title: The 14q22.2 colorectal cancer variant rs4444235 shows cis-acting regulation of BMP4.
abstract: Common genetic variation at human 14q22.2 tagged by rs4444235 is significantly associated with colorectal cancer (CRC) risk. Re-sequencing was used to comprehensively annotate the 17kb region of strong linkage disequilibrium encompassing rs4444235. Through bioinformatic analyses using H3K4Me1, H3K4Me3, and DNase-I hypersensitivity chromatin signatures and evolutionary conservation we identified seven candidate disease-causing single-nucleotide polymorphisms mapping to six regions within the 17-kb region predicted to have regulatory potential. Reporter gene studies of these regions demonstrated that the element to which rs4444235 maps acts as an allele-specific transcriptional enhancer. Allele-specific expression studies in CRC cell lines heterozygous for rs4444235 showed significantly increased expression of bone morphogenetic protein-4 (BMP4) associated with the risk allele (P<0.001). These data provide evidence for a functional basis for the non-coding risk variant rs4444235 at 14q22.2 and emphasizes the importance of genetic variation in the BMP pathway genes as determinants of CRC risk.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Surrey, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Lubbe
authors.forename: A M
authors.initials: AM
authors.lastname: Pittman
authors.forename: B
authors.initials: B
authors.lastname: Olver
authors.forename: A
authors.initials: A
authors.lastname: Lloyd
authors.forename: J
authors.initials: J
authors.lastname: Vijayakrishnan
authors.forename: S
authors.initials: S
authors.lastname: Naranjo
authors.forename: S
authors.initials: S
authors.lastname: Dobbins
authors.forename: P
authors.initials: P
authors.lastname: Broderick
authors.forename: J L
authors.initials: JL
authors.lastname: Gómez-Skarmeta
authors.forename: R S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000483:Alleles; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14; D015179:Colorectal Neoplasms / Q000209:etiology / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide
chemical_list: C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4