Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Abstract

BackgroundMany genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor β1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. Design and MethodsWe investigated the impact of single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor β1, on outcomes in 427 myeloablative-conditioned transplanted patients. In addition, transforming growth factor β1 plasma levels were measured in 263 patients and 327 donors. ResultsPatients homozygous for the single nucleotide polymorphism at codon 10 had increased non-relapse mortality (at 3 years: 46.8% versus 29.4%, P=0.014) and reduced overall survival (at 5 years 29.3% versus 42.2%, P=0.013); the differences remained statistically significant in multivariate analysis. Donor genotype alone had no impact, although multiple single nucleotide polymorphisms within the pair were significantly associated with higher non-relapse mortality (at 3 years: 44% versus 29%, P=0.021) and decreased overall survival (at 5 years: 33.8% versus 41.9%, P=0.033). In the 10/10 HLA matched transplants (n=280), recipients of non-wild type grafts tended to have a higher incidence of acute graft-versus-host disease grades II-IV (P=0.052). In multivariate analysis, when analyzed with patients' genotype, the incidences of both overall and grades II-IV acute graft-versushost disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs. ConclusionsWe conclude that increasing numbers of single nucleotide polymorphisms in codon 10 of TGFB1 in patients and donors are associated with a worse outcome following hematopoietic stem cell transplantation from unrelated donors.Key words: stem cell transplantation, TGF-β1, polymorphisms, survival, graft-versus-host disease.Citation: Berro M, Mayor NP, Maldonado-Torres H, Cooke L, Kusminsky G, Marsh SGE, Madrigal JA, and Shaw BE. Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation. Haematologica. 2010; 95:276-283. doi:10.3324/haematol.2009 This is an open-access paper.Association of functional polymorphisms of the transforming growth factor B1 gene with survival and graft-versus-host disease after unrelated donor hematopoietic stem cell transplantation

Impact of Immunogenetic Polymorphisms in Bone Marrow Failure Syndromes

“…The A/A, T/A, and T/T IFN-genotypes for base -874 have been reported to correspond to low, intermediate, and high in vitro cytokine production, respectively [59][60][61][62][63][64]. According with the data already reported, we confirmed that the frequency of the hypersecreting genotype T/T of the IFN-was most over represented in the AA population compared to controls [39,58]. By contrast, there were no significant differences in the polymorphism of IFN-at position +874 between all MDS and each subgroup of MDS patients and healthy controls.…”

Transforming growth factor-β1 functional polymorphisms in myeloablative sibling hematopoietic stem cell transplantation

“…the myeloablative cohort, as we have previously observed in UD HSCT. 31 It is well recognized that this highly toxic conditioning produces an inflammatory scenario known as 'cytokine storm'. 36,37 In a murine model, the conditioning regimen did alter the contribution of CD8+ or CD4+ subsets to the total FOXP3+ pool with functional importance in defining transplant outcome and are important for protection from GvHD.…”

“…30 We have previously published an association of +29C4T SNP and HSCT from unrelated donors (UD). 31 Patients with +29CC genotype experienced a higher non relapse mortality (NRM) and reduced overall survival (OS) compared with the TC and TT genotypes. The impact of this polymorphism on the outcome of sibling donor HSCT is on debate as several studies have given conflicting results, especially in aGvHD.…”

Concise Review: Workshop Review: Understanding and Assessing the Risks of Stem Cell-Based Therapies

“…Further screening for herpes simplex virus, Epstein‐Barr virus, and adenoviruses may also be required in addition to screening for cell type‐ and location‐specific viruses [140]. Genotype screening for donor cells has also been suggested [141], with some reports of specific genetic polymorphisms associated with differential GVHD severity and outcome in allogeneic HSC transplants [142, 143].…”