Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors

Ostrovsky, Olga; Shimoni, Avichai; Rand, Avital; Vlodavsky, Israël; Nagler, Arnon

doi:10.1182/blood-2009-08-236455

Cited by 49 publications

(67 citation statements)

References 53 publications

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“…Elevated expression of the heparanase gene has been identified as a risk factor for acute GVHD, as well as other factors, inducing increased activity of adhesion molecules [63]. Defibrotide was found to suppress heparanase expression [64], which could, in turn, reduce the risk of acute GVHD, as well as favorably influence the expression of adhesion molecules, as described above.…”

Section: Mechanism Of Action Of Defibrotidementioning

confidence: 78%

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Corbacioglu

Kernan

Lehmann

et al. 2012

Expert Review of Hematology

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Section: Mechanism Of Action Of Defibrotidementioning

confidence: 78%

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Corbacioglu

Kernan

Lehmann

et al. 2012

Expert Review of Hematology

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“…In fact, Ostrovsky et al reported that rs4364254 trended toward a lower cumulative risk for grades II-IV and III-IV aGVHD in the recessive model. 12 Unfortunately, we were not able to impute the genotypes for rs4693608, the key HSPE SNP that was associated with aGVHD risk. For MTHFR, we observed an association with the same genome and donor type, but the observed effect was opposite to that of the original publication.…”

Section: Discussionmentioning

confidence: 99%

“…12 Because the imputed rs4693608 genotype did not meet our quality control threshold, we were not able to perform a disparity analysis, and therefore we restricted our analysis to rs4364254, which was directly genotyped. The donor genotype for rs4364254 was significantly associated with a 1.2-fold increase (P ϭ .042) in risk for grade IIb-IV aGVHD after URD HCT in the dominant multivariate model (Table 3, Figure 2B).…”

Section: Org Frommentioning

confidence: 99%

Evaluation of published single nucleotide polymorphisms associated with acute GVHD

Chien

Zhang

Fan

et al. 2012

Blood

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Candidate genetic associations with acute GVHD (aGVHD) were evaluated with the use of genotyped and imputed singlenucleotide polymorphism data from genome-wide scans of 1298 allogeneic hematopoietic cell transplantation (HCT) donors and recipients. Of 40 previously reported candidate SNPs, 6 were successfully genotyped, and 10 were imputed and passed criteria for analysis. Patient and donor genotypes were assessed for association with grades IIb-IV and III-IV aGVHD, stratified by donor type, in univariate and multivariate allelic, recessive and dominant models. Use of imputed genotypes to replicate previous IL10 associations was validated. Similar to previous publications, the IL6 donor genotype for rs1800795 was associated with a 20%-50% increased risk for grade IIb-IV aGVHD after unrelated HCT in the allelic (adjusted P ‫؍‬ .011) and recessive (adjusted P ‫؍‬ .0013) models. The donor genotype was associated with a 60% increase in risk for grade III-IV aGVHD after related HCT (adjusted P ‫؍‬ .028). Other associations were found for IL2, CTLA4, HPSE, and MTHFR but were inconsistent with original publications. These results illustrate the advantages of using imputed single-nucleotide polymorphism data in genetic analyses and demonstrate the importance of validation in genetic association studies.

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“…2 Previous investigations have revealed that several single-nucleotide polymorphisms (SNPs), which impact on individual immune response to infections and inflammatory reactions are associated with SCT outcomes including the risk of acute GVHD. [3][4][5][6][7][8][9][10][11][12] IL-17, also known as IL-17A, is the hallmark cytokine of a new T-helper subset termed Th17. [13][14][15][16] gdT cells, macrophages and neutrophils are sources of IL-17 as well.…”

Section: Introductionmentioning

confidence: 99%

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

Espinoza

Takami

Onizuka

et al. 2011

Bone Marrow Transplant

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IL-17 has an important role in the host defense against extracellular pathogens and the pathophysiology of autoimmune diseases. This study retrospectively examined the impact of a single-nucleotide polymorphism (rs2275913, G197A) in the IL-17 gene of a total 510 recipients with hematologic malignancies and their unrelated donors on the clinical outcomes in HLAmatched myeloablative (discovery study) and nonmyeloablative (validation study) BMT through the Japan Marrow Donor Program (JMDP). In the discovery study, the presence of a 197A genotype in the recipient resulted in a higher incidence of grades II-IV acute GVHD (hazard ratio (HR), 1.87; 95% confidence interval (CI), 1.23-2.85; P ¼ 0.004). The donor IL-17A genotype did not significantly influence the transplant outcomes. The validation study showed a trend toward an association of the recipient 197A genotype with an increased risk of grades III-IV acute GVHD (HR, 5.84; 95% CI,; P ¼ 0.09), as well as a significantly increased risk for chronic GVHD (HR, 3.86; 95% CI, 1.29-11.59; P ¼ 0.02). These results suggest an association of the 197A genotype in the recipient side with the development of acute GVHD.

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Genetic variations in the heparanase gene (HPSE) associate with increased risk of GVHD following allogeneic stem cell transplantation: effect of discrepancy between recipients and donors

Abstract: Graft-versus-host disease (GVHD) is

Cited by 49 publications

References 53 publications

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Defibrotide for the treatment of hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation

Evaluation of published single nucleotide polymorphisms associated with acute GVHD

A single nucleotide polymorphism of IL-17 gene in the recipient is associated with acute GVHD after HLA-matched unrelated BMT

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