0 11 Polymorphic polymorphic JJ 12 23 nucleotides nucleotide NNS 24 30 within within IN 31 34 the the DT 35 40 human human JJ 41 45 IL-4 il-4 NN 46 54 promoter promoter NN 55 59 that that WDT 60 67 mediate mediate VBP 68 82 overexpression overexpression NN 83 85 of of IN 86 89 the the DT 90 94 gene gene NN 94 95 . . . 97 102 Atopy Atopy NNP 102 103 , , , 104 109 which which WDT 110 121 predisposes predispose VBZ 122 133 individuals individual NNS 134 136 to to TO 137 144 develop develop VB 145 151 asthma asthma NN 151 152 , , , 153 159 severe severe JJ 160 168 systemic systemic JJ 169 180 anaphylaxis anaphylaxis NN 180 181 , , , 182 185 and and CC 186 192 atopic atopic JJ 193 203 dermatitis dermatitis NN 203 204 , , , 205 207 is be VBZ 208 215 usually usually RB 216 226 associated associate VBN 227 231 with with IN 232 244 dramatically dramatically RB 245 253 elevated elevated JJ 254 259 total total JJ 260 265 serum serum NN 266 269 IgE ige NN 270 276 levels level NNS 277 280 and and CC 281 283 is be VBZ 284 291 thought think VBN 292 294 to to TO 295 297 be be VB 298 308 controlled control VBN 309 311 by by IN 312 313 a a DT 314 319 major major JJ 320 334 susceptibility susceptibility NN 335 339 gene gene NN 340 343 and and CC 344 352 multiple multiple JJ 353 358 minor minor JJ 359 373 susceptibility susceptibility NN 374 379 genes gene NNS 379 380 . . . 381 382 A a DT 383 389 recent recent JJ 390 398 sib-pair sib-pair NN 399 407 analysis analysis NN 408 416 revealed reveal VBD 417 418 a a DT 419 424 tight tight JJ 425 432 linkage linkage NN 433 440 between between IN 441 448 markers marker NNS 449 451 on on IN 452 458 5q31.1 5q31.1 NN 459 462 and and CC 463 464 a a DT 465 470 major major JJ 471 485 susceptibility susceptibility NN 486 490 gene gene NN 491 502 controlling control VBG 503 508 total total JJ 509 514 serum serum NN 515 518 IgE ige NN 519 525 levels level NNS 525 526 . . . 527 530 Due due JJ 531 533 to to TO 534 537 its its PRP$ 538 546 location location NN 547 553 within within IN 554 558 this this DT 559 566 cluster cluster NN 567 570 and and CC 571 574 its its PRP$ 575 583 biologic biologic JJ 584 588 role role NN 589 591 in in IN 592 594 Ig ig NN 595 600 class class NN 601 610 switching switching NN 611 614 and and CC 615 618 Th2 th2 NN 619 623 cell cell NN 624 639 differentiation differentiation NN 639 640 , , , 641 644 the the DT 645 649 IL-4 il-4 NN 650 654 gene gene NN 655 658 has have VBZ 659 666 emerged emerge VBN 667 669 as as IN 670 673 one one CD 674 679 major major JJ 680 689 candidate candidate NN 690 693 for for IN 694 697 the the DT 698 703 atopy atopy NN 704 708 gene gene NN 708 709 . . . 710 712 In in IN 713 716 one one CD 717 722 model model NN 722 723 , , , 724 737 polymorphisms polymorphism NNS 738 744 within within IN 745 749 IL-4 il-4 NN 750 760 regulatory regulatory JJ 761 769 elements element NNS 770 775 might might MD 776 782 result result VB 783 785 in in IN 786 800 overexpression overexpression NN 801 803 of of IN 804 807 the the DT 808 812 gene gene NN 812 813 , , , 814 824 amplifying amplify VBG 825 828 Th2 th2 NN 829 833 cell cell NN 834 849 differentiation differentiation NN 850 853 and and CC 854 859 class class NN 860 869 switching switching NN 870 872 to to TO 873 876 IgE IgE NNP 876 877 . . . 878 880 In in IN 881 888 support support NN 889 891 of of IN 892 896 this this DT 897 902 model model NN 902 903 , , , 904 906 we we PRP 907 913 report report VBP 914 918 that that IN 919 922 the the DT 923 928 human human JJ 929 933 IL-4 il-4 NN 934 942 promoter promoter NN 943 949 exists exist VBZ 950 952 in in IN 953 961 multiple multiple JJ 962 969 allelic allelic JJ 970 975 forms form NNS 976 980 that that WDT 981 988 exhibit exhibit VBP 989 997 distinct distinct JJ 998 1013 transcriptional transcriptional JJ 1014 1024 activities activity NNS 1025 1027 in in IN 1028 1041 IL-4-positive il-4-positive JJ 1042 1043 T t NN 1044 1049 cells cell NNS 1049 1050 . . . 1051 1052 A a DT 1053 1063 particular particular JJ 1064 1070 allele allele NN 1071 1074 has have VBZ 1075 1077 an an DT 1078 1087 unusually unusually RB 1088 1092 high high JJ 1093 1108 transcriptional transcriptional JJ 1109 1117 activity activity NN 1117 1118 . . . 1119 1120 A a DT 1121 1131 nucleotide nucleotide NN 1132 1144 substitution substitution NN 1145 1151 within within IN 1152 1153 a a DT 1154 1162 recently recently RB 1163 1172 described describe VBN 1173 1178 OAP40 oap40 NN 1179 1186 element element NN 1187 1194 located located JJ 1195 1199 just just RB 1200 1208 upstream upstream RB 1209 1211 of of IN 1212 1214 an an DT 1215 1220 NF-AT NF-AT NNP 1221 1225 site site NN 1226 1227 ( ( ( 1227 1228 P p NN 1229 1237 sequence sequence NN 1237 1238 ) ) ) 1239 1246 appears appear VBZ 1247 1249 to to TO 1250 1252 be be VB 1253 1260 largely largely RB 1261 1272 responsible responsible JJ 1273 1276 for for IN 1277 1280 the the DT 1281 1290 increased increase VBN 1291 1299 promotor promotor NN 1300 1308 strength strength NN 1309 1311 of of IN 1312 1316 this this DT 1317 1327 particular particular JJ 1328 1335 allelic allelic JJ 1336 1340 form form NN 1341 1343 of of IN 1344 1347 the the DT 1348 1352 IL-4 il-4 NN 1353 1361 promoter promoter NN 1361 1362 . . . 1363 1365 In in IN 1366 1371 EMSAs EMSA NNP 1371 1372 , , , 1373 1377 this this DT 1378 1390 substitution substitution NN 1391 1398 results result VBZ 1399 1401 in in IN 1402 1403 a a DT 1404 1412 markedly markedly RB 1413 1421 enhanced enhance VBN 1422 1430 affinity affinity NN 1431 1434 for for IN 1435 1452 sequence-specific sequence-specific JJ 1453 1462 complexes complex NNS 1463 1473 exhibiting exhibit VBG 1474 1476 an an DT 1477 1481 AP-1 ap-1 NN 1482 1493 specificity specificity NN 1493 1494 . . . 1495 1498 The the DT 1499 1513 identification identification NN 1514 1516 of of IN 1517 1524 allelic allelic JJ 1525 1536 nucleotides nucleotide NNS 1536 1537 , , , 1538 1543 which which WDT 1544 1551 results result VBZ 1552 1554 in in IN 1555 1569 overexpression overexpression NN 1570 1572 of of IN 1573 1576 the the DT 1577 1581 IL-4 il-4 NN 1582 1586 gene gene NN 1586 1587 , , , 1588 1596 provides provide VBZ 1597 1605 specific specific JJ 1606 1613 targets target NNS 1614 1617 for for IN 1618 1619 a a DT 1620 1633 comprehensive comprehensive JJ 1634 1643 screening screening NN 1644 1646 of of IN 1647 1653 atopic atopic JJ 1654 1657 and and CC 1658 1667 nonatopic nonatopic JJ 1668 1679 individuals individual NNS 1680 1683 and and CC 1684 1687 may may MD 1688 1695 provide provide VB 1696 1697 a a DT 1698 1702 clue clue NN 1703 1706 for for IN 1707 1714 genetic genetic JJ 1715 1729 predisposition predisposition NN 1730 1733 for for IN 1734 1739 atopy atopy NN 1739 1740 . . .