Cohorta | Treatment element | Study individualsb n (%) | Frequency of cases and controls per rs6744284 genotypec n (%) | Risk in heterozygotes and homozygotesd |
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TT | TC | CC |
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Controls | Cases | Total | Controls | Cases | Controls | Cases | Controls | Cases | ORTC(95% CI) | P | ORTT (95% CI) | P |
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1 | Protocol IA/IB | 215(33%) | 435(67%) | 650 | 7(10%) | 63(90%) | 81(29%) | 195(71%) | 127(42%) | 177(58%) | 1.73(1.22-2.44) | 0.002 | 6.46(2.86-14.57) | < 0.001 |
1 | Protocol IA | 254(40%) | 372(60%) | 626 | 12(18%) | 54(82%) | 95(36%) | 171(64%) | 147(50%) | 147(50%) | 1.80(1.28-2.53) | < 0.001 | 4.50(2.31-8.76) | < 0.001 |
1 | Protocol IB | 352(67%) | 269(43%) | 621 | 17(25%) | 50(75%) | 131(51%) | 127(49%) | 204(69%) | 92(31%) | 2.15(1.52-3.04) | < 0.001 | 6.52(3.57-11.92) | < 0.001 |
1 | Protocol M | 302(61%) | 190(39%) | 492 | 17(34%) | 33(66%) | 126(61%) | 82(39%) | 159(68%) | 75(32%) | 1.38(0.93-2.04) | 0.106 | 4.12(2.16-7.85) | < 0.001 |
1 | Protocol II/III | 349(76%) | 110(24%) | 459 | 16 (37%) | 27(63%) | 139(75%) | 47(25%) | 194(84%) | 36(16%) | 1.82(1.12-2.96) | 0.015 | 9.09(4.46-18.56) | < 0.001 |
1 | HR blocks | 44(41%) | 63 (59%) | 107 | 1 (8%) | 12(92%) | 15(34%) | 29(66%) | 28(56%) | 22(44%) | 2.46(1.07-5.68) | 0.035 | 15.27(1.84-126.61) | 0.012 |
2 | Protocol IA/IB | 79(35%) | 145 (65%) | 224 | 3 (13%) | 20(87%) | 27(28%) | 71(72%) | 49(48%) | 54(52%) | 2.39(1.33-4.30) | 0.004 | 6.05(1.69-21.62) | 0.006 |
1 + 2e | Protocol IA/IB | 294(34%) | 580(66%) | 874 | 10(3%) | 108(37%) | 176(60%) | 83(14%) | 266(46%) | 231(40%) | 1.88(1.39-2.53) | < 0.001 | 6.32(3.19-12.54) | < 0.001 |
- a Association of rs6744284 genotypes with hyperbilirubinemia was tested in two independent cohorts derived from the AIEOP-BFM ALL 2000 trial: 650 patients of the derivation cohort (1) were analyzed according to the maximum bilirubin levels detected during protocols I (induction (IA) and consolidation (IB), M (extracompartment therapy), II or III (late intensification) and HR (high-risk block treatment). The 224 patients of the replication cohort (2) were analyzed based on the bilirubin levels detected during induction/consolidation (protocols IA/IB), only
- b As in the initial genome-wide analysis performed for induction/consolidation (protocols IA/IB), individuals of the other protocol elements demonstrating hyperbilirubinemia(CTC grades 1-4) were considered as cases and compared to control patients with normal bilirubin levels (controls, CTC grade 0). Toxicity grading was according to the Common Toxicity Criteria (CTC) of the National Cancer Institute, version 2
- c The amount of controls and cases per specified rs6744284 genotype is given as indicated: homozygotes for the risk/minor allele (TT), heterozygotes (TC) and homozygotes for the major allele (CC)
- d Genotypic association was analyzed using binary logistic regression. Odds ratios (OR) and corresponding 95% confidence intervals (CI) are listed for heterozygous (TC) and homozygous genotypes (TT)
- e Combining both datasets the allelic association of rs6744284 with hyperbilirubinemia during protocol IA/IB reached genomewide significance (OR, 2.1, CI, 1.70-2.68, P(X2) = 5.75 × 10−11)