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 Feb;95(2):276-83
Date
08/29/2009Pubmed ID
19713222Pubmed Central ID
PMC2817031DOI
10.3324/haematol.2009.010835Scopus ID
2-s2.0-76549092266 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
BACKGROUND: Many genetic factors play major roles in the outcome of hematopoietic stem cell transplants from unrelated donors. Transforming growth factor 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 single nucleotide polymorphisms at codons 10 and 25 of TGFB1, the gene encoding for transforming growth factor beta1, on outcomes in 427 mye-loablative-conditioned transplanted patients. In addition, transforming growth factor beta1 plasma levels were measured in 263 patients and 327 donors.
RESULTS: Patients 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-versus-host disease were increased (P=0.025 and P=0.009, respectively) in non-wild-type pairs.
CONCLUSIONS: We 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.
Author List
Berro M, Mayor NP, Maldonado-Torres H, Cooke L, Kusminsky G, Marsh SG, Madrigal JA, Shaw BEAuthor
Bronwen E. Shaw MBChB, PhD Center Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultCohort Studies
Female
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Humans
Male
Polymorphism, Single Nucleotide
Survival Analysis
Transforming Growth Factor beta1
Transplantation, Homologous
Treatment Outcome