNPs to have been associated with drug response or expression, four can be mapped to the mouse Abcb1a crystal structure based on pair-wise alignment (Supplementary Figure 1).24,25 These are E26/3151C4G (P1051A) (#ns25), E27/3322T4C (W1108R) (#ns31), E27/ 3421T4A (S1141T) (#ns33) and E29/3751G4A (V1251I) (#ns36) (Figure 2b).

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ABCB1 p.Val1251Ile 21625253:120:492

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125 This Figure 4 Location and conservation of (a) E8/554G4T (G185V), (b) E12/1199G4A (S400N), (c) E26/3151C4G (P1051A), (d) E27/3322T4C (W1108R), (e) E27/3421T4A (S1141T), (f) E29/3751G4A (V1251I).

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ABCB1 p.Val1251Ile 21625253:125:186

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139 SNP E29/3751G4A (V1251I) (#ns36) was found to increase BODIPY-FL-paclitaxel accumulation and modulate the effect of cyclosporine A on the intracellular accumulation of BODIPY-FL-paclitaxel transport.50 When mapped to the crystal structure, V1251I resides at the outer surface of the C-terminal NBD (Figures 2b and 4f).

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ABCB1 p.Val1251Ile 21625253:139:17

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ABCB1 p.Val1251Ile 21625253:139:240

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142 Hence, of these several SNPs that had been previously associated with functional differences, most of them (E26/3151C4G (P1051A) (#ns25), E27/3421T4A (S1141T) (#ns33) and E29/3751G4A (V1251I) (#ns36) reside at the outer surface of the C-terminal NBD except for SNP E27/ 3322T4C (W1108R) (#ns31), which resides within the interior of the C-terminal NBD (Table 1, Figure 2b and flash movie http://pfs.nus.edu.sg/demo_src/abcb1.html).

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ABCB1 p.Val1251Ile 21625253:142:184

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143 Except for SNP E29/3751G4A (V1251I) (#ns36) with high individual conservation score (480%), the other three SNPs have below average conservation scores (o46%).

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ABCB1 p.Val1251Ile 21625253:143:28

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154 Except for synonymous SNP E27/3435C4T (I1145I) (#s20) and non-synonymous SNPs E29/3751G4A (V1251I) (#ns36) and E26/3262G4A (D1088N) (#ns28), these previously associated SNPs have below average individual conservation scores (o46%) and only average regional 31 structure conservation scores (40-60%) suggesting that there is some tolerance of variability in these regions of the P-gp protein, perhaps facilitating differences in substrate specificity of the different polymorphs.

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ABCB1 p.Val1251Ile 21625253:154:91

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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.

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ABCB1 p.Val1251Ile 20103563:6832:327

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72 Predictions of the Functional Effects of 40 nsSNPs in ABC Transporters Comon name HUGO name Mutation NBD Prediction BSEP ABCB11 E592Q NBD1 Neutral BSEP ABCB11 N591S NBD1 Neutral BSEP ABCB11 Q558H NBD1 Neutral BSEP ABCB11 V444A NBD1 Neutral BSEP ABCB11 E1186K NBD2 Disease MDR1 ABCB1 P1051A NBD2 Neutral MDR1 ABCB1 S1141T NBD2 Neutral MDR1 ABCB1 T1256K NBD2 Disease MDR1 ABCB1 V1251I NBD2 Neutral MDR1 ABCB1 W1108R NBD2 Disease MRP2 ABCC2 I670T NBD1 Disease MRP2 ABCC2 L849R NBD1 Disease MRP2 ABCC2 C1515Y NBD2 Disease MRP3 ABCC3 D770N NBD1 Neutral MRP3 ABCC3 K718M NBD1 Neutral MRP3 ABCC3 T809M NBD1 Disease MRP3 ABCC3 V765L NBD1 Disease MRP3 ABCC3 Q1365R NBD2 Disease MRP3 ABCC3 R1297H NBD2 Disease MRP3 ABCC3 R1348C NBD2 Disease MRP3 ABCC3 R1381S NBD2 Disease MRP4 ABCC4 G487E NBD1 Disease MRP4 ABCC4 K498E NBD1 Neutral MRP4 ABCC4 R1220Q NBD2 Neutral MRP4 ABCC4 T1142M NBD2 Neutral MRP4 ABCC4 V1071I NBD2 Neutral MRP6 ABCC6 I1330L NBD1 Neutral MRP6 ABCC6 I742V NBD1 Neutral MRP6 ABCC6 P664S NBD1 Neutral MRP6 ABCC6 R724K NBD1 Neutral MRP6 ABCC6 R769K NBD1 Neutral MRP6 ABCC6 A1291T NBD2 Neutral MRP6 ABCC6 E1369K NBD2 Neutral MRP6 ABCC6 G1327E NBD2 Disease MRP6 ABCC6 L1416R NBD2 Disease MRP6 ABCC6 R1268Q NBD2 Disease MRP6 ABCC6 R1461H NBD2 Disease MXR ABCG2 I206L NBD1 Neutral MXR ABCG2 P269S NBD1 Disease MXR ABCG2 Q141K NBD1 Neutral nsSNPs.

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ABCB1 p.Val1251Ile 20799350:72:376

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164 Finally, in transfected HEK293T cells, the S1141T variant showed increased function, suggesting that the transporter is functioning normally, but also with substrate dependence as for the V1251I nsSNP.38 This variant was predicted correctly to be neutral.

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ABCB1 p.Val1251Ile 20799350:164:188

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165 The V1251I variant of P-glycoprotein showed decreased transport of BODIPY-FL-paclitaxel, but increased transport of calcein-AM in an assay using transfected HEK293T cells.

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ABCB1 p.Val1251Ile 20799350:165:4

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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].

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ABCB1 p.Val1251Ile 19285158:152:115

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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].

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ABCB1 p.Val1251Ile 19285158:153:115

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49 Based on the results of DNA sequence analysis, the c.3751G>Agenetic variant is a non-synonymous mutation, which caused by G toAmutations in exon29 of human MDR1 gene and led to the valine (Val) to isoleucine (Ile) amino acid replacement (p.Val1251Ile, Reference sequences GenBank IDs: NG_011513.1, NM_000927.4 and NP_000918.2).

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ABCB1 p.Val1251Ile 24175826:49:240

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74 Sequence analyses indicate that this genetic variant results into the p.Val1251Ile amino acid replacement.

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ABCB1 p.Val1251Ile 24175826:74:72

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67 Only a few reports have described the functional consequences of rare variants in cell models, e.g. variants 266T[C (rs35810889, p.M89T), 1199G[A/T/C (rs2229109, p.S400N/I/T), 1985T[G (rs35657960, p.L662R), 2005C[T (rs35023033, p.R669C), 3322T[C (rs35730308, p.T1108R) and 3751G[A (rs28364274, p.V1251I) [50-52].

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ABCB1 p.Val1251Ile 25860377:67:296

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80 Positions in different coding Table 1 Characteristics of the studies and cohorts included in the meta-analysis Name of studies Country Ethnicity Type of case/control Genotyping method Quality scores Age Male/female ratio Variant site Genotype frequency of case/control HWE Case Control Case Control 1/1 1/2 2/2 Mean SD Mean SD Chen Y [29] China Chinese HCC a /HP PCR-RFLP 6 55.8 14.7 54.5 13.9 91/9 90/10 2677G>T/A 18/19 56/53 26/28 0.492 Minoru F-1 [30] Japan Japanese HCC b /HP PCR-SSCP 8 70 7 - - 43/15 61 2677G>T/A 12/16 29/30 17/15 0.900 Minoru F-2 [30] Japan Japanese HCC b /HP PCR-SSCP 8 70 7 - - 43/15 61 3435C>T 16/14 29/39 13/8 0.023 Ren YQ [31] China Chinese HCC a /HP CRS-PCR 7 58.7 11.3 55.8 15.6 512/177 499/181 4125A>C 299/312 289/303 101/65 0.487 Gao J-1 [32] China Chinese HCC a /HP CRS-PCR 7 57.9 13.7 53.5 14.9 278/75 269/66 335T>C 141/172 150/128 62/35 0.132 Gao J-2 [32] China Chinese HCC a /HP CRS-PCR 7 57.9 13.7 53.5 14.9 278/75 269/66 3073A>C 116/155 158/139 79/41 0.261 Rui J [33] China Chinese HCC a /HP MALDI-TOF-MS 8 46 - 48 - 95/14 90/19 1236C>T 19/22 54/48 36/39 0.310 Yang D-1 [34] China Chinese HCC a /HP CRS-PCR 8 59.2 14.3 58.3 15.3 418/287 429/297 159G>T 312/342 298/308 95/76 0.591 Yang D-2 [34] China Chinese HCC a /HP CRS-PCR 8 59.2 14.3 58.3 15.3 418/287 429/297 1465C>T 294/367 306/292 105/67 0.420 Li XF [35] China Chinese HCC a /HP CRS-PCR 8 58.6 14.5 59.1 13.5 409/236 445/213 3751G>A 283/325 271/286 91/47 0.136 Wan YY [36] China Chinese HCC a /HP CRS-PCR 8 57.7 13.2 58.6 14.2 399/233 435/210 1564A>T 278/311 266/276 88/58 0.772 Total 4407 4436 1788/2055 1906/1902 713/479 1/1, 1/2, and 2/2 represent wild homozygous genotype, wild/mutant heterozygous genotype, and mutant homozygous genotype, respectively HCC hepatocellular carcinoma, HP healthy people, CHC chronic hepatitis C, CHB chronic hepatitis B, B-^ unclear, PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism, PCR-SSCP polymerase chain reaction-single-strand conformation polymorphism, CRS-PCR created restriction site-polymerase chain reaction, MALDI-TOF-MS matrix-assisted laser desorption ionization timeof-flight mass spectrometry a Hepatitis B-related HCC b Hepatitis C-related HCC Table 2 Characteristics of the MDR1 polymorphisms included in the meta-analysis Studies Polymorphism site Exon location Variation type A.A. alteration FI a FI score a Feature key P. location description b P. function description b Chen Y [29] 2677G>T/A Exon 21 Nonsynonymous S893A Neutral -0.98 Topological domain Cytoplasmic ABC transmembrane type 1 S893T Low 1.66 Topological domain Cytoplasmic ABC transmembrane type 1 Minoru F-1 [30] 2677G>T/A Exon 21 Nonsynonymous S893A Neutral -0.98 Topological domain Cytoplasmic ABC transmembrane type 1 S893T Low 1.66 Topological domain Cytoplasmic ABC transmembrane type 1 Minoru F-2 [30] 3435C>T Exon 26 Synonymous - - - Topological domain Cytoplasmic ABC transporter Ren YQ [31] 4125A>C Exon 28 Nonsynonymous E1211A Low 1.805 Topological domain Cytoplasmic ABC transporter Gao J-1 [32] 335T>C 5'-UTR Noncoding - - - - - - Gao J-2 [32] 3073A>C Exon 22 Nonsynonymous L860F Medium 2.715 Transmembrane Helical ABC transmembrane type 1 Rui J [33] 1236C>T Exon 12 Synonymous - - - Topological domain Cytoplasmic ABC transporter Yang D-1 [34] 159G>T Exon 5 Synonymous - - - Transmembrane Helical ABC transmembrane type 1 Yang D-2 [34] 1465C>T Exon 14 Nonsynonymous R489C Medium 1.97 Topological domain Cytoplasmic ABC transporter Li XF [35] 3751G>A Exon 28 Nonsynonymous V1251I Neutral -0.365 Topological domain Cytoplasmic ABC transporter Wan YY [36] 1564A>T Exon 15 Nonsynonymous T522S Low 1.42 Topological domain Cytoplasmic ABC transporter A.A. amino acid, FI functional impact, ABC ATP-binding cassette a The functional impact is evaluated using online MutationAssessor.org b Location of SNP in the protein structure is assessed by Uniprot.org online service sequence subgroup analyses revealed that cytoplasmic polymorphisms correlated with a significantly higher HCC risk (cytoplasmic subgroup: OR=1.28, 95 % CI 1.19-1.37; P<0.00001), whereas transmembrane polymorphisms exhibited site-specific results (Gao J-2, 2013: OR=1.65, 95 % CI 1.32-2.05, P<0.0001; Yang D-1, 2013: OR=1.65, 95 % CI 0.98-1.33, P=0.10).

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ABCB1 p.Val1251Ile 25861753:80:3532

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