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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, AA; (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. pp. 276-283.

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Abstract

Background Many genetic factors play a major role in the outcome of unrelated donors (UD) hematopoietic stem cell transplantation (HSCT). Transforming growth factor b1 (TGF-beta1) is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. DESIGN AND METHODS: We investigated the impact of TGFB1 single nucleotide polymorphisms (SNPs) at codons 10 and 25 on outcomes in 427 myeloablative-conditioned transplant patients. In addition, TGF-beta1 plasma levels were measured in 263 patients and 327 donors. RESULTS: Patients homozygous for the SNP at codon 10 had increased non-relapse mortality (NRM) (3 years 46.8% vs. 29.4%, p=0.014) and reduced overall survival (OS) (5 years 29.3% vs. 42.2%, p=0.013), which remained significant in multivariate analysis for NRM (Hazard ratio (HR): 1.9; 95% confidence interval (CI) 1.23-2.96, p=0.004) and OS (HR: 1.5, 95% CI 1.00-2.28, p=0.048). There was no impact of donor genotype alone, although multiple SNPs within the pair were significantly associated with higher NRM (3 years 44% vs. 29%, p=0.021) and decreased OS (5 years 33.8% vs. 41.9%, p=0.033). In the 10/10 HLA matched transplants (n=280), non-wild type (wt) donors showed a trend to increase the incidence of acute graft-versus-host disease (aGvHD) II-IV (p=0.052). In multivariate analysis, when analyzed with patient genotype, non-wt pairs increased the incidence of overall aGvHD (Odds Ratio (OR): 2.2, 95% CI 1.11-4.7; p=0.025) and aGvHD II-IV (OR: 15.1, 95% CI 1.96-117.4; p=0.009). Conclusions We conclude that increasing numbers of SNPs in TGFB1 codon 10 in patients and donors is associated with a worse outcome following UD-HSCT.

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
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/1320366
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