scholarly journals Single Nucleotide Polymorphisms of Paneth Cell Antimicrobial Alpha Defensin-5 (DEFA5) are Associated with Acute Graft-Versus-Host Disease: Results From Analysis of BMT-CTN0201 Samples

2018 ◽  
Vol 24 (3) ◽  
pp. S174-S175
Author(s):  
Armin Rashidi ◽  
Ryan Shanley ◽  
Shernan G. Holtan ◽  
Margaret L. MacMillan ◽  
Sophia Yohe ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Graft Versus Host Disease ◽  
Paneth Cell ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Single-Nucleotide Polymorphisms Within the Thrombomodulin Gene (THBD) Predict Mortality in Patients With Graft-Versus-Host Disease

2014 ◽  
Vol 32 (30) ◽  
pp. 3421-3427 ◽  
Author(s):  
Sivaramakrishna P. Rachakonda ◽  
Olaf Penack ◽  
Sascha Dietrich ◽  
Olga Blau ◽  
Igor Wolfgang Blau ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Graft Versus Host Disease ◽  
Risk Groups ◽  
Independent Effect ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Training Cohort ◽  
Host Disease ◽  
Graft Versus Host ◽  
Increased Risk

Purpose Steroid-refractory graft-versus-host disease (GVHD) is a major and often fatal complication after allogeneic stem-cell transplantation (alloSCT). Although the pathophysiology of steroid refractoriness is not fully understood, evidence is accumulating that endothelial cell stress is involved, and endothelial thrombomodulin (THBD) plays a role in this process. Here we assess whether single-nucleotide polymorphisms (SNPs) within the THBD gene predict outcome after alloSCT. Patients and Methods Seven SNPs within the THBD gene were studied (rs1962, rs1042579, rs1042580, rs3176123, rs3176124, rs3176126, and rs3176134) in a training cohort of 306 patients. The relevant genotypes were then validated in an independent cohort (n = 321). Results In the training cohort, an increased risk of nonrelapse mortality (NRM) was associated with three of seven SNPs tested: rs1962, rs1042579 (in linkage disequilibrium with rs3176123), and rs1042580. When patients were divided into risk groups (one v no high-risk SNP), a strong correlation with NRM was observed (hazard ratio [HR], 2.31; 95% CI, 1.36 to 3.95; P = .002). More specifically, NRM was predicted by THBD SNPs in patients who later developed GVHD (HR, 3.03; 95% CI, 1.61 to 5.68; P < .001) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariable analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM. All findings could be reproduced in the validation cohort. Conclusion THBD SNPs predict mortality of manifest GVHD but not the risk of acquiring GVHD, supporting the hypothesis that endothelial vulnerability contributes to GVHD refractoriness.

Single Nucleotide Polymorphisms Within The Thrombomodulin Gene (THBD) Predict Risk Of Non-Relapse Mortality In Patients With Graft-Versus-Host Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4589-4589
Author(s):  
Thomas Luft ◽  
Olaf Penack ◽  
Olga Blau ◽  
Sascha Dietrich ◽  
Berend H. Isermann ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Graft Versus Host Disease ◽  
Validation Cohort ◽  
Endothelial Damage ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Training Cohort ◽  
Host Disease ◽  
Graft Versus Host ◽  
Steroid Refractory

Purpose Acute graft-versus-host disease (GVHD) is a major complication after allogeneic stem cell transplantation (allo-SCT). With the current treatment approaches focussing on escalating immunosuppression, mortality rates of therapy-refractory disease courses are approx. 80-90%, underlining the medical need for novel therapeutic concepts. The pathophysiology of refractory GVHD is incompletely understood, however, recent evidence points towards a crucial role for endothelial damage. We have previously shown that steroid-refractory GVHD associates with increasing serum thrombomodulin (TM) levels 1, 2 and loss of endothelial TM expression 3, a constellation that indicates endothelial stress. However prior to allo-SCT, baseline TM levels did not predict steroid-refractory GVHD or survival. We hypothesized that endothelial vulnerability caused by single nucleotide polymorphisms within the TM gene (THBD) is a risk factor for refractory GVHD predicting outcome after allo-SCT. Patients and Methods Seven SNPs within the THBD gene were studied (rs1962.TC, rs1042579.TC, rs1042580.AG, rs3176123.TG, rs3176124GA, rs3176126.GA and rs3176134.CT) in a training cohort of 465 allografted patients. The relevant genotypes were then re-assessed in an independent validation cohort (n=386). Results Allele frequencies of seven THBD SNPs allowed meaningful statistical correlation with outcome after allo-SCT. An increased risk of non-relapse mortality (NRM) was associated with three SNPs: rs1962.CC, rs1042579.TT (455V) and rs1042580.GG. When patients were divided into risk cohorts (one vs. no high-risk SNP), a strong correlation with NRM was observed in both cohorts (training cohort: p=0.002, HR 2.32 CI 1.36-3.95; validation cohort: p=0.007, HR 2.13, CI 1.23-3.70) (Figure 1). NRM was predicted by THBD SNPs in particular for patients who later develop GVHD (validation cohort: p=0.00056, HR 3.03 CI 5.68-1.61, training cohort: p=0.012, HR 2.38 CI 1.21-4.69) but not in patients without GVHD. In contrast, THBD SNPs did not predict incidence of acute GVHD. Multivariate analyses adjusting for clinical variables confirmed the independent effect of THBD SNPs on NRM in both cohorts. Conclusions Our results demonstrate that THBD-SNPs predict mortality of GVHD patients without influencing GVHD incidence. This supports our hypothesis that endothelial vulnerability contributes to therapy refractory courses of the disease. Rather than focussing on the escalation of combinations of (endothelial cell toxic) immunosuppressive drugs, therapeutic approaches aiming at endothelial protection should be evaluated. 1. Dietrich S, Falk CS, Benner A, et al. Endothelial vulnerability and endothelial damage are associated with risk of graft-versus-host disease and response to steroid treatment. Biol Blood Marrow Transplant 2013; 19(1): 22-7. 2. Luft T, Dietrich S, Falk C, et al. Steroid-refractory GVHD: T-cell attack within a vulnerable endothelial system. Blood 2011; 118(6): 1685-92. 3. Andrulis M, Dietrich S, Longerich T, et al. Loss of endothelial thrombomodulin predicts response to steroid therapy and survival in acute intestinal graft-versus-host disease. Haematologica 2012; 97(11): 1674-7. Disclosures: Dreger: Riemser Pharma : Consultancy, Honoraria, Research Funding.

scholarly journals Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation

Blood ◽  
2013 ◽  
Vol 121 (10) ◽  
pp. 1896-1905 ◽  
Author(s):  
Effie W. Petersdorf ◽  
Mari Malkki ◽  
Mary M. Horowitz ◽  
Stephen R. Spellman ◽  
Michael D. Haagenson ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Graft Versus Host Disease ◽  
Hematopoietic Cell Transplantation ◽  
Unrelated Donor ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Graft Versus Host ◽  
Key Points ◽  
Mhc Haplotype ◽  
Hla Haplotypes

Key Points HLA haplotypes encode single nucleotide polymorphisms (SNPs) that are associated with risks after HLA-mismatched unrelated donor HCT. SNPs associated with graft-versus-host disease (GVHD) are independent of those associated with relapse.

Single Nucleotide Polymorphisms in CD40L Predict Endothelial Complications and Mortality After Allogeneic Stem-Cell Transplantation

2018 ◽  
Vol 36 (8) ◽  
pp. 789-800 ◽  
Author(s):  
Sivaramakrishna P. Rachakonda ◽  
Hao Dai ◽  
Olaf Penack ◽  
Olga Blau ◽  
Igor Wolfgang Blau ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Graft Versus Host Disease ◽  
Allogeneic Stem Cell Transplantation ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Graft Versus Host ◽  
Increased Risk ◽  
Acute Graft

Purpose Endothelial vulnerability is a potential risk factor for complications after allogeneic stem-cell transplantation (alloSCT). The CD40/CD40 ligand (CD40L) axis contributes to inflammatory diseases and is upregulated in endothelial cells upon activation, suggesting a role in alloSCT biology. Here, we studied single nucleotide polymorphisms (SNPs) in the CD40L gene in recipients of alloSCT. Patients and Methods Three CD40L SNPs (rs3092920, rs3092952, rs3092936) were analyzed for association with transplant-associated thrombotic microangiopathy, overall nonrelapse mortality (NRM), and NRM after acute graft-versus-host disease in 294 recipients of alloSCT without statin-based endothelial prophylaxis (SEP). The significant genotype was then put into perspective with established thrombomodulin ( THBD) gene polymorphisms. Findings were validated in an independent cohort without SEP and in an additional 344 patients who received SEP. Results The rs3092936 CC/CT genotype was associated with an increased risk of transplant-associated thrombotic microangiopathy ( P = .001), overall NRM ( P = .03), and NRM after acute graft-versus-host disease ( P = .01). The rs3092936 CC/CT genotype was largely mutually exclusive of high-risk THBD SNPs. Both CD40L and THBD SNPs predicted adverse overall survival (OS) and overall NRM to a similar extent in training cohort (OS, P = .04; NRM, P < .001) and validation cohort (OS, P = .01; NRM, P = .001) without SEP. In contrast, SEP completely abolished the influence of the high-risk CD40L and THBD SNPs ( P = .40). Conclusion An increased risk of endothelial complications can be predicted before alloSCT by genetic markers in the recipient’s genome. The normalization of mortality risks in patients treated with SEP suggests a way of overcoming the negative effect of high-risk genotypes and warrants further clinical validation.

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