Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Claire Palles, Laura Chegwidden, Xinzhong Li, John M. Findlay, Gary Farnham, Francesc Castro Giner, Maikel P. Peppelenbosch, Michal Kovac, Claire L. Adams, Hans Prenen, Sarah Briggs, Rebecca Harrison, Scott Sanders, David MacDonald, Chris Haigh, Art Tucker, Sharon Love, Manoj Nanji, John deCaestecker, David FerryBarrie Rathbone, Julie Hapeshi, Hugh Barr, Paul Moayyedi, Peter Watson, Barbara Zietek, Neera Maroo, Laura Gay, Tim Underwood, Lisa Boulter, Hugh McMurtry, David Monk, Praful Patel, Krish Ragunath, David Al Dulaimi, Iain Murray, Konrad Koss, Andrew Veitch, Nigel Trudgill, Chuka Nwokolo, Bjorn Rembacken, Paul Atherfold, Elaine Green, Yeng Ang, Ernst J. Kuipers, Wu Chow, Stuart Paterson, Sudarshan Kadri, Ian Beales, Charles Grimley, Paul Mullins, Conrad Beckett, Mark Farrant, Andrew Dixon, Sean Kelly, Matthew Johnson, Shahjehan Wajed, Anjan Dhar, Elinor Sawyer, Rebecca Roylance, Lynn Onstad, Marilie D. Gammon, Douglas A. Corley, Nicholas J. Shaheen, Nigel C. Bird, Laura J. Hardie, Brian J. Reid, Weimin Ye, Geoffrey Liu, Yvonne Romero, Leslie Bernstein, Anna H. Wu, Alan G. Casson, Rebecca Fitzgerald, David C. Whiteman, Harvey A. Risch, David M. Levine, Tom L. Vaughan, Auke P. Verhaar, Jan van den Brande, Eelke L. Toxopeus, Manon C. Spaander, Bas P.L. Wijnhoven, Luc J.W. van der Laan, Kausilia Krishnadath, Cisca Wijmenga, Gosia Trynka, Ross McManus, John V. Reynolds, Jacintha O'Sullivan, Padraic MacMathuna, Sarah A. McGarrigle, Dermot Kelleher, Severine Vermeire, Isabelle Cleynen, Raf Bisschops, Ian Tomlinson, Januscz Janokowski

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Abstract

Background & Aims Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. Methods We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. Results We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09–1.18; P = 1.8 × 10−11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86–0.93; P = 7.5 × 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9). Conclusions We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.
Original languageEnglish
Pages (from-to)367-378
JournalGastroenterology
Volume148
Issue number2
DOIs
Publication statusPublished - Feb 2015
Externally publishedYes

Bibliographical note

Open access funded by Wellcome Trust.
Cancer Research UK Peninsula Schools of Medicine and Dentistry School Wellcome Trust AstraZeneca UK educational grant

Funder

Discovery Phase and Immunochip replication were funded by the Wellcome Trust IPOD grant (084722/Z/08/Z). In addition, sample collection for all phases was core supported by the Cancer Research UK funded AspECT, ChOPIN and Handel trials. CoRGI and GLACIER were also funded by Cancer Research UK.

Keywords

  • EAC
  • Intestinal Metaplasia
  • Susceptibility
  • Cancer

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    Palles, C., Chegwidden, L., Li, X., Findlay, J. M., Farnham, G., Giner, F. C., ... Janokowski, J. (2015). Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus. Gastroenterology, 148(2), 367-378. https://doi.org/10.1053/j.gastro.2014.10.041