Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Research output: Contribution to journalJournal articleResearchpeer-review

  • Maya Ghoussaini
  • Stacey L Edwards
  • Kyriaki Michailidou
  • Silje Nord
  • Richard Cowper-Sal Lari
  • Kinjal Desai
  • Siddhartha Kar
  • Kristine M Hillman
  • Susanne Kaufmann
  • Dylan M Glubb
  • Jonathan Beesley
  • Joe Dennis
  • Manjeet K Bolla
  • Qin Wang
  • Ed Dicks
  • Qi Guo
  • Marjanka K Schmidt
  • Mitul Shah
  • Robert Luben
  • Judith Brown
  • Kamila Czene
  • Hatef Darabi
  • Mikael Eriksson
  • Daniel Klevebring
  • Bojesen, Stig Egil
  • Nordestgaard, Børge
  • Sune F Nielsen
  • Henrik Flyger
  • Diether Lambrechts
  • Bernard Thienpont
  • Patrick Neven
  • Hans Wildiers
  • Annegien Broeks
  • Laura J Van't Veer
  • Emiel J Th Rutgers
  • Fergus J Couch
  • Janet E Olson
  • Emily Hallberg
  • Celine Vachon
  • Jenny Chang-Claude
  • Anja Rudolph
  • Petra Seibold
  • Dieter Flesch-Janys
  • Julian Peto
  • Isabel Dos-Santos-Silva
  • Lorna Gibson
  • Heli Nevanlinna
  • Taru A Muranen
  • Kristiina Aittomäki
  • Carl Blomqvist
  • Australian Ovarian Cancer Management Group

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 languageEnglish
JournalNature Communications
Pages (from-to)1-12
Number of pages12
Publication statusPublished - 2014

ID: 135547968