Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation.
Adolescent
Antineoplastic Agents, Alkylating
/ pharmacokinetics
Busulfan
/ pharmacokinetics
Child
Child, Preschool
Cohort Studies
DNA Modification Methylases
/ genetics
DNA Repair
/ genetics
DNA Repair Enzymes
/ genetics
Female
Genetic Testing
Genetic Variation
Graft vs Host Disease
/ genetics
Hematopoietic Stem Cell Transplantation
/ adverse effects
Heterozygote
Humans
Incidence
Male
Predictive Value of Tests
Retrospective Studies
Risk Factors
Tumor Suppressor Proteins
/ genetics
Journal
The pharmacogenomics journal
ISSN: 1473-1150
Titre abrégé: Pharmacogenomics J
Pays: United States
ID NLM: 101083949
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
11
11
2020
accepted:
06
04
2021
revised:
26
02
2021
pubmed:
30
10
2021
medline:
11
3
2022
entrez:
29
10
2021
Statut:
ppublish
Résumé
Acute Graft versus Host Disease (aGvHD) grades 2-4 occurs in 15-60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2-4 in 60 pediatric patients. The cumulative incidence of aGvHD 2-4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2-4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3-191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2-4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06-3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.
Identifiants
pubmed: 34711928
doi: 10.1038/s41397-021-00251-7
pii: 10.1038/s41397-021-00251-7
pmc: PMC8794787
doi:
Substances chimiques
Antineoplastic Agents, Alkylating
0
Tumor Suppressor Proteins
0
DNA Modification Methylases
EC 2.1.1.-
MGMT protein, human
EC 2.1.1.63
DNA Repair Enzymes
EC 6.5.1.-
Busulfan
G1LN9045DK
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
9-18Informations de copyright
© 2021. The Author(s).
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