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.

中文翻译：

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接受造血干细胞移植的小儿患者肝正弦梗阻综合征的遗传易感性。

窦性阻塞综合征（SOS）是公认的并可能危及生命的造血干细胞移植（HSCT）并发症。SOS源自内皮细胞损伤和肝细胞损伤，这主要归因于移植条件疗法，也归因于其他患者，疾病和治疗相关因素。了解与SOS发生有关的危险因素对于及早开始治疗或预防至关重要。关于遗传贡献的知识是有限的。迄今为止，很少有研究选择了一组基因。为了更全面地了解遗传成分，我们使用了来自全外显子组测序的遗传变异体进行了整个外显子组关联研究。该分析是在一个发现队列中进行的，该队列由87名接受含白消安的调理方案的HSCT患儿组成。经过多次校正校正后，鉴定出八个铅单核苷酸多态性（SNP），随后在验证队列中进行分析（n = 182）。成功复制了三个SNP，包括分别位于UGT2B10，BHLHE22和KIAA1715基因中的rs17146905（P = .001），rs16931326（P = .04）和rs2289971（P = .03）。UGT2B10和KIAA1715保留在多变量模型中，同时控制GSTA1启动子中的非遗传​​协变量和先前确定的风险变量。注意到调理方案对联想的调节。KIAA1715取决于条件疗法的强度，而UGT2B10的效果同样适用于所有这些。还观察到相关基因座的联合作用（P = .00006），与基因型相关的SOS风险为9.8。据我们所知，这是第一项针对全基因组水平上SOS遗传成分并鉴定出导致SOS风险更高的新遗传变异的研究，这可能对个性化的预防和治疗策略很有用。