Dipartimento di Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Università Cattolica del Sacro Cuore, Rome, Italy.
Int J Lab Hematol. 2023 Dec;45(6):935-944. doi: 10.1111/ijlh.14159. Epub 2023 Aug 30.
The heparanase (HPSE) gene is highly polymorphic, but only a minority of its single nucleotide polymorphisms (SNPs) have been studied. Among these, rs4693608 and rs4364254 SNPs are closely associated with mRNA expression and HPSE protein levels in healthy subjects. Given the association between HPSE and inflammatory response, we aimed to evaluate whether HPSE rs4693608 and rs4364254 SNPs could have an impact on graft-versus-host disease after allogeneic stem cell transplants (HSCT).
A total of 228 consecutive patients who underwent HSCT at our center between 2005 and 2018 were included. The rs4693608 SNP was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, while the rs4364254 was detected by allele-specific amplification.
The recipient-donor discrepancy for rs4364254 HPSE SNP was significantly associated with grade II-IV aGvHD (HR 1.75, p = 0.03). Patients were stratified into risk groups as follows: low-risk group (LDR) including TT-TT, TT-CT, CT-TT, CC-CC; high-risk group (HDR) including CC-CT, CC-TT, CT-CC, CT-CT, TT-CC. Day 100 cumulative incidence of grade II-IV aGvHD was 23.4% in the LDR group and 41.4% in the HDR group (p = 0.01). One-year cumulative incidence of moderate/severe cGvHD was 42.6% in the LDR group and 58.6% in the HDR group (p = 0.04). Independent variables for moderate/severe cGvHD in patients who received myeloablative conditioning included donor rs4693608 SNP (GA/AA vs. GG: HR 6.86, p = 0.008), rs4693608-rs4364254 SNP combination in recipient (HR/MR vs. LR: HR 3.67, p = 0.01), and previous grade II-IV aGvHD (HR 3.28, p = 0.0005). Finally, donors with rs4364254 SNP CC conferred increased transplant-related mortality (TRM) (39.1% vs. 25%, p = 0.03) and decreased graft-relapse free survival (GRFS) (23.5% vs. 34.4%, p = 0.04) compared with CT or TT genotypes.
The differences in incidence of GvHD according to recipient-donor genotype combinations suggests a possible role for rs4364254 HPSE SNP in predicting GvHD. A high level of HPSE, particularly linked to CC genotype of rs4364254 SNP may promote alloreactive T lymphocytes activation and migration toward target organs.
肝素酶（HPSE）基因高度多态性，但只有少数的单核苷酸多态性（SNP）已被研究。其中，rs4693608 和 rs4364254 SNP 与健康受试者的 mRNA 表达和 HPSE 蛋白水平密切相关。鉴于 HPSE 与炎症反应之间的关系，我们旨在评估 HPSE rs4693608 和 rs4364254 SNP 是否会对异基因造血干细胞移植（HSCT）后移植物抗宿主病（GVHD）产生影响。
我们纳入了 2005 年至 2018 年期间在我们中心接受 HSCT 的 228 例连续患者。rs4693608 SNP 通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析确定，而 rs4364254 通过等位基因特异性扩增检测。
受者-供者 rs4364254 HPSE SNP 差异与 II-IV 级 aGvHD 显著相关（HR 1.75，p=0.03）。患者被分为风险组如下：低危组（LDR）包括 TT-TT、TT-CT、CT-TT、CC-CC；高危组（HDR）包括 CC-CT、CC-TT、CT-CC、CT-CT、TT-CC。LDR 组第 100 天 II-IV 级 aGvHD 的累积发生率为 23.4%，HDR 组为 41.4%（p=0.01）。LDR 组中中度/重度 cGvHD 的 1 年累积发生率为 42.6%，HDR 组为 58.6%（p=0.04）。接受清髓性 conditioning 的患者中，中度/重度 cGvHD 的独立变量包括供体 rs4693608 SNP（GA/AA 与 GG：HR 6.86，p=0.008）、受者 rs4693608-rs4364254 SNP 组合（HR/MR 与 LR：HR 3.67，p=0.01）和 II-IV 级 aGvHD 病史（HR 3.28，p=0.0005）。最后，与 CT 或 TT 基因型相比，CC 基因型的供体 rs4364254 SNP 导致移植相关死亡率（TRM）升高（39.1% vs. 25%，p=0.03）和移植物无复发存活（GRFS）降低（23.5% vs. 34.4%，p=0.04）。
根据受者-供者基因型组合发生 GvHD 的差异表明，rs4364254 HPSE SNP 可能在预测 GvHD 方面发挥作用。高水平的 HPSE，特别是与 rs4364254 SNP 的 CC 基因型相关，可能会促进同种反应性 T 淋巴细胞向靶器官的激活和迁移。
