The University of Southampton
University of Southampton Institutional Repository

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus
Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus
Background & aims: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma (EAC). Increased risk for 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. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma in CRTC1 and BARX1, and within 100 kb FOXP1. We aimed to identify SNPs that increased risk for BE in a genome-wide association study (GWAS) and to validate previously reported associations.

Methods: we performed a GWAS to identify variants associated with BE and further analyzed promising variants identified by the BEACON. We performed genotype analysis of 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 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. We also identified 3 SNPS already identified by the BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, near ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10?9).

Conclusions: we identified 2 loci associated with risk for BE and provide data to support a locus previously associated with risk in the BEACON. 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
eac, intestinal metaplasia, susceptibility, cancer
0016-5085
367-378
Palles, Claire
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Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M, Farnham, Garry, Giner, Francesc Castro, Peppelenbosch, Maikel P, Kovac, Michal, Adams, Claire L, Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, deCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J, Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Reid, Brian J, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Fitzgerald, Rebecca, Whiteman, David C, Risch, Harvey A, Levine, David M, Vaughan, Tom L, Verhaar, Auke P, van den Brande, Jan, Toxopeus, Eelke L, Spaander, Manon C, Wijnhoven, Bas P L, van der Laan, Luc J W, Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V, O'Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A, Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian and Jankowski, Janusz (2015) Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus. Gastroenterology, 148 (2), 367-378. (doi:10.1053/j.gastro.2014.10.041). (PMID:25447851)

Record type: Article

Abstract

Background & aims: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma (EAC). Increased risk for 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. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma in CRTC1 and BARX1, and within 100 kb FOXP1. We aimed to identify SNPs that increased risk for BE in a genome-wide association study (GWAS) and to validate previously reported associations.

Methods: we performed a GWAS to identify variants associated with BE and further analyzed promising variants identified by the BEACON. We performed genotype analysis of 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 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. We also identified 3 SNPS already identified by the BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, near ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10?9).

Conclusions: we identified 2 loci associated with risk for BE and provide data to support a locus previously associated with risk in the BEACON. 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

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e-pub ahead of print date: 5 November 2014
Published date: February 2015
Keywords: eac, intestinal metaplasia, susceptibility, cancer
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 373407
URI: http://eprints.soton.ac.uk/id/eprint/373407
ISSN: 0016-5085
PURE UUID: 9d735613-1bb5-4c98-89e8-3386cbd842bd
ORCID for Tim Underwood: ORCID iD orcid.org/0000-0001-9455-2188

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Date deposited: 16 Jan 2015 13:25
Last modified: 15 Mar 2024 03:17

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Contributors

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

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