title: Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors.
abstract: Transforming growth factor β-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, 'p001', showed significantly reduced overall survival (5-year overall survival 30.7% for p001/p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year non-relapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04-2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06-2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor β-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor β-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms.
authors.affiliation: Anthony Nolan Research Institute, London, UK Cancer Institute, University College London, UK Centro de Investigaciones en Hematología y Trastornos Afines (CIHATA), Universidad de Costa Rica, San José, Costa Rica.
authors.forename: Esteban
authors.initials: E
authors.lastname: Arrieta-Bolaños
authors.affiliation: Anthony Nolan Research Institute, London, UK Cancer Institute, University College London, UK.
authors.forename: Neema P
authors.initials: NP
authors.lastname: Mayor
authors.affiliation: Anthony Nolan Research Institute, London, UK Cancer Institute, University College London, UK.
authors.forename: Steven G E
authors.initials: SG
authors.lastname: Marsh
authors.affiliation: Anthony Nolan Research Institute, London, UK Cancer Institute, University College London, UK a.madrigal@ucl.ac.uk.
authors.forename: J Alejandro
authors.initials: JA
authors.lastname: Madrigal
authors.affiliation: Haematology Department, Hammersmith Hospital, London, UK.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Apperley
authors.affiliation: BSBMT Data Registry, Guy's Hospital, London, UK.
authors.forename: Keiren
authors.initials: K
authors.lastname: Kirkland
authors.affiliation: Department of Haematology, University College London, Royal Free Campus, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Mackinnon
authors.affiliation: Adult BMT Unit, University Hospitals Bristol NHS Trust, Bristol, UK.
authors.forename: David I
authors.initials: DI
authors.lastname: Marks
authors.affiliation: Bone Marrow Transplant Unit, Beatson West of Scotland Cancer Centre, Glasgow, UK.
authors.forename: Grant
authors.initials: G
authors.lastname: McQuaker
authors.affiliation: BSBMT Data Registry, Guy's Hospital, London, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Perry
authors.affiliation: Section of Haemato-oncology, Royal Marsden Hospital, London, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Potter
authors.affiliation: Centre for Clinical Haematology, Nottingham University Hospital, and Academic Haematology, Nottingham University Hospitals, UK.
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Russell
authors.affiliation: Department of Haematology, University College Hospital, London, UK.
authors.forename: Kirsty
authors.initials: K
authors.lastname: Thomson
authors.affiliation: Anthony Nolan Research Institute, London, UK Cancer Institute, University College London, UK.
authors.forename: Bronwen E
authors.initials: BE
authors.lastname: Shaw
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D015870:Gene Expression; D005838:Genotype; D019337:Hematologic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D012045:Regulatory Sequences, Nucleic Acid; D018570:Risk Assessment; D017422:Sequence Analysis, DNA; D035781:Siblings; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D066027:Transplant Recipients; D014184:Transplantation, Homologous; D061349:Unrelated Donors
chemical_list: C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1