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

Blood ◽  
2012 ◽  
Vol 119 (26) ◽  
pp. 6365-6372 ◽  
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.

scholarly journals The Association Between Single-Nucleotide Polymorphisms of Co-Stimulatory Genes Within Non-HLA Region and the Prognosis of Leukemia Patients With Hematopoietic Stem Cell Transplantation

2021 ◽  
Vol 12 ◽  
Author(s):  
Ding-Ping Chen ◽  
Su-Wei Chang ◽  
Po-Nan Wang ◽  
Wei-Tzu Lin ◽  
Fang-Ping Hsu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Single Nucleotide Polymorphisms ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Adverse Outcomes ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Hematopoietic Stem

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.

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

Blood ◽  
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.

Impact of High-Resolution HLA Matching on Outcomes of Unrelated Donor Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5446-5446
Author(s):  
Seok Yun Kang ◽  
Hyeoung Il Kim ◽  
Hyun Woo Lee ◽  
Jun Ho Jang ◽  
Joon Seong Park ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Resolution ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Survival Data ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Hla Matching ◽  
Hematopoietic Stem

Abstract Objective: We assessed the impact of high-resolution genotypic results of human leukocyte antigen (HLA) for all major class I and II loci between donors and recipients in the outcome of unrelated hematopoietic stem cell transplantation (HSCT). Method: Between 1999 and 2005, high-resolution genotyping for HLA-A, -B, -C and -DRB1 was performed for 23 unrelated HSCT. All the patients were typed as HLA identical by serologic technique and then they were also typed HLA identical by high resolution technique. Unrelated bone marrow transplantation using DNA-based high resolution HLA compatibilities were considered in the analyses of clinical outcomes such as hematopoietic engraftment, acute GVHD, and survival. And then, we compared with patients who received related HSCT (same institute, same duration) and also unrelated HSCT data from IBMTR. Results: Median follow up duration was 9 months (1–51). Fifteen patients were male and 8 were female. Median age was 22 years (range 6–52). Median time from diagnosis to transplantation was 7 months (range 4–63). Eight patients of acute myeloid leukemia (AML), 6 of chronic myeloid leukemia (CML, 2 of 6 were in blast crisis), 4 of acute lymphoid leukemia (ALL), 3 of severe aplastic anemia and each case of juvenile myelomonocytic leukemia and myelodysplastic syndrome were enrolled. Median value of total nucleated cell and CD34 positive cell count was 3.51 (1.06–20.7) x 108/kg and 4.88 (1.33–46.9) x 106/kg, respectively. The conditioning regimen and prophylaxis for graft versus host disease (GVHD) were not different from conventional HSCT except one case of non-myeloablative transplantation. Median value of granulocytic (absolute granulocyte count > 500/mm3) and platelet (> 20,000/mm3) engraftment were D + 16, D + 17, respectively. Grade II acute GVHD developed in 4 patients (2 patients subsequently proceded to chronic GVHD). Treatment related mortality was 2 out of 23 patients (8.7%). Median value of overall survival duration was 30 months. For AML patients, 3-year survival rate was 72.9 %. Conclusions: Our survival data for unrelated HSCT based on high resolution genotyped HLA matching was superior to unrelated HSCT. Although the sample size is small, the survival data of AML patients (CR1 at transplant) was superior to the survivals of related HSCT, as well as that of unrelated HSCT. The findings were that transplantation using unrelated donors selected by high-resolution genotype identity improves the transplantation outcomes similar degree to the result of the related HSCT.

Chimerism Assay Using Single Nucleotide Polymorphisms Adjacent and in Linkage-Disequilibrium Enables Sensitive Disease Relapse Monitoring after Hematopoietic Stem-Cell Transplantation

2021 ◽  
Author(s):  
JinJu Kim ◽  
Woobin Yun ◽  
Yu Jin Park ◽  
Jieun Seo ◽  
Richard Dong Wook Lee ◽  
...  
Keyword(s):  
Stem Cell ◽  
Linkage Disequilibrium ◽  
Hematopoietic Stem Cell Transplantation ◽  
Single Nucleotide Polymorphisms ◽  
Stem Cell Transplantation ◽  
Error Rates ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Hematopoietic Stem ◽  
Baseline Error

Abstract Background Short tandem repeat (STR)-based chimerism analysis has been widely used for chimerism monitoring after hematopoietic stem-cell transplantation (HSCT), but technical artifacts can be problematic. We designed a chimerism assay using single nucleotide polymorphisms (SNPs) adjacent and in linkage-disequilibrium (CASAL), which doubly checked for SNP pairs, and thus could reduce background errors and increase analytical sensitivity. Methods CASAL targeted 84 SNP pairs within 10 bp distance and in perfect linkage-disequilibrium. Using undiluted and serially diluted samples, baseline error rates, and linearity was calculated. Clinical performance of CASAL was evaluated in comparison with a conventional STR assay, using 191 posttransplant samples from 42 patients with HSCT. Results CASAL had ∼10 times lower baseline error rates compared to that of ordinary next-generation sequencing. Limit of detection and quantification of CASAL were estimated to be 0.09 and 0.39%, respectively, with a linear range of 0.1–100%. CASAL correlated well with STR assay (r2 = 0.99) and the higher sensitivity enabled detection of low-level recipient chimerism and earlier prediction of relapse. Conclusions CASAL is a simple, analytically sensitive and accurate assay that can be used in clinical samples after HSCT with a higher performance compared to that of traditional assays. It should also be useful in other forensic and archeological testing.

scholarly journals Association between single nucleotide polymorphisms within HLA region and disease relapse for patients with hematopoietic stem cell transplantation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ding-Ping Chen ◽  
Su-Wei Chang ◽  
Po-Nan Wang ◽  
Fang-Ping Hus ◽  
Ching-Ping Tseng
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Single Nucleotide Polymorphisms ◽  
Stem Cell Transplantation ◽  
Gene Promoter ◽  
Nucleotide Polymorphisms ◽  
Disease Relapse ◽  
Single Nucleotide ◽  
Hematopoietic Stem ◽  
Increased Risk

Abstract Disease relapse occurs in patients with leukemia even hematopoietic stem cell transplantation (HSCT) was performed with human leukocyte antigen (HLA)-matched donors. As revealed previously by Petersdorf et al., there are nine single nucleotide polymorphisms (SNPs) located in the HLA region that potentially modulate the efficacy of HSCT. In this study, we investigated whether or not the genomic variants 500 base pairs flanking the nine transplantation-related SNPs were related to the risk of post-HSCT relapse for patients with leukemia (n = 141). The genomic DNAs collected from 85 patients with acute myeloid leukemia (AML), 56 patients with acute lymphocytic leukemia (ALL), and their respective HLA-matched donors were subject to SNPs analysis, conferred by the mode of mismatch between donor-recipient pair or by recipient or donor genotype analysis. Seven SNPs were revealed to associate with the risk of relapse post-HSCT. For patients with AML, the increased risk of post-HSCT relapse was associated with the donor SNP of rs111394117 in the intron of NOTCH4 gene, and the recipient SNPs of rs213210 in the ring finger protein 1 (RING1) gene promoter, and rs17220087 and rs17213693 in the intron of HLA-DOB gene. For patients with ALL, the increased risk of post-HSCT relapse was associated with the donor SNP of rs213210 in the RING1 gene promoter, and the recipient SNPs of rs79327197 in the HLA-DOA gene promoter, rs2009658 in the telomeric end of lymphotoxin-alpha (LTA) gene, rs17220087 and rs17213693 in the intron of HLA-DOB gene, and rs2070120 in the 3′-UTR of HLA-DOB gene. This study sheds new insight into selecting better candidate donors for performing HSCT in patients with AML and ALL.

Extended TNF Genotyping Identifies TNF -857T as a Risk Factor for Acute Graft-Versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 39-39
Author(s):  
Charles Mullighan ◽  
Sue L. Heatley ◽  
Natalie R. Villalta ◽  
Kathleen V. Doherty ◽  
Silke Danner ◽  
...  
Keyword(s):  
Stem Cell ◽  
Linkage Disequilibrium ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Acute Gvhd ◽  
Nucleotide Polymorphisms ◽  
Hematopoietic Stem ◽  
Grade Ii

Abstract Extensive evidence supports a role for non-HLA immunogenetic polymorphisms in determining risk and severity of acute GVHD following allogeneic hematopoietic stem cell transplantation (HCT). Tumor necrosis factor (TNF) polymorphisms have been frequently associated with GVHD risk. However, TNF is highly polymorphic and the TNF polymorphism(s) most strongly associated with GVHD remain to be determined. We previously studied three TNF single nucleotide polymorphisms (SNPs; −308, −238 and 488) in a retrospective study of 160 myeloablative HLA-matched related allo-HCTs and found a highly significant association between the intronic TNF 488A allele and risk and severity of acute GVHD and early mortality (Transplantation 2004;27:587). It was unclear if this association was primarily with TNF 488A or secondary to other functionally important TNF alleles in linkage disequilibrium. To clarify the importance of TNF variants in GVHD, we performed extended genotyping of TNF promoter SNPs in the previously described cohort, and in a prospective cohort of myeloablative (n=78) and non-myeloablative (n=56) sibling HLA-matched allo-HCT. Six TNF polymorphisms (−1030, −863, −857, −308, −238, 488) were genotyped in donors and recipients by PCR-SSP. TNF −308/−238/488 haplotypes were directly amplified by PCR, and full TNF haplotypes inferred using Haploview. The incidence of acute GVHD was 53% and 45.8% for myeloablative and non-myeloablative transplants, respectively. Nine TNF haplotypes were identified, and the TNF 488A allele was in strong, but not complete linkage disequilibrium with TNF −857T. TNF −857T was more strongly associated with acute GVHD (OR 11.1) and grade II–IV GVHD (OR 12.3) than 488A (acute GVHD OR 8.6 and grade II–IV GVHD OR 8.9) in the first cohort. These alleles were also associated with acute GVHD in the second cohort, but only in recipients receiving myeloablative conditioning (all acute GVHD, TNF 488A OR 2.9, −857T OR 3.4). Non-significant trends were observed with grade II–IV GVHD, possibly reflecting the reduced frequency of this complication in the later cohort (29% v. 48%). No association or trends were seen in non-myeloablative transplants. Moreover, no associations were identified with the extensively studied −308 or −238 SNPs in either cohort. Together, these data confirm the association between TNF polymorphisms and GVHD in myeloablative transplants, and suggest that −857T, which lies in closer proximity to TNF regulatory regions than 488A, may be the most useful marker for risk prediction. Our results also suggest that the immunogenetic determinants of GVHD vary according to the intensity of conditioning. Further work examining non-myeloablative transplants is required.

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