DataSheet_2_A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes.docx

IntroductionData on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce.
MethodsWe performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres.
ResultsThe single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations.
DiscussionThus, new genes were identified, potentially influencing the outcome of HSCT.

**引言** 造血干细胞移植（hematopoietic stem cell transplantation, HSCT）受者术后不良结局的基因组易感性相关数据较为匮乏。
**方法** 本研究开展全基因组关联研究（genome-wide association study, GWAS），旨在筛选与受者生存/死亡、疾病复发以及重度移植物抗宿主病（severe graft-versus-host disease, sGvHD）相关的基因；我们针对来自3个中心的1392名欧洲血统造血干细胞移植受者的数据，拟合了比例风险模型与亚分布模型。
**结果** 位于神经元生长导向信号素3C（semaphorin 3C, SEMA3C）基因内含子区的单核苷酸多态性（single nucleotide polymorphism, SNP）rs17154454，与无事件生存期和sGvHD存在全基因组显著关联（p=7.0×10^-8、p=7.5×10^-8）。进一步研究发现，桩蛋白基因（PXN）内的SNP与未发生复发或sGvHD即死亡的结局相关；此外，浆细胞瘤变异易位1基因（PVT1，一种长链非编码RNA基因）、黑皮质素5受体基因（MC5R）以及含WW结构域氧化还原酶基因（WWOX）内的SNP均与sGvHD的发生相关。功能机制分析佐证了本次观测到的关联结果。
**讨论** 本研究鉴定出了若干可能影响造血干细胞移植结局的新基因。