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

  • Author(s): Ghoussaini, Maya
  • Edwards, Stacey L
  • Michailidou, Kyriaki
  • Nord, Silje
  • Cowper-Sal Lari, Richard
  • Desai, Kinjal
  • Kar, Siddhartha
  • Hillman, Kristine M
  • Kaufmann, Susanne
  • Glubb, Dylan M
  • Beesley, Jonathan
  • Dennis, Joe
  • Bolla, Manjeet K
  • Wang, Qin
  • Dicks, Ed
  • Guo, Qi
  • Schmidt, Marjanka K
  • Shah, Mitul
  • Luben, Robert
  • Brown, Judith
  • Czene, Kamila
  • Darabi, Hatef
  • Eriksson, Mikael
  • Klevebring, Daniel
  • Bojesen, Stig E
  • Nordestgaard, Børge G
  • Nielsen, Sune F
  • Flyger, Henrik
  • Lambrechts, Diether
  • Thienpont, Bernard
  • Neven, Patrick
  • Wildiers, Hans
  • Broeks, Annegien
  • Van't Veer, Laura J
  • Th Rutgers, Emiel J
  • Couch, Fergus J
  • Olson, Janet E
  • Hallberg, Emily
  • Vachon, Celine
  • Chang-Claude, Jenny
  • Rudolph, Anja
  • Seibold, Petra
  • Flesch-Janys, Dieter
  • Peto, Julian
  • Dos-Santos-Silva, Isabel
  • Gibson, Lorna
  • Nevanlinna, Heli
  • Muranen, Taru A
  • Aittomäki, Kristiina
  • Blomqvist, Carl
  • Hall, Per
  • Li, Jingmei
  • Liu, Jianjun
  • Humphreys, Keith
  • Kang, Daehee
  • Choi, Ji-Yeob
  • Park, Sue K
  • Noh, Dong-Young
  • Matsuo, Keitaro
  • Ito, Hidemi
  • Iwata, Hiroji
  • Yatabe, Yasushi
  • Guénel, Pascal
  • Truong, Thérèse
  • Menegaux, Florence
  • Sanchez, Marie
  • Burwinkel, Barbara
  • Marme, Frederik
  • Schneeweiss, Andreas
  • Sohn, Christof
  • Wu, Anna H
  • Tseng, Chiu-Chen
  • Van Den Berg, David
  • Stram, Daniel O
  • Benitez, Javier
  • Zamora, M Pilar
  • Perez, Jose Ignacio Arias
  • Menéndez, Primitiva
  • Shu, Xiao-Ou
  • Lu, Wei
  • Gao, Yu-Tang
  • Cai, Qiuyin
  • Cox, Angela
  • Cross, Simon S
  • Reed, Malcolm WR
  • Andrulis, Irene L
  • Knight, Julia A
  • Glendon, Gord
  • Tchatchou, Sandrine
  • Sawyer, Elinor J
  • Tomlinson, Ian
  • Kerin, Michael J
  • Miller, Nicola
  • Haiman, Christopher A
  • Henderson, Brian E
  • Schumacher, Fredrick
  • Le Marchand, Loic
  • Lindblom, Annika
  • Margolin, Sara
  • Teo, Soo Hwang
  • Yip, Cheng Har
  • Lee, Daphne SC
  • Wong, Tien Y
  • Hooning, Maartje J
  • Martens, John WM
  • Collée, J Margriet
  • van Deurzen, Carolien HM
  • Hopper, John L
  • Southey, Melissa C
  • Tsimiklis, Helen
  • Kapuscinski, Miroslav K
  • Shen, Chen-Yang
  • Wu, Pei-Ei
  • Yu, Jyh-Cherng
  • Chen, Shou-Tung
  • Alnæs, Grethe Grenaker
  • Borresen-Dale, Anne-Lise
  • Giles, Graham G
  • Milne, Roger L
  • McLean, Catriona
  • Muir, Kenneth
  • Lophatananon, Artitaya
  • Stewart-Brown, Sarah
  • Siriwanarangsan, Pornthep
  • Hartman, Mikael
  • Miao, Hui
  • Buhari, Shaik Ahmad Bin Syed
  • Teo, Yik Ying
  • Fasching, Peter A
  • Haeberle, Lothar
  • Ekici, Arif B
  • Beckmann, Matthias W
  • Brenner, Hermann
  • Dieffenbach, Aida Karina
  • Arndt, Volker
  • Stegmaier, Christa
  • Swerdlow, Anthony
  • Ashworth, Alan
  • Orr, Nick
  • Schoemaker, Minouk J
  • García-Closas, Montserrat
  • Figueroa, Jonine
  • Chanock, Stephen J
  • Lissowska, Jolanta
  • Simard, Jacques
  • Goldberg, Mark S
  • Labrèche, France
  • Dumont, Martine
  • Winqvist, Robert
  • Pylkäs, Katri
  • Jukkola-Vuorinen, Arja
  • Brauch, Hiltrud
  • Brüning, Thomas
  • Koto, Yon-Dschun
  • Radice, Paolo
  • Peterlongo, Paolo
  • Bonanni, Bernardo
  • Volorio, Sara
  • Dörk, Thilo
  • Bogdanova, Natalia V
  • Helbig, Sonja
  • Mannermaa, Arto
  • Kataja, Vesa
  • Kosma, Veli-Matti
  • Hartikainen, Jaana M
  • Devilee, Peter
  • Tollenaar, Robert AEM
  • Seynaeve, Caroline
  • Van Asperen, Christi J
  • Jakubowska, Anna
  • Lubinski, Jan
  • Jaworska-Bieniek, Katarzyna
  • Durda, Katarzyna
  • Slager, Susan
  • Toland, Amanda E
  • Ambrosone, Christine B
  • Yannoukakos, Drakoulis
  • Sangrajrang, Suleeporn
  • Gaborieau, Valerie
  • Brennan, Paul
  • McKay, James
  • Hamann, Ute
  • Torres, Diana
  • Zheng, Wei
  • Long, Jirong
  • Anton-Culver, Hoda
  • Neuhausen, Susan L
  • Luccarini, Craig
  • Baynes, Caroline
  • Ahmed, Shahana
  • Maranian, Mel
  • Healey, Catherine S
  • González-Neira, Anna
  • Pita, Guillermo
  • Alonso, M Rosario
  • Alvarez, Nuria
  • Herrero, Daniel
  • Tessier, Daniel C
  • Vincent, Daniel
  • Bacot, Francois
  • de Santiago, Ines
  • Carroll, Jason
  • Caldas, Carlos
  • Brown, Melissa A
  • Lupien, Mathieu
  • Kristensen, Vessela N
  • Pharoah, Paul DP
  • Chenevix-Trench, Georgia
  • French, Juliet D
  • Easton, Douglas F
  • Dunning, Alison M
  • Australian Ovarian Cancer Management Group
  • Australian Ovarian Cancer Management Group
  • et al.
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.

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