title: Bioinformatic and functional analysis of TGFBR1 polymorphisms.
abstract: OBJECTIVE
  The transforming growth factor-beta (TGFB) pathway has substantial impact on cellular functions, cell proliferation, and apoptosis. We used bioinformatics, gene expression, and cell biological assays to evaluate the functionality of frequent inherited germline polymorphisms in the TGFB receptor 1 (TGFBR1).
  
  
  METHODS
  In an exploratory (n=55) and confirmatory (n=106) study, we analyzed the TGFB1 pathway after incubation with TGFbeta1 ligand and after exposure to X-rays in peripheral blood human mononuclear cells. Expression of TGFB pathway genes was assessed by real-time PCR, and cellular viability was analyzed by flow cytometry. A total of six polymorphisms including the deletion variant (*6A) were identified to tag currently known common genetic variations in TGFBR1 and were analyzed in relation to the phenotypes.
  
  
  RESULTS
  In accordance with a negative feedback mechanism, incubations with the ligand TGFbeta1 was followed by up-regulation of the intracellular SMAD7 and down-regulation of the SMAD3 mRNA molecules. The TGFBR1*6A deletion variant attenuated the suppression of SMAD3 in response to TGFbeta1 (P=0.02, in both studies). Moreover, cells harboring *6A were more sensitive toward cytotoxic effects of irradiation (P=0.001 after adjustment for age and sex). Cells were particularly prone toward radiation toxicity when carrying, in addition to *6A, the variant allele of rs11568785, which exhibits a strong genetic selection signature.
  
  
  CONCLUSIONS
  The *6A deletion and the linked rs11568785 polymorphisms seem to attenuate TGFB signaling. This should be considered not only for clinical-epidemiological studies on cancer susceptibility but may also be relevant for side effects from drugs or radiotherapy.
authors.affiliation: Department of Clinical Pharmacology, University Medicine Göttingen, Georg-August-University, Göttingen, Germany. mschirmer@med.uni-goettingen.de
authors.forename: Markus A
authors.initials: MA
authors.lastname: Schirmer
authors.forename: Arne O
authors.initials: AO
authors.lastname: Hoffmann
authors.forename: Radu
authors.initials: R
authors.lastname: Campean
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Janke
authors.forename: Laura M
authors.initials: LM
authors.lastname: Zidek
authors.forename: Marion
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Moritz
authors.initials: M
authors.lastname: Kruse
authors.forename: Daniel
authors.initials: D
authors.lastname: Sehrt
authors.forename: Mladen V
authors.initials: MV
authors.lastname: Tzvetkov
authors.forename: Margret
authors.initials: M
authors.lastname: Rave-Fränk
authors.forename: Jürgen
authors.initials: J
authors.lastname: Brockmöller
mesh_terms: D000328:Adult; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D019295:Computational Biology / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000528:radiation effects; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014965:X-Rays; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human