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 Ferry; Barrie 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

doi:10.1053/j.gastro.2014.10.041

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 Ferry

Barrie 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 language	English
Pages (from-to)	367-378
Journal	Gastroenterology
Volume	148
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2014.10.041
Publication status	Published - Feb 2015
Externally published	Yes

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.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

EAC
Intestinal Metaplasia
Susceptibility
Cancer

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Palles, C., Chegwidden, L., Li, X., Findlay, J. M., Farnham, G., Giner, F. C., Peppelenbosch, M. P., Kovac, M., Adams, C. L., Prenen, H., Briggs, S., Harrison, R., Sanders, S., MacDonald, D., Haigh, C., Tucker, A., Love, S., Nanji, M., deCaestecker, J., ... 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

Palles, C, Chegwidden, L, Li, X, Findlay, JM, Farnham, G, Giner, FC, Peppelenbosch, MP, Kovac, M, Adams, CL, Prenen, H, Briggs, S, Harrison, R, Sanders, S, MacDonald, D, Haigh, C, Tucker, A, Love, S, Nanji, M, deCaestecker, J, Ferry, D, Rathbone, B, Hapeshi, J, Barr, H, Moayyedi, P, Watson, P, Zietek, B, Maroo, N, Gay, L, Underwood, T, Boulter, L, McMurtry, H, Monk, D, Patel, P, Ragunath, K, Al Dulaimi, D, Murray, I, Koss, K, Veitch, A, Trudgill, N, Nwokolo, C, Rembacken, B, Atherfold, P, Green, E, Ang, Y, Kuipers, EJ, Chow, W, Paterson, S, Kadri, S, Beales, I, Grimley, C, Mullins, P, Beckett, C, Farrant, M, Dixon, A, Kelly, S, Johnson, M, Wajed, S, Dhar, A, Sawyer, E, Roylance, R, Onstad, L, Gammon, MD, Corley, DA, Shaheen, NJ, Bird, NC, Hardie, LJ, Reid, BJ, Ye, W, Liu, G, Romero, Y, Bernstein, L, Wu, AH, Casson, AG, Fitzgerald, R, Whiteman, DC, Risch, HA, Levine, DM, Vaughan, TL, Verhaar, AP, van den Brande, J, Toxopeus, EL, Spaander, MC, Wijnhoven, BPL, van der Laan, LJW, Krishnadath, K, Wijmenga, C, Trynka, G, McManus, R, Reynolds, JV, O'Sullivan, J, MacMathuna, P, McGarrigle, SA, Kelleher, D, Vermeire, S, Cleynen, I, Bisschops, R, Tomlinson, I & Janokowski, J 2015, 'Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus', Gastroenterology, vol. 148, no. 2, pp. 367-378. https://doi.org/10.1053/j.gastro.2014.10.041

@article{3d796810975a4bc6948b51c6a1fdca94,

title = "Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett{\textquoteright}s Esophagus",

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.",

keywords = "EAC, Intestinal Metaplasia, Susceptibility, Cancer",

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

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

year = "2015",

month = feb,

doi = "10.1053/j.gastro.2014.10.041",

language = "English",

volume = "148",

pages = "367--378",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "2",

}

TY - JOUR

T1 - Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

AU - Palles, Claire

AU - Chegwidden, Laura

AU - Li, Xinzhong

AU - Findlay, John M.

AU - Farnham, Gary

AU - Giner, Francesc Castro

AU - Peppelenbosch, Maikel P.

AU - Kovac, Michal

AU - Adams, Claire L.

AU - Prenen, Hans

AU - Briggs, Sarah

AU - Harrison, Rebecca

AU - Sanders, Scott

AU - MacDonald, David

AU - Haigh, Chris

AU - Tucker, Art

AU - Love, Sharon

AU - Nanji, Manoj

AU - deCaestecker, John

AU - Ferry, David

AU - Rathbone, Barrie

AU - Hapeshi, Julie

AU - Barr, Hugh

AU - Moayyedi, Paul

AU - Watson, Peter

AU - Zietek, Barbara

AU - Maroo, Neera

AU - Gay, Laura

AU - Underwood, Tim

AU - Boulter, Lisa

AU - McMurtry, Hugh

AU - Monk, David

AU - Patel, Praful

AU - Ragunath, Krish

AU - Al Dulaimi, David

AU - Murray, Iain

AU - Koss, Konrad

AU - Veitch, Andrew

AU - Trudgill, Nigel

AU - Nwokolo, Chuka

AU - Rembacken, Bjorn

AU - Atherfold, Paul

AU - Green, Elaine

AU - Ang, Yeng

AU - Kuipers, Ernst J.

AU - Chow, Wu

AU - Paterson, Stuart

AU - Kadri, Sudarshan

AU - Beales, Ian

AU - Grimley, Charles

AU - Mullins, Paul

AU - Beckett, Conrad

AU - Farrant, Mark

AU - Dixon, Andrew

AU - Kelly, Sean

AU - Johnson, Matthew

AU - Wajed, Shahjehan

AU - Dhar, Anjan

AU - Sawyer, Elinor

AU - Roylance, Rebecca

AU - Onstad, Lynn

AU - Gammon, Marilie D.

AU - Corley, Douglas A.

AU - Shaheen, Nicholas J.

AU - Bird, Nigel C.

AU - Hardie, Laura J.

AU - Reid, Brian J.

AU - Ye, Weimin

AU - Liu, Geoffrey

AU - Romero, Yvonne

AU - Bernstein, Leslie

AU - Wu, Anna H.

AU - Casson, Alan G.

AU - Fitzgerald, Rebecca

AU - Whiteman, David C.

AU - Risch, Harvey A.

AU - Levine, David M.

AU - Vaughan, Tom L.

AU - Verhaar, Auke P.

AU - van den Brande, Jan

AU - Toxopeus, Eelke L.

AU - Spaander, Manon C.

AU - Wijnhoven, Bas P.L.

AU - van der Laan, Luc J.W.

AU - Krishnadath, Kausilia

AU - Wijmenga, Cisca

AU - Trynka, Gosia

AU - McManus, Ross

AU - Reynolds, John V.

AU - O'Sullivan, Jacintha

AU - MacMathuna, Padraic

AU - McGarrigle, Sarah A.

AU - Kelleher, Dermot

AU - Vermeire, Severine

AU - Cleynen, Isabelle

AU - Bisschops, Raf

AU - Tomlinson, Ian

AU - Janokowski, Januscz

N1 - Open access funded by Wellcome Trust. Cancer Research UK Peninsula Schools of Medicine and Dentistry School Wellcome Trust AstraZeneca UK educational grant

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

KW - EAC

KW - Intestinal Metaplasia

KW - Susceptibility

KW - Cancer

U2 - 10.1053/j.gastro.2014.10.041

DO - 10.1053/j.gastro.2014.10.041

M3 - Article

SN - 0016-5085

SN - 1528-0012

VL - 148

SP - 367

EP - 378

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -

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

Abstract

Bibliographical note

Funder

UN SDGs

Keywords

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