title: A putatively functional haplotype in the gene encoding transforming growth factor beta-1 as a potential biomarker for radiosensitivity.
abstract: OBJECTIVE
  To determine whether genetic variability in TGFB1 is related to circulating transforming growth factor-β1 (TGF-β1) plasma concentrations after radiotherapy and to radiosensitivity of lymphoid cells.
  
  
  METHODS
  Transforming growth factor-β1 plasma concentrations (n=79) were measured in patients 1 year after radiotherapy and chromosomal aberrations (n=71) ex vivo before therapy start. Furthermore, TGF-β1 secretion and apoptosis were measured in isolated peripheral blood mononuclear cells of 55 healthy volunteers. These phenotypes were analyzed in relation to five germline polymorphisms in the 5' region of the TGFB1 gene. Because of high linkage disequilibrium, these five polymorphisms reflect frequent genetic variation in this region. A presumed impact of TGF-β1 on DNA damage or repair was measured as micronucleus formation in 30 lymphoblastoid cell lines.
  
  
  RESULTS
  We identified a hypofunctional genetic haplotype termed H3 tagging the 5' region of the TGFB1 gene encoding TGF-β1. H3 was associated with lower TGF-β1 plasma concentrations in patients (p=0.01) and reduced TGF-β1 secretion in irradiated peripheral blood mononuclear cells (p=0.003). Furthermore, cells with H3 were less prone to induction of chromosomal aberrations (p=0.001) and apoptosis (p=0.003) by irradiation. The hypothesis that high TGF-β1 could sensitize cells to DNA damage was further supported by increased micronuclei formation in 30 lymphoblastoid cell lines when preincubated with TGF-β1 before irradiation (p=0.04).
  
  
  CONCLUSIONS
  On the basis of TGF-β1 plasma levels and radiation sensitivity of lymphoid cells, this study revealed a putatively hypofunctional TGFB1 haplotype. The significance of this haplotype and the suggested link between TGF-β1 function and DNA integrity should be further explored in other cell types, as well as other experimental and clinical conditions.
authors.affiliation: Department of Clinical Pharmacology, University Medical Center Göttingen, Göttingen, Germany. mschirmer@med.uni-goettingen.de
authors.forename: Markus A
authors.initials: MA
authors.lastname: Schirmer
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
authors.forename: Margret
authors.initials: M
authors.lastname: Rave-Fränk
authors.forename: Patricia
authors.initials: P
authors.lastname: Virsik
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilken
authors.forename: Elna
authors.initials: E
authors.lastname: Kühnle
authors.forename: Radu
authors.initials: R
authors.lastname: Campean
authors.forename: Arne O
authors.initials: AO
authors.lastname: Hoffmann
authors.forename: Katarina
authors.initials: K
authors.lastname: Müller
authors.forename: Robert G
authors.initials: RG
authors.lastname: Goetze
authors.forename: Michael
authors.initials: M
authors.lastname: Neumann
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Janke
authors.forename: Fatima
authors.initials: F
authors.lastname: Nasser
authors.forename: Hendrik A
authors.initials: HA
authors.lastname: Wolff
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.forename: Heinz
authors.initials: H
authors.lastname: Schmidberger
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Hess
authors.forename: Hans
authors.initials: H
authors.lastname: Christiansen
authors.forename: Andrea
authors.initials: A
authors.lastname: Hille
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D004249:DNA Damage; D005260:Female; D006239:Haplotypes / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D015810:Linkage Disequilibrium; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000187:drug effects; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011836:Radiation Tolerance / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000097:blood* / Q000235:genetics*
chemical_list: D015415:Biomarkers; D053773:Transforming Growth Factor beta1