title: Little evidence for association between the TGFBR1*6A variant and colorectal cancer: a family-based association study on non-syndromic family members from Australia and Spain.
abstract: BACKGROUND
  Genome-wide linkage studies have identified the 9q22 chromosomal region as linked with colorectal cancer (CRC) predisposition. A candidate gene in this region is transforming growth factor β receptor 1 (TGFBR1). Investigation of TGFBR1 has focused on the common genetic variant rs11466445, a short exonic deletion of nine base pairs which results in truncation of a stretch of nine alanine residues to six alanine residues in the gene product. While the six alanine (*6A) allele has been reported to be associated with increased risk of CRC in some population based study groups this association remains the subject of robust debate. To date, reports have been limited to population-based case-control association studies, or case-control studies of CRC families selecting one affected individual per family. No study has yet taken advantage of all the genetic information provided by multiplex CRC families.
  
  
  METHODS
  We have tested for an association between rs11466445 and risk of CRC using several family-based statistical tests in a new study group comprising members of non-syndromic high risk CRC families sourced from three familial cancer centres, two in Australia and one in Spain.
  
  
  RESULTS
  We report a finding of a nominally significant result using the pedigree-based association test approach (PBAT; p = 0.028), while other family-based tests were non-significant, but with a p-value <; 0.10 in each instance. These other tests included the Generalised Disequilibrium Test (GDT; p = 0.085), parent of origin GDT Generalised Disequilibrium Test (GDT-PO; p = 0.081) and empirical Family-Based Association Test (FBAT; p = 0.096, additive model). Related-person case-control testing using the "More Powerful" Quasi-Likelihood Score Test did not provide any evidence for association (MQLS; p = 0.41).
  
  
  CONCLUSIONS
  After conservatively taking into account considerations for multiple hypothesis testing, we find little evidence for an association between the TGFBR1*6A allele and CRC risk in these families. The weak support for an increase in risk in CRC predisposed families is in agreement with recent meta-analyses of case-control studies, which estimate only a modest increase in sporadic CRC risk among 6*A allele carriers.
authors: CSIRO Preventative Health Flagship, Sydney, NSW, Australia. jason.ross@csiro.au.
authors: Jason P
authors: JP
authors: Ross
authors: Linda J
authors: LJ
authors: Lockett
authors: Bruce
authors: B
authors: Tabor
authors: Ian W
authors: IW
authors: Saunders
authors: Graeme P
authors: GP
authors: Young
authors: Finlay
authors: F
authors: Macrae
authors: Ignacio
authors: I
authors: Blanco
authors: Gabriel
authors: G
authors: Capella
authors: Glenn S
authors: GS
authors: Brown
authors: Trevor J
authors: TJ
authors: Lockett
authors: Garry N
authors: GN
authors: Hannan
mesh_terms: D000328:Adult; D000368:Aged; D001315:Australia; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D017384:Sequence Deletion; D013030:Spain
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human