Abstract |
Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 ( mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.
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Authors | Alan M Pittman, Silvia Naranjo, Emily Webb, Peter Broderick, Esther H Lips, Tom van Wezel, Hans Morreau, Kate Sullivan, Sarah Fielding, Philip Twiss, Jayaram Vijayakrishnan, Fernando Casares, Mobshra Qureshi, José Luis Gómez-Skarmeta, Richard S Houlston |
Journal | Genome research
(Genome Res)
Vol. 19
Issue 6
Pg. 987-93
(Jun 2009)
ISSN: 1088-9051 [Print] United States |
PMID | 19395656
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Nuclear Proteins
- SMAD7 protein, human
- Smad7 Protein
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Topics |
- Aged
- Alleles
- Animals
- Cell Line, Tumor
- Chromosome Mapping
- Chromosomes, Human, Pair 18
(genetics)
- Colorectal Neoplasms
(genetics, pathology)
- Electrophoretic Mobility Shift Assay
- Female
- Gene Expression
- Gene Frequency
- Genetic Predisposition to Disease
(genetics)
- Genetic Variation
- Genotype
- Humans
- Male
- Middle Aged
- Nuclear Proteins
(metabolism)
- Polymorphism, Single Nucleotide
- Protein Binding
- Risk Factors
- Sequence Analysis, DNA
- Smad7 Protein
(genetics, metabolism)
- Xenopus laevis
(embryology, genetics)
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