ABCMdb

PMID: 21625253

Wolf SJ, Bachtiar M, Wang J, Sim TS, Chong SS, Lee CG
An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics.
Pharmacogenomics J. 2011 Oct;11(5):315-25. doi: 10.1038/tpj.2011.16. Epub 2011 May 31., [PubMed]

Sentences

No. Mutations Sentence Comment

45 ABCB1 p.Cys1074Trp In fact, one ns-SNP (E26/ 3222A4C (C1074W), ns#27 in Figure 2b) lies within the Walker A motif of the C-NBD itself (Table 1, Figure 1). Login to comment 48 ABCB1 p.Asn183Ser ABCB1 p.Ser400Asn ABCB1 p.Gln1107Pro ABCB1 p.Ser1141Thr ABCB1 p.Pro1051Ala ABCB1 p.Arg669Cys ABCB1 p.Val1251Ile ABCB1 p.Met89Thr ABCB1 p.Trp1108Arg ABCB1 p.Ile261Val ABCB1 p.Gly1063Ala ABCB1 p.Ala599Thr ABCB1 p.Val801Met ABCB1 p.Phe17Leu ABCB1 p.Arg593His ABCB1 p.Arg593Cys ABCB1 p.Asp613Tyr ABCB1 p.Ser1137Ile ABCB1 p.Ile836Val ABCB1 p.Asp800Asn ABCB1 p.Lys1168Glu ABCB1 p.Ile144Thr ABCB1 p.Asp1088Asn ABCB1 p.Lys1099Glu ABCB1 p.Glu1223Asp ABCB1 p.Ile736Lys ABCB1 p.Glu566Lys ABCB1 p.Cys1074Trp ABCB1 p.Ala761Ser 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. Login to comment 85 ABCB1 p.Ser893Ala This non-synonymous SNP confers one of two amino-acid substitutions at position 893 (Ser893Ala/Thr). Login to comment 90 ABCB1 p.Ser893Ala Many contradictory results are reported and as such no definitive conclusion has been Figure 3 Location and conservation of (a) E13/1236C4T (G412G), (b) E22/2677G4T/A (S893A/T) and (c) E27/3435C4T (I1145I). Login to comment 97 ABCB1 p.Gly185Val The classic E8/554G4T (G185V) polymorphism that influences drug specificity resides in close 3D proximity to two other non-synonymous polymorphisms in a region that is less evolutionary conserved Although research into ABCB1 polymorphisms appears to focus on E13/1236C4T, E22/2677G4T/A and E27/ 3435C4T, it is important to note that a number of additional non-synonymous SNPs have been associated with drug pharmacokinetics, drug response, protein expression and disease progression. Login to comment 99 ABCB1 p.Gly185Val One of these SNPs, E8/554G4T (#ns7 in Figure 2b) confers the classic amino-acid substitution G185V that was reported more than 20 years ago to confer changes in drug specificity of vinblastine and colchicine.39 This glycine residue was suggested to have a pivotal role in transmitting conformational changes between the catalytic sites and the drug binding sites.40 Combining molecular dynamics simulations with atomic detail homology modeling, it was further proposed that this improved efflux involves a reduction in non-polar van der Waals forces, which would otherwise secure colchicine to its binding site near or at residue 185. Login to comment 100 ABCB1 p.Asn183Ser ABCB1 p.Asn183Ser ABCB1 p.Ile144Thr ABCB1 p.Ile144Thr With the substitution of glycine for a more bulky valine residue, such interactions are removed, allowing for improved dissociation and efflux rates.40,41 Interestingly, as shown in Figure 4a, in the crystal structure, this SNP resides in close 3D proximity with a molecular distance of 10.9 and 5.2 A˚ to two other nonsynonymous SNPs, namely E7/431T4C (I144T) (#ns4 in Figure 2b) and E8/548A4G (N183S) (#ns6 in Figure 2b), respectively. Login to comment 106 ABCB1 p.Gly185Val It would be interesting to evaluate if these two closeby SNPs also have similar roles in influencing conformational changes between the catalytic sites and the drug binding sites or influence the role of G185V. Login to comment 109 ABCB1 p.Ser400Asn ABCB1 p.Ser400Asn The evolutionary non-conserved E12/1199G4A (S400N), which alters drug pharmacokinetics and response, resides in an evolutionary conserved region SNP E12/1199G4A (S400N) (#ns9 in Figure 2b), which occurs at o4% in Caucasians and Africans but is not found in Asians (Supplementary Table 2) represents another nsSNP that has been associated with drug pharmacokinetics. Login to comment 110 ABCB1 p.Ser400Asn ABCB1 p.Ser400Asn Through cell-based experiments using limited substrates, Kimchi-Sarfaty et al.42 inferred that substrate specificity was not significantly influenced by the any of the nonsynonymous coding SNPs including S400N. Login to comment 113 ABCB1 p.Ser400Asn Cellular uptake and permeability of five HIV protease inhibitors, especially ritonavir and saquinavir, was increased in cells carrying the minor allele.44 This SNP was also reported to confer resistance to vinblastine, vincristine, paclitaxel and etoposide, but not doxorubicin.45,46 Interestingly, a novel T allele of this SNP (E12/1199G4A (S400N)) coding for the amino acid, isoleucine (I), was identified in 2.3% of leukemia patients. Login to comment 116 ABCB1 p.Ser400Asn Although only two patients with heterozygous (G/A) genotype were identified, their mean progression-free survival was only 2 months compared with 19 months for patients who are homozygous for the G allele.48 From the 3D crystal structure, this polymorphism (S400N) was found to lie in the same turn region between two b-sheets as Gly412, which corresponds to the codon housing the synonymous SNP E13/1236C4T (Figure 4b) (see flash movie at http://pfs.nus.edu.sg/demo_src/abcb1.html). Login to comment 120 ABCB1 p.Ser1141Thr ABCB1 p.Pro1051Ala ABCB1 p.Val1251Ile ABCB1 p.Trp1108Arg 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). Login to comment 124 ABCB1 p.Pro1051Ala We highlight the E26/3151C4G (#ns25) SNP, which is translated to P1051A substitution (Figures 2b and 4c). Login to comment 125 ABCB1 p.Gly185Val ABCB1 p.Ser400Asn ABCB1 p.Ser1141Thr ABCB1 p.Pro1051Ala ABCB1 p.Val1251Ile ABCB1 p.Trp1108Arg 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). Login to comment 129 ABCB1 p.Ser400Asn It resides within a turn region between two opposing b-sheets in an almost similar fashion to that of #ns9 E12/1199G4A (S400N) (Figure 4b), close to the well-conserved A-loop (Tyrosine 1040) and Walker A motif that is crucial for ATP activity.15,18 This residue has an individual conservation score of just 18.2% but have a regional conservation score of B60% (Table 1, Figure 4c) suggesting that during the evolution of the protein, there is also considerable tolerance of variation at this residue but not of the surrounding residues. Login to comment 131 ABCB1 p.Asn21Asp ABCB1 p.Arg669Cys ABCB1 p.Leu662Arg ABCB1 p.Met89Thr These are E3/61A4G (N21D), E5/266C4T (M89T), E17/1985T4C (L662R), E17/2005C4T (R669C). Login to comment 132 ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp ABCB1 p.Asn21Asp ABCB1 p.Ser1141Thr ABCB1 p.Ser1141Thr ABCB1 p.Ser1141Thr ABCB1 p.Ser1141Thr ABCB1 p.Ser1141Thr ABCB1 p.Ser1141Thr ABCB1 p.Arg669Cys ABCB1 p.Arg669Cys ABCB1 p.Arg669Cys ABCB1 p.Arg669Cys ABCB1 p.Leu662Arg ABCB1 p.Met89Thr ABCB1 p.Trp1108Arg ABCB1 p.Trp1108Arg ABCB1 p.Trp1108Arg ABCB1 p.Trp1108Arg ABCB1 p.Trp1108Arg ABCB1 p.Trp1108Arg ABCB1 p.Trp1108Arg When in haplotype with the intensely studied SNPs E13/1236C4T (#s6), E22/2677G4T/A (#ns22) and E27/3435C4T (#s20), SNP E3/61A4G (N21D), which cannot be mapped to the 3D crystal structure, was reported to increase BODIPY-FL-paclitaxel accumulation and modulate the effect of cyclosporine A on the intracellular accumulation of BODIPY-FL-paclitaxel transport.50 However, the N21D substitution was found not to influence cyclosporine A pharmacokinetics in another study.51 In yet another study, the N21D polymorphism was reported to influence the trough but not the peak plasma levels concentration of methadone.52 Using a yeast-based assay, SNP E27/3421T4A (S1141T) (#ns33) and several SNPs that cannot be mapped to the crystal structure (E5/266C4T (M89T), E17/1985T4C (L662R), E17/2005C4T (R669C)) were reported to increase drug resistance to two or more drugs whereas SNP E27/ 3322T4C (W1108R) (#ns31) decreased drug resistance.49 Curiously, in another study, the E17/2005C4T (R669C) SNP was reported to be associated with decreased resistance to paclitaxel and etoposide in transfected LLC-PK1 cells.53 The increased resistance by SNP E17/2005C4T (R669C) was found to be reversed by SNP E27/3322T4C (W1108R) (#ns31).49 In another study using HEK293T cells, SNP E27/3421T4A (S1141T) (#ns33) was reported to be less sensitive to cyclosporine A inhibition of BODIPY-FL-paclitaxel transport.50 It was suggested that as the resistance profiles of SNPs E27/3421T4A (S1141T) (#ns33), E27/3322T4C (W1108R) (#ns31) and diplotype E27/3322T4C (W1108R)- E17/ 2005C4T (R669C)) display the largest variation across substrates, the region where S1141T (#ns33) and W1108R (#ns31) reside might contribute to the substrate discrimination activity of P-gp.49 The 3D crystal structure reveals that both S1141T (#ns33) and W1108R (#ns31) reside at the C-terminal NBD of the P-gp protein with S1141T (#ns33) residing on the outer surface and W1108R (#ns31) residing in the interior of the NBD (Figures 2b, 4d and 4e and flash movie http:// pfs.nus.edu.sg/demo_src/abcb1.html). Login to comment 133 ABCB1 p.Ser1141Thr Interestingly, SNP E27/3421T4A (S1141T) (#ns33) occurs at reasonably high frequency (44%) in the African population but is not found in the non-African populations (Supplementary Table 2). Login to comment 136 ABCB1 p.Trp1108Arg No genotype information is available with regards to the other SNP E27/3322T4C (W1108R) (#ns31). Login to comment 137 ABCB1 p.Ser1141Thr This SNP is even less conserved than SNP E27/3421T4A (S1141T) (#ns33) and also less conserved than its immediate surroundings as it has an individual conservation score of only 27.3% and a regional conservation score of 43.5% (Table 1, Figure 4e). Login to comment 139 ABCB1 p.Val1251Ile ABCB1 p.Val1251Ile 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). Login to comment 142 ABCB1 p.Ser1141Thr ABCB1 p.Pro1051Ala ABCB1 p.Val1251Ile ABCB1 p.Trp1108Arg 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). Login to comment 143 ABCB1 p.Val1251Ile Except for SNP E29/3751G4A (V1251I) (#ns36) with high individual conservation score (480%), the other three SNPs have below average conservation scores (o46%). Login to comment 151 ABCB1 p.Ser893Ala Of the remaining 10 previously associated SNPs, which can be mapped to the 3D structure, none reside in the substrate-binding region highlighted by Aller et al.12 Only one SNP, E8/554G4T (G185) (#ns7) resides within the membrane whereas another SNP (E22/2677G4T/A (S893A/ T) (#ns22)) resides in the region between the membrane and the cytosolic N-terminal NBD in the crystal structure, although this residue is part of TM10 (Figure 2). Login to comment 153 ABCB1 p.Ser1141Thr Genotype data that are available for 8 of these 14 previously associated SNPs revealed that the frequencies of these SNPs differed greatly among the various populations examined with SNP E27/ 3421T4A (S1141T) (#ns33) occurring only in the African Americans (Supplementary Table 2). Login to comment 154 ABCB1 p.Val1251Ile ABCB1 p.Asp1088Asn 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. Login to comment