The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation

To avoid graft rejection, the hematopoietic stem cells with matched classical human leukocyte antigen (HLA) alleles are the primary choice for clinical allogeneic transplantation. However, even if the fully HLA-matched hematopoietic stem cells are used for transplantation, some patients still have poor prognosis after hematopoietic stem cell transplantation (HSCT), suggesting that the HLA system was not the only determinant of the outcomes of HSCT. In this study, we investigated whether the single-nucleotide polymorphisms (SNPs) of the co-stimulatory genes within non-HLA regions were related to the outcomes of HSCT. The genomic DNAs of 163 patients who had acute leukemia and received HSCT and their respective donors were collected for analysis. Thirty-four SNPs located in the four co-stimulatory genes including cytotoxic T-lymphocyte associated protein 4 (CTLA4), CD28, tumor necrosis factor ligand superfamily 4 (TNFSF4), and programmed cell death protein 1 (PDCD1) were selected to explore their relationship with the adverse outcomes after transplantation, including mortality, cytomegalovirus infection, graft-versus-host disease, and relapse. Our results revealed that nine SNPs in the CTLA4 gene, five SNPs in the PDCD1 gene, two SNPs in the TNFSF4 gene, and four SNPs in the CD28 gene were significantly associated with the occurrence of adverse outcomes post-HSCT. These SNPs may play important roles in immune response to allografts post-HSCT and can be the targets for developing strategy to identify appropriate donors.

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Faculty Opinions recommendation of Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717957357.793461843 ◽

2012 ◽

Author(s):

Effie Petersdorf

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Single Nucleotide Polymorphisms ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Hematopoietic Stem

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Donor Genotypes For Interleukin-17A Gene Single Nucleotide Polymorphisms (SNPs) Allow Anticipation Of Complications After HLA-Identical Allogeneic Stem Cell Transplantation (allo-SCT)

Blood ◽

10.1182/blood.v122.21.4619.4619 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4619-4619

Author(s):

Elena Buces ◽

Carolina Martínez-Laperche ◽

Milagros González-Rivera ◽

A Bosch-Vizcaya ◽

Beatriz Martin-Antonio ◽

...

Keyword(s):

Stem Cell ◽

Single Nucleotide Polymorphisms ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Hematopoietic Stem ◽

Increased Risk

Introduction Graft versus host disease (GvHD) is the main cause of morbimortality after allogeneic stem cell transplantation (allo-SCT). Several single-nucleotide polymorphisms (SNPs) in in the promoter region of cytokine genes have shown to alter their expression and are therefore associated with donor-recipient alloreactivity and, ultimately, with SCT outcome. Interleukin 17 (IL-17) is secreted by CD4+ T-cells and has been implicated in the pathogenesis of various autoimmune diseases but its importance in SCT is not well-known. Objective To analyse the influence of IL-17A SNP genotypes on the risk and severity of GvHD and other complications after HLA-identical allo-SCT. Patients and Methods Genomic DNA obtained from peripheral blood samples belonging to 546 patients and their HLA-identical sibling donors (Table 1) included in the DNA Bank of the Spanish Group for Hematopoietic Stem Cell Transplantation (GETH). Genotyping of the polymorphisms of interest, rs8193036 (-737C>T), rs2275913 (-197G>A), rs3819024 (-444A>G), rs4711998 (-877A>G), were performed by multiplex primer extension followed by mass spectrometry (MALDI-TOF; Sequenom MassArray). Results Genotype frequencies are shown in Table 2 and the association between IL-17A genotypes and complications after allo-SCT are shown in Table 3. Patients transplanted from donors harboring genotype CC for the SNP rs8193036 show increased risk of grade III-IV acute GvHD (7/26 vs 47/397, p=0.035) and of grade II-IV acute GvHD (13/26 vs 133/409, p=0.048). Patients transplanted from donors harboring allele A in the SNP rs4711998 show increased risk of extensive chronic GvHD (53/161 vs 43/177, p=0.045). Relapse rate was not related with IL-17A SNP genotypes. Finally a higher risk of toxicity-related mortality (TRM) was observed in patients transplanted from donors harboring allele A for SNP rs2275913 (78/293 vs 46/227, p=0.048), donors harboring allele G for SNP rs3819024 (78/279 vs 46/242, p=0.011) and donors harboring allele A for SNP rs4711998 (68/250 vs 55/229, p=0.044). Conclusions IL-17A SNP genotyping might be useful to anticipate complications after sibling HLA-identical allo-SCT and, therefore, to improve the clinical management of transplanted patients. This results further support the idea of a genetic predisposition to certain complications after allo-SCT. Paper presented on behalf of the GvHD/Immunotherapy committee of the Spanish Group for Hematopoietic Transplantation (GETH). Disclosures: No relevant conflicts of interest to declare.

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Single Nucleotide Polymorphisms in MORC4, CD14, and TLR4 Are Related to Outcome of Allogeneic Stem Cell Transplantation

Annals of Transplantation ◽

10.12659/aot.895389 ◽

2016 ◽

Vol 21 ◽

pp. 56-67 ◽

Cited By ~ 6

Author(s):

Elisabeth Norén ◽

Deepti Verma ◽

Peter Söderkvist ◽

Tilman Weisselberg ◽

Jan Söderman ◽

...

Keyword(s):

Stem Cell ◽

Single Nucleotide Polymorphisms ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Nucleotide Polymorphisms ◽

Single Nucleotide

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Single nucleotide polymorphisms and outcome risk in unrelated mismatched hematopoietic stem cell transplantation: an exploration study

Blood ◽

10.1182/blood-2012-01-406785 ◽

2012 ◽

Vol 119 (26) ◽

pp. 6365-6372 ◽

Cited By ~ 27

Author(s):

Christian Harkensee ◽

Akira Oka ◽

Makoto Onizuka ◽

Peter G. Middleton ◽

Hidetoshi Inoko ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Single Nucleotide Polymorphisms ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Acute Gvhd ◽

Nucleotide Polymorphisms ◽

Hla Matching ◽

Single Nucleotide ◽

Hematopoietic Stem

Genetic risk factors contribute to adverse outcome of hematopoietic stem cell transplantation (HSCT). Mismatching of the HLA complex most strongly determines outcomes, whereas non-HLA genetic polymorphisms are also having an impact. Although the majority of HSCTs are mismatched, only few studies have investigated the effects of non-HLA polymorphisms in the unrelated HSCT and HLA-mismatched setting. To understand these effects, we genotyped 41 previously studied single nucleotide polymorphisms (SNPs) in 2 independent, large cohorts of HSCT donor-recipient pairs (n = 460 and 462 pairs) from a homogeneous genetic background. The study population was chosen to pragmatically represent a large clinically homogeneous group (acute leukemia), allowing all degrees of HLA matching. The TNF-1031 donor-recipient genotype mismatch association with acute GVHD grade 4 was the only consistent association identified. Analysis of a subgroup of higher HLA matching showed consistent associations of the recipient IL2-330 GT genotype with risk of chronic GVHD, and the donor CTLA4-CT60 GG genotype with protection from acute GVHD. These associations are strong candidates for prediction of risk in a clinical setting. This study shows that non-HLA gene polymorphisms are of relevance for predicting HSCT outcome, even for HLA mismatched transplants.

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