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

M Ghoussaini, SL Edwards, K Michailidou, S Nord, RCS Lari, K Desai, S Kar, KM Hillman, S Kaufmann, DM Glubb, J Beesley, J Dennis, MK Bolla, Q (Qing) Wang, E Dicks, Q Guo, MK (Marjanka) Schmidt, M Shah, R Luben, J BrownK Czene, H Darabi, M Eriksson, D Klevebring, SE Bojesen, BG Nordestgaard, SF Nielsen, H Flyger, D Lambrechts, B Thienpont, P Neven, H Wildiers, A Broeks, LJ (Laura) van 't Veer, EJT Rutgers, FJ Couch, JE Olson, E Hallberg, C Vachon, J Chang-Claude, A Rudolph, P Seibold, D Flesch-Janys, J Peto, I dos-Santos-Silva, L Gibson, H Nevanlinna, TA Muranen, K Aittomaki, C Blomqvist, P Hall, JM Li, JJ Liu, K Humphreys, D Kang, JY Choi, SK Park, DY Noh, K Matsuo, H Ito, H Iwata, Y Yatabe, P Guenel, F Menegaux, M Sanchez, B Burwinkel, F Marme, A Schneeweiss, C Sohn, AH Wu, CC Tseng, D van den Berg, DO Stram, J Benitez, MP Zamora, JIA Perez, P Menendez, XO Shu, W Lu, YT Gao, QY Cai, A Cox, SS Cross, MWR Reed, IL Andrulis, JA Knight, G Glendon, S Tchatchou, EJ Sawyer, I Tomlinson, MJ Kerin, N Miller, CA Haiman, BE Henderson, F Schumacher, L Le Marchand, A Lindblom, S Margolin, SH Teo, CH Yip, DSC Lee, TY (Tien Yin) Wong, Maartje Hooning, John Martens, Margriet Collee, Carolien van Deurzen, JL Hopper, MC Southey, H Tsimiklis, MK Kapuscinski, CY Shen, PE Wu, JC Yu, ST Chen, GG Alnaes, AL Borresen-Dale, GG Giles, RL Milne, C McLean, K Muir, A Lophatananon, S Stewart-Brown, P Siriwanarangsan, M Hartman, H Miao, SAB Buhari, YY Teo, PA Fasching, L Haeberle, AB Ekici, MW Beckmann, H Brenner, AK Dieffenbach, V Arndt, C Stegmaier, A Swerdlow, A Ashworth, N Orr, MJ Schoemaker, M Garcia-Closas, J Figueroa, SJ Chanock, J Lissowska, J Simard, MS Goldberg, F Labreche, M Dumont, R Winqvist, K Pylkas, A Jukkola-Vuorinen, H Brauch, T Bruning, YD Koto, P Radice, P Peterlongo, B Bonanni, S Volorio, T Dork, NV Bogdanova, S Helbig, A Mannermaa, V Kataja, VM Kosma, JM Hartikainen, P Devilee, RAEM Tollenaar, Caroline Seynaeve, CJ van Asperen, A Jakubowska, J Lubinski, K Jaworska-Bieniek, K Durda, S Slager, AE Toland, CB Ambrosone, D Yannoukakos, S Sangrajrang, V Gaborieau, P Brennan, J Mckay, U Hamann, D Torres, W Zheng, JR Long, H Anton-Culver, SL Neuhausen, C Luccarini, C Baynes, S (Shahana) Ahmed, M Maranian, CS Healey, A Gonzalez-Neira, G Pita, MR Alonso, N Alvarez, D Herrero, DC Tessier, D Vincent, F Bacot, I de Santiago, J Carroll, C Caldas, MA Brown, M Lupien, VN Kristensen, PDP Pharoah, G Chenevix-Trench, JD French, DF Easton, AM Dunning, Thanh Dam Truong

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Abstract

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 x 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 languageUndefined/Unknown
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 2014

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