Heparanase polymorphisms: influence on incidence of hepatic sinusoidal obstruction syndrome in children undergoing allogeneic hematopoietic stem cell transplantation

Abstract

Purpose: Sinusoidal obstruction syndrome (SOS) is a life-threatening early complication after hematopoietic stem cell transplantation (HSCT), and until now, examinations about the influence of genetic risk factors are extremely rare. The purpose of this study was to identify an association between heparanase (HPSE) single nucleotide polymorphisms (SNPs) and SOS in children undergoing allogeneic HSCT.

Methods: We retrospectively analyzed the distribution of the both HPSE SNPs rs4693608 and rs4364254 and the occurrence of SOS after allogeneic HSCT in 160 children with malignant and non-malignant diseases.

Results: Patients with HPSE genotypes GG or AG of rs4693608 (G>A) had a significantly reduced incidence of SOS on day 100 after HSCT compared to patients with genotype AA (4.7 vs. 14.3 %, P = 0.038). In addition, incidence of SOS in patients with genotype CC or CT of rs4364254 (C>T) was significantly decreased in comparison with patients with genotype TT (2.3 vs. 14.7 %, P = 0.004). Interestingly, no patient with genotype CC developed SOS. Because both SNPs co-occur in vivo, we generated subsets: AA-TT, GG-CC, and a group with remaining SNP combinations. We found significant differences between all three patient groups (P = 0.035). Patients with AA-TT showed the highest incidence of SOS (16.7 %), while SOS did not appear in patients with GG-CC (0 %) and residual combinations were numerically in-between (4.9 %). An impact caused by main patient and donor characteristics, established risk factors for SOS, and conditioning regimen could be excluded in multivariate analyses.

Conclusions: HPSE polymorphisms turned out to be significant independent risk factors (P = 0.030) for development of SOS and should be evaluated in further trials.

Fig. 1

Association of cumulative incidence of sinusoidal obstruction syndrome (SOS) on day 100 after hematopoietic stem cell transplantation (HSCT) and heparanase (HPSE) single nucleotide polymorphisms (SNPs) investigated in a cohort of 155 children undergoing allogeneic HSCT. Cumulative incidence curves summarize incidence of SOS until day 100 post-HSCT in patients genotyped for HPSE SNP rs4693608 (a) and rs4364254 (b). c Distribution of incidences for the three risk groups H1, H2, and H3 depending on HPSE SNP combinations of rs4693608 and rs4364254. d Cumulative incidence of SOS in patients who were genotyped for AA–TT or all other HPSE SNP combination

Fig. 2

Distribution of HPSE polymorphisms in patients with and without SOS. Most patients with SOS had genotype AA–TT (H1, n = 7). Group H2 (n = 5) consisted of three patients with AG–TT and one patient with AG–TC and GG–TC, respectively. In patients with genotype GG–CC (H3), SOS was not observed. Most of our patients without occurence of SOS had a genotype of group H2 (AG–TC n = 49, AG–TT n = 22, GG–TC n = 11, AA–TC n = 7, AG–CC n = 7, GG–TT n = 1). Thirty-five patients were genotyped for AA–TT (H1) and a minority of 11 patients for GG–CC (H3)

Fig. 3

Demonstration of transplant-related mortality (TRM) depending on HPSE rs4364254 genotype in patients undergoing allogeneic HSCT. A trend for a lower TRM in patients with polymorphism CC is shown