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Table 3 Association between rs6744284 genotype and risk of hyperbilirubinemia during different treatment elements

From: Chemotherapy-related hyperbilirubinemia in pediatric acute lymphoblastic leukemia: a genome-wide association study from the AIEOP-BFM ALL study group

Cohorta

Treatment element

Study individualsb

n (%)

Frequency of cases and controls per rs6744284 genotypec

n (%)

Risk in heterozygotes and homozygotesd

TT

TC

CC

Controls

Cases

Total

Controls

Cases

Controls

Cases

Controls

Cases

ORTC(95% CI)

P

ORTT (95% CI)

P

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

  1. 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
  2. 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
  3. 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)
  4. 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)
  5. 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)