Association between SLC19A1 gene polymorphism and high dose methotrexate toxicity in childhood acute lymphoblastic leukaemia and non Hodgkin malignant lymphoma: introducing a haplotype based approach
, , , and | Sep 18, 2017
About this article
Article Category: Research Article
Published Online: Sep 18, 2017
Page range: 455 - 462
Received: Feb 14, 2017
Accepted: Aug 18, 2017
DOI: https://doi.org/10.1515/raon-2017-0040
© 2017 Barbara Faganel Kotnik, Janez Jazbec, Petra Bohanec Grabar, Cristina Rodriguez-Antona, Vita Dolzan
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Figure 1
The impact of SLC19A1 genotypes on the occurrence of any and specific MTX-induced adverse events using multivariate analysis – an additive model
| SNP ID | Any adverse events | Leukopenia | Thrombocytopenia | Mucositis | Neurotoxicity | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| OR | P | OR | P | OR | P | OR | P | OR | P | |
| (CI 95%) | (CI 95%) | (CI 95%) | (CI 95%) | (CI 95%) | ||||||
| 0.719 | 0.360 | 0.609 | 0.150 | 1.170 | 0.696 | 1.292 | 0.579 | 0.542 | 0.361 | |
| (0.354–1.458) | (0.310–1.197) | (0.532–2.576) | (0.525–3.170) | (0.146–2.016) | ||||||
| 1.392 | 0.360 | 1.643 | 0.150 | 0.855 | 0.696 | 0.775 | 0.579 | 0.542 | 0.361 | |
| (0.686–2.824) | (0.836–3.230) | (0.388–1.881) | (0.316–1.906) | (0.146–2.016) | ||||||
| 1.221 | 0.583 | 1.684 | 0.136 | 0.556 | 0.172 | 0.476 | 0.130 | 0.453 | 0.236 | |
| (0.599–2.490) | (0.849–3.339) | (0.240–1.291) | (0.182–1.243) | (0.122–1.677) | ||||||
| 1.411 | 0.349 | 1.742 | 0.113 | 0.689 | 0.374 | 0.705 | 0.454 | 0.596 | 0.434 | |
| (0.686–2.899) | (0.878–3.458) | (0.303–1.566) | (0.283–1.759) | (0.163–2.182) | ||||||
| 0.849 | 0.772 | 1.393 | 0.545 | 0.854 | 0.821 | 0.672 | 0.606 | 1.226 | 0.800 | |
| (0.280–2.572) | (0.476–4.079) | (0.218–3.349) | (0.148–3.055) | (0.255–5.899) | ||||||
| 1.475 | 0.478 | 1.825 | 0.238 | 1.688 | 0.368 | 0.930 | 0.914 | 1.061 | 0.939 | |
| (0.504–4.318) | (0.672–4.956) | (0.540–5.280) | (0.249–3.473) | (0.232–4.861) | ||||||
| 1.261 | 0.483 | 0.740 | 0.351 | 1.652 | 0.185 | 2.160 | 0.081 | 1.693 | 0.337 | |
| (0.666–2.412) | (0.392–1.394) | (0.786–3.473) | (0.909–5.129) | (0.577–4.967) | ||||||
The influence of rs2838958 genotype on mucositis development - univariate logistic regression analysis
| Degree of moscositis | rs2838958 genotype | OR(95%CI) | P | |
|---|---|---|---|---|
| TT (%) | TC + CC (%) | |||
| 18 (66.7) | 53 (89.8) | reference | ||
| 4 (14.8) | 4 (6.8) | 0.340 (0.077–1.500) | 0.154 | |
| 4 (14.8) | 2 (3.4) | 0.170 (0.029–1.007) | 0.051 | |
| 1 (3.7) | 0 (0.0) | - Calculation was not possible | ||
| 9 (33.3) | 6 (10.2) | 0.226 (0.071–0.725) | 0.009 | |
| 0.59 | 0.14 | 0.007 | ||
Demographic and clinical characteristics of children with ALL/NHML and MTX treatment toxicity
| Characteristic | ALL patients |
|---|---|
| (N = 88) | |
| Gender (%) | |
| Male | 41 (46.6) |
| Female | 47 (53.4) |
| Median age at diagnosis, years (range) | 4.58 (0.3–16.6) |
| Median body surface area, m2 (range) | 0.73 (0.4–1.9) |
| Leukaemia subtype (%); | |
| B-cell | 72 (81.8) |
| T-cell | 13 (14.7) |
| Undetermined | 3 (3.4) |
| Median No. leukocytes at diagnosis, 109 cells/L (range) | 9.35 (1–1650) |
| Median No. thrombocytes at diagnosis, 109 cells/L (range) | 72 (3–553) |
| Median haemoglobin conc., g/l (range) | 84 (43–148) |
| Median % of blasts at diagnosis (range) | 23.5 (0–97) |
| Median MTX dose, mg (range) | 3300 (540–9200) |
| Relapse | 8 (9.2) data is missing for one patient |
| Exitus | 4 (4.6) data is missing for one patient |
| All MTX-induced ADEs data was collected after the first cycle of MTX | 48 (54.5) |
| Leukopenia | 33 (37.5) |
| Thrombocytopenia | 16 (18.2) |
| Mucositis | 15 (17.0) |
| Neurotoxicity | 7 (8.0) data is missing for one patient |
The impact of gender, age, treatment regimen and SLC19A1 haplotypes on the occurrence of any and specific (thrombocytopenia, mucositis, and neurotoxicity) MTX-induced adverse events
| All | Thrombocytopenia | Mucositis | Neurotoxicity | |||||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P | OR (95% CI) | P | |
| 2.385 | 0.078 | 1.615 | 0.413 | 1.523 | 0.520 | 0.531 | 0.475 | |
| (0.908–6.259) | (5.134–5.076) | (0.423–5.472) | (0.093–3.024) | |||||
| 1.028 | 0.588 | 9.526 | 0.440 | 1.054 | 0.396 | 1.088 | 0.289 | |
| (0.931–1.134) | (8.422–1.078) | (0.935–1.190) | (0.931–1.272) | |||||
| 2.050 | 0.031 p < 0.05; H2 was the reference haplotype | 9.839 | 0.962 | 1.676 | 0.255 | 1.282 | 0.678 | |
| (1.065–3.943) | (4.620–2.095) | (0.689–4.075) | (0.397–4.139) | |||||
| 1.000 | 0.943 | 6.615 | 0.352 | 0.419 | 0.096 | 0.309 | 0.120 | |
| (0.472–2.117) | (2.769–1.579) | (0.150–1.167) | (0.070–1.364) | |||||
| 1.110 | 0.844 | 9.220 | 0.891 | 0.593 | 0.515 | 0.951 | 0.934 | |
| (0.335–3.618) | (2.254–3.750) | (0.122–2.877) | (0.175–5.150) | |||||
| 0.143 | 0.030 p < 0.05; H2 was the reference haplotype | 3.617 | 0.379 | 0.005 | 0.985 | 0.014 | 0.992 | |
| (0.023–0.852) | (4.568–2.541) | (0.0–NC) | (0.0–NC) | |||||
| 2.002 | 0.275 | 9.113 | 0.871 | 2.002 | 0.275 | 2.002 | 0.275 | |
| (0.580–6.775) | (2.607–3.171) | (0.580–6.775) | (0.580–6.775) | |||||
SLC19A1 haplotype frequencies in patients with ALL and NHML
| Haplotype SNP rs1131596, rs1051266, rs2838958, rs2838956, rs17004785, rs12483377, rs2838951 from 5’ to 3’, respectively | Frequency | Standard error |
|---|---|---|
| H1 = CACCCCG | 0.396 | 0.037 |
| H2 = TGTTCCC | 0.334 | 0.036 |
| H3 = TGTTGTC | 0.094 | 0.022 |
| H4 = TGTTCCG | 0.053 | 0.017 |
| H5 = CATTCCC | 0.017 | 0.010 |
| Other | 0.106 |