University Hospital Regensburg, Department for Pediatric Hematology, Oncology and Stem Cell Transplantation, Regensburg, Germany.
Hematol Oncol Stem Cell Ther. 2023 Apr 4;16(3):217-229. doi: 10.1016/j.hemonc.2021.10.003.
Some of the early complications of hematopoietic stem cell transplantation (HSCT) concerning the small vessels can be summarized as transplant-associated systemic vasculopathies (TASV). One enzyme known to play a major role in inflammation, tissue remodeling, and repair processes as well as tumor metastasis is heparanase (HPSE). HPSE genetic variants have recently been associated with significant influence on the risk of developing certain TASV such as a sinusoidal obstruction syndrome. This study aimed to validate the two known HPSE single nucleotide polymorphisms (SNPs)-rs4693608 and rs4364254-as a genetic predictor of TASV in a cohort of 494 patients and were correlated retrospectively with the clinical course post-HSCT. Significant association was revealed for rs4364254, showing that the incidence of TASV (38.0% vs. 57.8%, p = .009) and in particular of acute graft-versus-host disease (aGvHD) (36.3% vs. 54.0%, p = .0138) was lower in wildtype CC carriers than in TC/TT carriers. Moreover, compared with all other genotypes, the allelic combination GG-CC had the lowest incidence of TASV (34.9% vs. 57.4%, p = .0109) and aGvHD in particular (34.9% vs. 53.5%, p = .0315). A competing risk regression analysis confirmed a significantly reduced risk for a TASV in patients with GG (subhazard ratio [SHR] = 0.670, p = .043) and CC (SHR = 0.598, p = .041) compared with the corresponding homozygote SNP as well as for allelic combinations correlated with low HPSE gene expression (SHR = 0.630, p = .016) and in correlation with clinical risk factors. In summary, our study emphasizes an association of HPSE gene SNPs with TASV, in particular with aGvHD, which could be implementable as pre-transplant risk stratification if validated prospectively.
造血干细胞移植（HSCT）后早期与小血管相关的一些并发症可归纳为移植相关系统性血管病（TASV）。肝素酶（HPSE）是一种已知在炎症、组织重塑和修复过程以及肿瘤转移中起主要作用的酶。最近，HPSE 基因变异与某些 TASV 如窦状隙阻塞综合征的发病风险显著相关。本研究旨在通过对 494 例患者的队列进行验证，将两个已知的 HPSE 单核苷酸多态性（SNP）rs4693608 和 rs4364254 作为 TASV 的遗传预测因子，并与 HSCT 后的临床过程进行回顾性相关分析。rs4364254 显示出显著的相关性，表明 TASV（38.0%比 57.8%，p=0.009），特别是急性移植物抗宿主病（aGvHD）（36.3%比 54.0%，p=0.0138）的发生率在野生型 CC 携带者中低于 TC/TT 携带者。此外，与所有其他基因型相比，等位基因组合 GG-CC 的 TASV（34.9%比 57.4%，p=0.0109）和 aGvHD（34.9%比 53.5%，p=0.0315）发生率最低。竞争风险回归分析证实，与相应的纯合 SNP 相比，GG（亚危险比[SHR]=0.670，p=0.043）和 CC（SHR=0.598，p=0.041）患者发生 TASV 的风险显著降低，以及与低 HPSE 基因表达相关的等位基因组合（SHR=0.630，p=0.016）和与临床危险因素相关的等位基因组合。总之，我们的研究强调了 HPSE 基因 SNP 与 TASV 的关联，特别是与 aGvHD 的关联，如果前瞻性验证，这些 SNP 可能作为移植前的风险分层。
