Genetic associations with immune-mediated outcomes after allogeneic hematopoietic cell transplantation.
Genetic associations with immune-mediated outcomes after allogeneic hematopoietic cell transplantation.
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DOI：
10.1182/bloodadvances.2021005620
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发表时间：
2022-04-26
期刊：
影响因子：
7.5
通讯作者：
Hansen, John A.
中科院分区：
文献类型：
--
作者：
Martin, Paul J.;Levine, David M.;Storer, Barry E.;Sather, Cassandra L.;Spellman, Stephen R.;Hansen, John A.
与DPB 1表达相关的受体变异与GVHD和无关HCT后复发的风险相关。需要更大的队列来检测与aGVHD、cGVHD和同种异体HCT后复发的其他基因型相关性。先前的研究已经确定了200多种与急性或慢性移植物抗宿主病（aGVHD; cGVHD）或异基因造血细胞移植（HCT）后复发性恶性肿瘤相关的遗传变异。我们在4270名欧洲血统的HCT受者队列和1827名同胞和1447名无血缘关系的受者亚队列中测试了这些候选供体和受体变异，这些受者具有10/10的HLA-A、B、C、DRB 1和DQB 1匹配的供体。我们还对这些相同的结果进行了全基因组关联研究（GWAS）。候选变异体的发现和复制分析鉴定了一组密切相关的受体HLA-DPB 1单核苷酸多态性（SNP），这些SNP与aGVHD风险增加和无关HCT后恶性肿瘤复发风险相应降低相关。这些结果反映了与HLA-DPB 1表达水平的相关性，以前的研究表明，影响aGVHD和复发的风险在无关的受体。我们的GWAS鉴定了cGVHD与NHS中X连锁受体内含子变体的位点的关联，NHS是一种调节肌动蛋白重塑和细胞形态的基因。在第二个重复队列中对这种关联的评估没有证实原始的重复结果，我们也没有就这一发现的有效性得出任何明确的结论。用于我们研究的队列比大多数以前的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。我们研究的基因组和疾病数据可与其他队列的数据结合进行进一步分析。
A recipient variant correlated with DPB1 expression is associated with the risks of GVHD and relapse after unrelated HCT. Larger cohorts would be needed to detect other genotypic associations with aGVHD, cGVHD, and relapse after allogeneic HCT. 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.
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影响因子：
14.9
作者：
Ward LD;Kellis M
通讯作者：
Kellis M
影响因子：
4
作者：
WALPOLE, IR;HOCKEY, A;NICOLL, A
通讯作者：
NICOLL, A
DOI：
10.1056/nejmoa1500140
发表时间：
2015-08-13
期刊：
The New England journal of medicine
影响因子：
--
作者：
Petersdorf EW;Malkki M;O'hUigin C;Carrington M;Gooley T;Haagenson MD;Horowitz MM;Spellman SR;Wang T;Stevenson P
通讯作者：
Stevenson P
影响因子：
4
作者：
Brooks, SP;Ebenezer, ND;Hardcastle, AJ
通讯作者：
Hardcastle, AJ
影响因子：
4.8
作者：
Goyal, R. K.;Lee, S. J.;Ferrell, R. E.
通讯作者：
Ferrell, R. E.