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Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor.

ABSTRACT: Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The ?-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to non-synonymous amino acid substitutions. We previously found an association between donor genotypes and increased treatment-related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confirmed an association between rs6897932C and multiple sclerosis. In this study, we evaluated the prognostic significance of IL-7R? SNP genotypes in 590-recipient/donor pairs that received HLA-matched unrelated donor HCT for haematological malignancies. Consistent with the primary studies, the rs1494555GG and rs1494558TT genotypes of the donor were associated with aGvHD and chronic GvHD in the univariate analysis. The Tallele of rs6897932 was suggestive of an association with increased frequency of relapse by univariate analysis (P = 0.017) and multivariate analysis (P = 0.015). In conclusion, this study provides further evidence of a role of the IL-7 pathway and IL-7R? SNPs in HCT.

SUBMITTER: Shamim Z

PROVIDER: S-EPMC3982186 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor.

Shamim Z Z Spellman S S Haagenson M M Wang T T Lee S J SJ Ryder L P LP Müller K K

Scandinavian journal of immunology 20130801 2

Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The α-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to non-synonymous amino acid substitutions. We previously found an association between donor genotypes and increased treatment-related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confir ...[more]

PMID: 23692589

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Project description:BackgroundIdentification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT.MethodsWe performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011.FindingsUsing meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10-8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 × 10-8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 × 10-8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 × 10-8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 × 10-8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 × 10-9) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p = 2.6 × 10-8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 × 10-8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 × 10-9). Results publicly available at https://fuma.ctglab.nl/browse.InterpretationThese data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies.FundingThis project was funded by grants from the National Institutes of Health, USA.

Project description:PurposeThe success of allogeneic hematopoietic stem cell transplantation (HSCT) is compromised by complications such as infection, relapse, and graft-versus-host disease (GVHD). The investigation of non-HLA immunogenetics, particularly of cytokines, could identify predictors of an unfavorable outcome after allogeneic HSCT. In this study, we examined the impact of single nucleotide polymorphisms (SNPs) within the promoter region of interleukin 6 (IL6) on the development of GVHD after pediatric allogeneic HSCT.MethodsIn this retrospective analysis, we included 320 pediatric patients with a median age of 10 years who underwent an allogeneic HSCT and their respective donors. We used TaqMan real-time polymerase chain reaction to analyze the SNPs IL6-174 (G/C) and IL6-597 (G/A). The IL6-174 polymorphism was examined in 300 recipients and 295 donors. The IL6-597 polymorphism was analyzed in 299 recipients and 296 donors. We investigated the influence of the IL6-174 and IL6-597 polymorphisms on overall survival, event-free survival, relapse incidence, transplant-related mortality, and the occurrence of GVHD.ResultsG polymorphism at position 174 of the recipient IL6 gene was associated with a higher incidence of acute GVHD (GG vs. GC/CC; P = 0.024). Patients with IL6-597 GG genotype developed acute GVHD more frequently than individuals with an A allele (GG vs. GA vs. AA; P = 0.013). IL6-174 GG homozygous recipients had a more frequent occurrence of chronic GVHD (GG vs. GC/CC; P = 0.049). We observed a significant increased risk of chronic GVHD in recipients with IL6-597 GG genotype (GG vs. GA vs. AA; P = 0.043). Polymorphisms of donors did not affect the incidence of acute GVHD and chronic GVHD. In multivariate analysis, the IL6-174 and IL6-597 SNPs were independent significant risk factors for acute GVHD (P = 0.030; P = 0.007, respectively) as well as for chronic GVHD (P = 0.045; P = 0.015, respectively). In addition, older age at time of transplantation turned out to be a significant risk factor for chronic GVHD (P = 0.003).ConclusionOur study identified the IL6-174 and IL6-597 GG genotypes of pediatric allogeneic HSCT recipients as genetic risk factors for the development of acute GVHD and chronic GVHD. After evaluations in further studies, these findings could implicate the adjustment of prophylactic measures to reduce the occurrence of acute GVHD and chronic GVHD.

Project description:IMPORTANCE:Telomeres protect chromosome ends and are markers of cellular aging and replicative capacity. OBJECTIVE:To evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia. DESIGN, PARTICIPANTS, AND SETTING:The study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013. EXPOSURES:Recipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution. MAIN OUTCOMES AND MEASURES:Overall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up. RESULTS:Longer donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P?=?.009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30). CONCLUSIONS AND RELEVANCE:Longer donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.

Project description:BackgroundAllogeneic hematopoietic cell transplantation (allo-HCT) using a mismatched unrelated donor (MMUD) and cord blood transplantation (CBT) are valid alternatives for patients without a fully human leukocyte antigen (HLA)-matched donor. Here, we compared the allo-HCT outcomes of CBT versus single-allele-mismatched MMUD allo-HCT with post-transplant cyclophosphamide (PTCy) in acute myeloid leukemia.MethodsPatients who underwent a first CBT without PTCy (N = 902) or allo-HCT from a (HLA 9/10) MMUD with PTCy (N = 280) were included in the study. A multivariate regression analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score-based 1:1 matching of patients (177 pairs) with known cytogenetic risk.ResultsThe incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% (p = 0.07) and 15% versus 11% (p = 0.16) for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%, p < 0.01) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%, p < 0.01) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR = 2.09, 95% CI 1.46-2.99, p < 0.0001), and relapse (HR = 1.35, 95% CI 1-1.83, p = 0.05), which resulted in worse leukemia-free survival (LFS) (HR = 1.68, 95% CI 1.34-2.12, p < 0.0001), overall survival (OS) (HR = 1.7, 95% CI 1.33-2.17, p < 0.0001), and GVHD-free, relapse-free survival (GRFS) (HR = 1.49, 95% CI 1.21-1.83, p < 0.0001) compared to MMUD. The risk of grade II-IV acute GVHD (p = 0.052) and chronic GVHD (p = 0.69) did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis.ConclusionsCBT was associated with lower LFS, OS, and GRFS due to higher NRM, compared to MMUD allo-HCT with PTCy. In the absence of a fully matched donor, 9/10 MMUD with PTCy may be preferred over CBT.

Dataset Information

Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor.

Publications

Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor.

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