title: Comprehensive assessment of variation at the transforming growth factor beta type 1 receptor locus and colorectal cancer predisposition.
abstract: The role of transforming growth factor beta receptor type 1 (TGFBR1) polymorphisms, particularly a coding CGC insertion (rs11466445, TGFBR1*6A/9A) in exon 1, has been extensively investigated in regard to colorectal cancer (CRC) risk. These investigations have generated conflicting results. More recently, allele-specific expression (ASE) of TGFBR1 mRNA has been suggested as predisposing to CRC, with a relative risk of nearly 10-fold and a population attributable risk of approximately 10%. Owing to the potential importance of TGFBR1 variants in CRC, we performed a comprehensive examination of tagging SNPs at and around the gene in 3,101 CRC cases and 3,334 controls of northern European ancestry. To test whether rare or subpolymorphic TGFBR1 variants were associated with CRC risk, we sequenced the gene's exons in a subset of patients. We also evaluated TGFBR1 ASE in a panel of CRC cases and controls. Overall, we found no association between TGFBR1 polymorphisms and CRC risk. The rare variant screen did not identify any changes of potentially pathogenic effects. No evidence of greater ASE in cases than controls was detected, and no haplotype around TGFBR1 could account for the ASE reported in other studies. We conclude that neither genetic variation nor ASE at TGFBR1 is likely to be a major CRC risk factor.
authors.affiliation: Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom. luis@well.ox.ac.uk
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Mike
authors.initials: M
authors.lastname: Churchman
authors.forename: Carolina
authors.initials: C
authors.lastname: Bonilla
authors.forename: Axel
authors.initials: A
authors.lastname: Walther
authors.forename: Jeremie H
authors.initials: JH
authors.lastname: Lefèvre
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.forename: Malcolm
authors.initials: M
authors.lastname: Dunlop
authors.forename: Richard
authors.initials: R
authors.lastname: Houlston
authors.forename: Walter F
authors.initials: WF
authors.lastname: Bodmer
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D017931:DNA Primers; D053773:Transforming Growth Factor beta1