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Scientific article
English

Genetic Susceptibility to Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation

Published inBiology of Blood and Marrow Transplantation, vol. 26, no. 5, p. 920-927
Publication date2020
Abstract

Sinusoidal obstruction syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease, and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected a set of genes. To get more comprehensive insight in the genetic component, we performed an exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following a busulfan-containing conditioning regimen. Eight lead single-nucleotide polymorphisms (SNPs) were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n = 182). Three SNPs were successfully replicated, including rs17146905 (P = .001), rs16931326 (P = .04), and rs2289971 (P = .03), located respectively in the UGT2B10, BHLHE22, and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in a multivariable model while controlling for nongenetic covariates and previously identified risk variants in the GSTA1 promoter. The modulation of associations by conditioning regimens was noted; KIAA1715 was dependent on the intensity of the conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed (P = .00006) with a genotype-related SOS risk of 9.8. To our knowledge, this is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring a higher risk of SOS, which might be useful for personalized prevention and treatment strategies.

Keywords
  • Association study
  • Busulfan
  • Genetic factors
  • Hematopoietic stem cell transplantation
  • Hepatic sinusoidal obstruction syndrome
  • Whole-exome sequencing
Funding
  • Swiss National Science Foundation - 153389
  • Autre - CANSEARCH Foundation
Citation (ISO format)
ANSARI DJABERI, Marc Georges et al. Genetic Susceptibility to Hepatic Sinusoidal Obstruction Syndrome in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation. In: Biology of Blood and Marrow Transplantation, 2020, vol. 26, n° 5, p. 920–927. doi: 10.1016/j.bbmt.2019.11.026
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Identifiers
ISSN of the journal1083-8791
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Technical informations

Creation10/21/2020 1:59:00 PM
First validation10/21/2020 1:59:00 PM
Update time03/15/2023 11:00:28 PM
Status update03/15/2023 11:00:25 PM
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