Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Department of Medicine, University of Washington School of Medicine, Seattle, WA.
Blood Adv. 2022 Apr 26;6(8):2608-2617. doi: 10.1182/bloodadvances.2021005620.
Previous studies have identified more than 200 genetic variants associated with acute or chronic graft-versus-host disease (aGVHD; cGVHD) or recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). We tested these candidate donor and recipient variants in a cohort of 4270 HCT recipients of European ancestry and in subcohorts of 1827 sibling and 1447 unrelated recipients who had 10/10 HLA-A, B, C, DRB1, and DQB1-matched donors. We also carried out a genome-wide association study (GWAS) for these same outcomes. The discovery and replication analysis of candidate variants identified a group of closely linked recipient HLA-DPB1 single-nucleotide polymorphisms (SNPs) associated with an increased risk of aGVHD and a corresponding decreased risk of recurrent malignancy after unrelated HCT. These results reflect a correlation with the level of HLA-DPB1 expression previously shown to affect the risks of aGVHD and relapse in unrelated recipients. Our GWAS identified an association of cGVHD with a locus of X-linked recipient intron variants in NHS, a gene that regulates actin remodeling and cell morphology. Evaluation of this association in a second replication cohort did not confirm the original replication results, and we did not reach any definitive conclusion regarding the validity of this discovery. The cohort used for our study is larger than those used in most previous HCT studies but is smaller than those typically used for other genotype-phenotype association studies. Genomic and disease data from our study are available for further analysis in combination with data from other cohorts.
先前的研究已经确定了 200 多种与异基因造血细胞移植（HCT）后急性或慢性移植物抗宿主病（aGVHD；cGVHD）或复发性恶性肿瘤相关的遗传变异。我们在一个由 4270 名欧洲血统 HCT 受者组成的队列中以及在 1827 名同胞和 1447 名无关受者的亚队列中测试了这些候选供体和受者变异，这些亚队列的供者均具有 10/10 HLA-A、B、C、DRB1 和 DQB1 匹配。我们还对这些相同的结果进行了全基因组关联研究（GWAS）。候选变异的发现和复制分析确定了一组紧密连锁的受者 HLA-DPB1 单核苷酸多态性（SNP），与无关 HCT 后 aGVHD 风险增加和复发性恶性肿瘤风险相应降低相关。这些结果反映了与先前显示影响无关受者 aGVHD 和复发风险的 HLA-DPB1 表达水平的相关性。我们的 GWAS 确定了 cGVHD 与 NHS 中 X 连锁受者内含子变异的一个位点相关联，该基因调节肌动蛋白重塑和细胞形态。在第二个复制队列中评估该关联并未证实最初的复制结果，并且我们对于该发现的有效性没有得出任何明确的结论。我们用于研究的队列比大多数先前的 HCT 研究中使用的队列大，但比通常用于其他基因型 - 表型关联研究的队列小。我们研究中使用的基因组和疾病数据可与其他队列的数据一起用于进一步分析。
