文章：

CXCR3配体的多态性可预测早期CXCL9恢复及重度慢性GVHD

Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD

原文发布日期：2021-02-27

DOI: 10.1038/s41408-021-00434-2

类型: Article

开放获取: 是

英文摘要：

Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9–11 SNPs as well as peri-transplant CXCL9–11 serum levels were analyzed in 688 patients without (training cohort; n = 287) or with statin-based endothelial protection cohort (n = 401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort (n = 202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33–4.64, P = 0.004) and validation cohort (HR 2.95, 95% CI 1.56–5.58, P = 0.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 (P < 0.001) and rs884004 (P < 0.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10–1.73, P = 0.006). This study identifies patients with high genetic risk to develop severe cGVHD.
 

摘要翻译： 

慢性移植物抗宿主病（cGVHD）是异基因干细胞移植（alloSCT）后死亡和发病的主要原因。严重cGVHD的个体风险仍难以预测，可能涉及CXCR3配体。本研究探讨了CXCL4、CXCL9、CXCL10和CXCL11的单核苷酸多态性（SNPs）及其在第+28天的血清水平在cGVHD发病机制中的作用。研究对688例患者（训练队列n=287，未接受治疗；他汀类药物内皮保护队列n=401）的18个CXCR3及CXCL4、CXCL9–11 SNPs以及移植前后CXCL9–11血清水平进行了分析。临床结局与血清水平和SNP状态进行关联分析。对具有显著意义的SNPs进一步通过荧光素酶报告基因实验验证。研究结果在独立队列（n=202）中得到验证。由四个CXCR3配体SNPs组成的联合遗传风险与严重cGVHD风险升高显著相关，在训练队列（风险比（HR）2.48，95%置信区间（CI）1.33–4.64，P=0.004）和验证队列（HR 2.95，95% CI 1.56–5.58，P=0.001）中均得到确认。在报告基因实验中，观察到rs884304（P<0.001）和rs884004（P<0.001）变异等位基因构建体中钙调神经磷酸酶抑制剂的抑制作用显著降低。alloSCT后第+28天CXCL9血清水平与遗传风险及严重cGVHD风险均相关（HR 1.38，95% CI 1.10–1.73，P=0.006）。本研究识别出具有高遗传风险发生严重cGVHD的患者。

原文链接：

Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD