Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation.
Novel genetic variants associated with mortality after unrelated donor allogeneic hematopoietic cell transplantation.
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DOI：
10.1016/j.eclinm.2021.101093
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发表时间：
2021-10
影响因子：
15.1
通讯作者：
Sucheston-Campbell LE
中科院分区：
文献类型：
--
作者：
Hahn T;Wang J;Preus LM;Karaesmen E;Rizvi A;Clay-Gilmour AI;Zhu Q;Wang Y;Yan L;Liu S;Stram DO;Pooler L;Sheng X;Haiman CA;Berg DVD;Webb A;Brock G;Spellman SR;Onel K;McCarthy PL;Pasquini MC;Sucheston-Campbell LE
识别非人类白细胞抗原 (HLA) 遗传风险因素可以通过额外基因座匹配或个体化风险预测来提高同种异体血液或骨髓移植 (BMT) 后的生存率。我们假设非 HLA 基因座对无关供体 (URD) BMT 后的 1 年总生存 (OS)、疾病相关死亡率 (DRM) 或移植相关死亡率 (TRM) 有显着影响。我们对 2,887 名急性髓系白血病 (AML)、骨髓增生异常综合征 (MDS) 和急性淋巴细胞白血病 (ALL) 患者及其 ≥8/8 HLA 匹配的 URD 进行了一项全基因组关联研究 (GWAS)，其中包括 2000 年至 2011 年治疗的两个独立队列。使用两个队列的荟萃分析，在以下方面确定了全基因组显着关联（p < 5 × 10−8）：受体基因组与 MBNL1 的 OS（rs9990017，HR = 1.4，95% CI 1.24–1.56，p = 3.3 × 10−8）以及供体-受体基因型与 LINC02774 的 OS 不匹配 （rs10927108，HR = 1.34，95% CI 1.21–1.48，p = 2.0 × 10−8）； PCNX4 处具有 DRM 的供体基因组（rs79076914，HR = 1.7，95% CI 1.41–2.05，p = 3.15 × 10−8），LINC01194（rs79498125，HR = 1.86，95% CI 1.49–2.31， p = 2.84 × 10−8), ARID5B （rs2167710，HR = 1.5，95% CI 1.31–1.73，p = 6.9 × 10−9）和 CT49（rs32250，HR = 1.44，95% CI1.26–1.64，p = 2.6 × 10−8）； PILRB 的受体基因组与 TRM (rs141591562，HR = 2.33，95% CI 1.74–3.12，p = 1.26 × 10−8) 以及 EPGN 和 MTHF2DL 与 TRM 之间的供体-受体基因型不匹配 (rs75868097，HR = 2.66，95% CI 1.92–3.58， p = 4.6 × 10−9)。结果可在 https://fuma.ctglab.nl/browse 上公开获取。这些数据提供了第一个证据，证明具有生化功能的新位点的非 HLA 常见遗传变异显着影响 1 年 URD-BMT 存活率。我们的研究结果对捐赠者的选择具有影响，可以指导治疗策略，并在未来的验证和功能研究后提供个体化的风险预测。该项目由美国国立卫生研究院资助
Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT. We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000–2011. Using meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10−8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24–1.56, p = 3.3 × 10−8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21–1.48, p = 2.0 × 10−8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41–2.05, p = 3.15 × 10−8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49–2.31, p = 2.84 × 10−8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31–1.73, p = 6.9 × 10−9) and CT49 (rs32250, HR = 1.44, 95% CI1.26–1.64, p = 2.6 × 10−8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74–3.12, p = 1.26 × 10−8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92–3.58, p = 4.6 × 10−9). Results publicly available at https://fuma.ctglab.nl/browse. These data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies. This project was funded by grants from the National Institutes of Health, USA
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影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
4.3
作者：
Majhail, Navneet S.;Chitphakdithai, Pintip;Logan, Brent;King, Roberta;Devine, Steven;Rossmann, Susan N.;Hale, Gregory;Hartzman, Robert J.;Karanes, Chatchada;Laport, Ginna G.;Nemecek, Eneida;Snyder, Edward L.;Switzer, Galen E.;Miller, John;Navarro, Willis;Confer, Dennis L.;Levine, John E.
通讯作者：
Levine, John E.
影响因子：
4.3
作者：
Hahn, Theresa;Sucheston-Campbell, Lara E.;McCarthy, Philip L.
通讯作者：
McCarthy, Philip L.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
45.3
作者：
Hahn, Theresa;McCarthy, Philip L., Jr.;Majhail, Navneet S.
通讯作者：
Majhail, Navneet S.