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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

Berro, M; Mayor, NP; Maldonado-Torres, H; Cooke, L; Kusminsky, G; Marsh, SGE; Madrigal, JA; (2010) 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. HAEMATOL-HEMATOL J , 95 (2) 276 - 283. 10.3324/haematol.2009.010835. Gold open access

Abstract

BackgroundMany genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor beta 1 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 beta 1, on outcomes in 427 myeloablative-conditioned transplanted patients. In addition, transforming growth factor beta 1 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%, versu s29.4%, 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-versus-host 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.

Type: Article
Title: 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
Open access status: An open access publication
DOI: 10.3324/haematol.2009.010835
Keywords: stem cell transplantation, TGF-beta 1, polymorphisms, survival, graft-versus-host disease, BONE-MARROW-TRANSPLANTATION, REGULATORY T-CELLS, FACTOR-BETA, GROWTH-FACTOR-BETA-1 GENE, TGF-BETA, RISK-ASSESSMENT, BREAST-CANCER, TGF-BETA-1, FIBROSIS, SUSCEPTIBILITY
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
URI: http://discovery.ucl.ac.uk/id/eprint/1320386
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