Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
Duke Scholars
Altmetric Attention Stats
Dimensions Citation Stats
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- RNA, Messenger
- Promoter Regions, Genetic
- Polymorphism, Single Nucleotide
- MCF-7 Cells
- Insulin-Like Growth Factor Binding Protein 5
- Humans
- Hepatocyte Nuclear Factor 3-alpha
- Genetic Predisposition to Disease
- Female
- Chromosomes, Human, Pair 2
Citation
Published In
DOI
EISSN
Publication Date
Volume
Start / End Page
Location
Related Subject Headings
- RNA, Messenger
- Promoter Regions, Genetic
- Polymorphism, Single Nucleotide
- MCF-7 Cells
- Insulin-Like Growth Factor Binding Protein 5
- Humans
- Hepatocyte Nuclear Factor 3-alpha
- Genetic Predisposition to Disease
- Female
- Chromosomes, Human, Pair 2