The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy
The genetic fingerprint of susceptibility for transplant-associated thrombotic microangiopathy
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DOI：
10.1182/blood-2015-08-663435
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发表时间：
2016-02-25
期刊：
影响因子：
20.3
通讯作者：
Davies, Stella M.
中科院分区：
文献类型：
--
作者：
Jodele, Sonata;Zhang, Kejian;Davies, Stella M.
移植相关血栓性微血管病（TA-TMA）常发生在造血干细胞移植（HSCT）后，可导致显著的发病率和死亡率。没有关于TA-TMA个体易感性的数据。我们对17个已知在补体激活中起作用的候选基因进行了假设驱动分析，作为HSCT受者TMA前瞻性研究的一部分。我们通过基因表达谱分析研究了基因变异的功能意义。在77名接受基因检测的患者中，34名患有TMA。65%的TMA患者至少有一个基因存在遗传变异，而无TMA的患者这一比例为9%（P < .0001）。在所有种族的TMA患者中，基因变异都增加了，但非白人比白人有更多的变异（2.5 [范围，0-7] vs 0 [范围，0-2]; P < .0001）。在>= 3个基因中的变异仅在非白人TMA患者中发现，并且与高死亡率（71%）相关。移植前样本的RNA测序分析显示，与那些没有TMA和没有基因变异的患者相比，具有基因变异的TMA患者的多种补体途径上调，包括通过计算机算法预测为可能良性的变异。我们的数据揭示了基于受体基因型的HSCT相关TMA遗传易感性的重要差异。这些数据将允许前瞻性的风险评估和干预，以防止高度敏感的移植受者的TMA。我们的研究结果可以解释，至少部分，种族差异先前报告的移植受体，并可能指导治疗策略，以改善结果。
Transplant-associated thrombotic microangiopathy (TA-TMA) occurs frequently after hematopoietic stem cell transplantation (HSCT) and can lead to significant morbidity and mortality. There are no data addressing individual susceptibility to TA-TMA. We performed a hypothesis-driven analysis of 17 candidate genes known to play a role in complement activation as part of a prospective study of TMA in HSCT recipients. We examined the functional significance of gene variants by using gene expression profiling. Among 77 patients undergoing genetic testing, 34 had TMA. Sixty-five percent of patients with TMA had genetic variants in at least one gene compared with 9% of patients without TMA (P < .0001). Gene variants were increased in patients of all races with TMA, but nonwhites had more variants than whites (2.5 [range, 0-7] vs 0 [range, 0-2]; P < .0001). Variants in >= 3 genes were identified only in nonwhites with TMA and were associated with high mortality (71%). RNA sequencing analysis of pretransplantation samples showed upregulation of multiple complement pathways in patients with TMA who had gene variants, including variants predicted as possibly benign by computer algorithm, compared with those without TMA and without gene variants. Our data reveal important differences in genetic susceptibility to HSCT-associated TMA based on recipient genotype. These data will allow prospective risk assessment and intervention to prevent TMA in highly susceptible transplant recipients. Our findings may explain, at least in part, racial disparities previously reported in transplant recipients and may guide treatment strategies to improve outcomes.