1.
Genetic susceptibility to hepatic sinusoidal obstruction syndrome in pediatric patients undergoing HSCT
Ansari, M., Petrykey, K., Rezgui, M. A., Vecchio, V. D., Cortyl, J., Ralph, R. O., Nava, T., Beaulieu, P., St-Onge, P., Mlakar, S. J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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 set of genes. To get more comprehensive insight in the genetic component, we performed 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 busulfan-containing conditioning regimen. Eight lead 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=0.001), rs16931326 (p=0.04) and rs2289971 (p=0.03), located respectively in UGT2B10, BHLHE22 and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in multivariable model while controlling for non-genetic covariates and previously identified risk variants in GSTA1 promoter. The modulation of associations by conditioning regimens was noted, KIAA1715 was dependent on the intensity of conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed (p=0.00006) with genotype-related SOS risk of 9.8. This is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring higher risk of SOS, which might be useful for personalized prevention and treatment strategies.
2.
Association of CTH variant with sinusoidal obstruction syndrome in children receiving intravenous busulfan and cyclophosphamide before hematopoietic stem cell transplantation
Huezo-Diaz Curtis, P., Uppugunduri, C. R., Muthukumaran, J., Rezgui, M. A., Peters, C., Bader, P., Duval, M., Bittencourt, H., Krajinovic, M., Ansari, M.
Pharmacogenomics Journal. , 2016 Oct 25. 2016
Abstract
Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (ORTT=10.6, 95% confidence interval (CI)=2.16, 51.54) and SOS risk, which was sex dependent (female patients, ORTT=21.82, 95% CI=3.590-132.649). The interaction between CTHc.1364 G>T and another risk variant (GSTA1*B) was explored. A recessive model with the use of GSTA1*B*B and CTH c.1364 TT genotypes proved to be useful at predicting SOS occurrence, indicating the possibility of using these gene variants as markers of SOS occurrence and to further individualize preemptive treatment aimed at reducing SOS incidence.The Pharmacogenomics Journal advance online publication, 25 October 2016; doi:10.1038/tpj.2016.65.