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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.

Original publication

DOI

10.1038/ncomms5999

Type

Journal article

Journal

Nat Commun

Publication Date

23/09/2014

Volume

4

Keywords

Breast Neoplasms, Cell Line, Tumor, Chromatin, Chromosomes, Human, Pair 2, Female, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 3-alpha, Humans, Insulin-Like Growth Factor Binding Protein 5, MCF-7 Cells, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Messenger