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

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 BrownKamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J. Vant 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, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji Yeob Choi, Sue K. Park, Dong Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H. Wu, Chiu Chen Tseng, David Van Den Berg, Daniel O. Stram, Javier Benitez, M. Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao Ou Shu, Wei Lu, Yu Tang Gao, Qiuyin Cai, Angela Cox, Simon S. Cross, Malcolm W.R. Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S.C. Lee, Tien Y. Wong, Maartje J. Hooning, John W.M. Martens, J. Margriet Collée, Carolien H.M. Van Deurzen, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Miroslav K. Kapuscinski, Chen Yang Shen, Pei Ei Wu, Jyh Cherng Yu, Shou Tung Chen, Grethe Grenaker Alnæs, Anne Lise Borresen-Dale, Graham G. Giles, Roger L. Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A. Fasching, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A.E.M. Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L. Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M. Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Ines De Santiago, Jason Carroll, Carlos Caldas, Melissa A. Brown, Mathieu Lupien, Vessela N. Kristensen, Paul D.P. Pharoah, Georgia Chenevix-Trench, Juliet D. French, Douglas F. Easton, Alison M. Dunning, Penny Webb, Anna De Fazio

Research output: Contribution to journalArticle

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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 × 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 (US)
Article number4999
JournalNature communications
Volume4
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Ghoussaini, M., Edwards, S. L., Michailidou, K., Nord, S., Cowper-Sal-lari, R., Desai, K., Kar, S., Hillman, K. M., Kaufmann, S., Glubb, D. M., Beesley, J., Dennis, J., Bolla, M. K., Wang, Q., Dicks, E., Guo, Q., Schmidt, M. K., Shah, M., Luben, R., ... De Fazio, A. (2014). Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation. Nature communications, 4, [4999]. https://doi.org/10.1038/ncomms5999