Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Zhan Su; Laura J. Gay; Amy Strange; Claire Palles; Gavin Band; David C. Whiteman; Francesco Lescai; Cordelia Langford; Manoj Nanji; Sarah Edkins; Anouk Van Der Winkel; David Levine; Peter Sasieni; Céline Bellenguez; Kimberley Howarth; Colin Freeman; Nigel Trudgill; Art T. Tucker; Matti Pirinen; Maikel P. Peppelenbosch; Luc J.W. Van Der Laan; Ernst J. Kuipers; Joost P.H. Drenth; Wilbert H. Peters; John V. Reynolds; Dermot P. Kelleher; Ross McManus; Heike Grabsch; Hans Prenen; Raf Bisschops; Kausila Krishnadath; Peter D. Siersema; Jantine W.P.M. Van Baal; Mark Middleton; Russell Petty; Richard Gillies; Nicola Burch; Pradeep Bhandari; Stuart Paterson; Cathryn Edwards; Ian Penman; Kishor Vaidya; Yeng Ang; Iain Murray; Praful Patel; Weimin Ye; Paul Mullins; Anna H. Wu; Nigel C. Bird; Helen Dallal; Nicholas J. Shaheen; Liam J. Murray; Konrad Koss; Leslie Bernstein; Yvonne Romero; Laura J. Hardie; Rui Zhang; Helen Winter; Douglas A. Corley; Simon Panter; Harvey A. Risch; Brian J. Reid; Ian Sargeant; Marilie D. Gammon; Howard Smart; Anjan Dhar; Hugh McMurtry; Haythem Ali; Geoffrey Liu; Alan G. Casson; Wong Ho Chow; Matt Rutter; Ashref Tawil; Danielle Morris; Chuka Nwokolo; Peter Isaacs; Colin Rodgers; Krish Ragunath; Chris MacDonald; Chris Haigh; David Monk; Gareth Davies; Saj Wajed; David Johnston; Michael Gibbons; Sue Cullen; Nicholas Church; Ruth Langley; Michael Griffin; Derek Alderson; Panos Deloukas; Sarah E. Hunt; Emma Gray; Serge Dronov; Simon C. Potter; Avazeh Tashakkori-Ghanbaria; Mark Anderson; Claire Brooks; Jenefer M. Blackwell; Elvira Bramon; Matthew A. Brown; Juan P. Casas; Aiden Corvin; Audrey Duncanson; Hugh S. Markus; Christopher G. Mathew; Colin N.A. Palmer; Robert Plomin; Anna Rautanen; Stephen J. Sawcer; Richard C. Trembath; Ananth C. Viswanathan; Nicholas Wood; Gosia Trynka; Cisca Wijmenga; Jean Baptiste Cazier; Paul Atherfold; Anna M. Nicholson; Nichola L. Gellatly; Deborah Glancy; Sheldon C. Cooper; David Cunningham; Tore Lind; Julie Hapeshi; David Ferry; Barrie Rathbone; Julia Brown; Sharon Love; Stephen Attwood; Stuart MacGregor; Peter Watson; Scott Sanders; Weronica Ek; Rebecca F. Harrison; Paul Moayyedi; John De Caestecker; Hugh Barr; Elia Stupka; Thomas L. Vaughan; Leena Peltonen; Chris C.A. Spencer; Ian Tomlinson; Peter Donnelly; Janusz A.Z. Jankowski

doi:10.1038/ng.2408

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Zhan Su, Laura J. Gay, Amy Strange, Claire Palles, Gavin Band, David C. Whiteman, Francesco Lescai, Cordelia Langford, Manoj Nanji, Sarah Edkins, Anouk Van Der Winkel, David Levine, Peter Sasieni, Céline Bellenguez, Kimberley Howarth, Colin Freeman, Nigel Trudgill, Art T. Tucker, Matti Pirinen, Maikel P. PeppelenboschLuc J.W. Van Der Laan, Ernst J. Kuipers, Joost P.H. Drenth, Wilbert H. Peters, John V. Reynolds, Dermot P. Kelleher, Ross McManus, Heike Grabsch, Hans Prenen, Raf Bisschops, Kausila Krishnadath, Peter D. Siersema, Jantine W.P.M. Van Baal, Mark Middleton, Russell Petty, Richard Gillies, Nicola Burch, Pradeep Bhandari, Stuart Paterson, Cathryn Edwards, Ian Penman, Kishor Vaidya, Yeng Ang, Iain Murray, Praful Patel, Weimin Ye, Paul Mullins, Anna H. Wu, Nigel C. Bird, Helen Dallal, Nicholas J. Shaheen, Liam J. Murray, Konrad Koss, Leslie Bernstein, Yvonne Romero, Laura J. Hardie, Rui Zhang, Helen Winter, Douglas A. Corley, Simon Panter, Harvey A. Risch, Brian J. Reid, Ian Sargeant, Marilie D. Gammon, Howard Smart, Anjan Dhar, Hugh McMurtry, Haythem Ali, Geoffrey Liu, Alan G. Casson, Wong Ho Chow, Matt Rutter, Ashref Tawil, Danielle Morris, Chuka Nwokolo, Peter Isaacs, Colin Rodgers, Krish Ragunath, Chris MacDonald, Chris Haigh, David Monk, Gareth Davies, Saj Wajed, David Johnston, Michael Gibbons, Sue Cullen, Nicholas Church, Ruth Langley, Michael Griffin, Derek Alderson, Panos Deloukas, Sarah E. Hunt, Emma Gray, Serge Dronov, Simon C. Potter, Avazeh Tashakkori-Ghanbaria, Mark Anderson, Claire Brooks, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Audrey Duncanson, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Ananth C. Viswanathan, Nicholas Wood, Gosia Trynka, Cisca Wijmenga, Jean Baptiste Cazier, Paul Atherfold, Anna M. Nicholson, Nichola L. Gellatly, Deborah Glancy, Sheldon C. Cooper, David Cunningham, Tore Lind, Julie Hapeshi, David Ferry, Barrie Rathbone, Julia Brown, Sharon Love, Stephen Attwood, Stuart MacGregor, Peter Watson, Scott Sanders, Weronica Ek, Rebecca F. Harrison, Paul Moayyedi, John De Caestecker, Hugh Barr, Elia Stupka, Thomas L. Vaughan, Leena Peltonen, Chris C.A. Spencer, Ian Tomlinson, Peter Donnelly, Janusz A.Z. Jankowski

Epidemiology

Research output: Contribution to journal › Article › peer-review

147 Scopus citations

Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P combined = 4.09 × 10^-9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P combined = 2.74 × 10^-10; OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Original language	English (US)
Pages (from-to)	1131-1136
Number of pages	6
Journal	Nature Genetics
Volume	44
Issue number	10
DOIs	https://doi.org/10.1038/ng.2408
State	Published - Oct 2012

ASJC Scopus subject areas

Genetics

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10.1038/ng.2408

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Su, Z., Gay, L. J., Strange, A., Palles, C., Band, G., Whiteman, D. C., Lescai, F., Langford, C., Nanji, M., Edkins, S., Van Der Winkel, A., Levine, D., Sasieni, P., Bellenguez, C., Howarth, K., Freeman, C., Trudgill, N., Tucker, A. T., Pirinen, M., ... Jankowski, J. A. Z. (2012). Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus. Nature Genetics, 44(10), 1131-1136. https://doi.org/10.1038/ng.2408

Su, Z, Gay, LJ, Strange, A, Palles, C, Band, G, Whiteman, DC, Lescai, F, Langford, C, Nanji, M, Edkins, S, Van Der Winkel, A, Levine, D, Sasieni, P, Bellenguez, C, Howarth, K, Freeman, C, Trudgill, N, Tucker, AT, Pirinen, M, Peppelenbosch, MP, Van Der Laan, LJW, Kuipers, EJ, Drenth, JPH, Peters, WH, Reynolds, JV, Kelleher, DP, McManus, R, Grabsch, H, Prenen, H, Bisschops, R, Krishnadath, K, Siersema, PD, Van Baal, JWPM, Middleton, M, Petty, R, Gillies, R, Burch, N, Bhandari, P, Paterson, S, Edwards, C, Penman, I, Vaidya, K, Ang, Y, Murray, I, Patel, P, Ye, W, Mullins, P, Wu, AH, Bird, NC, Dallal, H, Shaheen, NJ, Murray, LJ, Koss, K, Bernstein, L, Romero, Y, Hardie, LJ, Zhang, R, Winter, H, Corley, DA, Panter, S, Risch, HA, Reid, BJ, Sargeant, I, Gammon, MD, Smart, H, Dhar, A, McMurtry, H, Ali, H, Liu, G, Casson, AG, Chow, WH, Rutter, M, Tawil, A, Morris, D, Nwokolo, C, Isaacs, P, Rodgers, C, Ragunath, K, MacDonald, C, Haigh, C, Monk, D, Davies, G, Wajed, S, Johnston, D, Gibbons, M, Cullen, S, Church, N, Langley, R, Griffin, M, Alderson, D, Deloukas, P, Hunt, SE, Gray, E, Dronov, S, Potter, SC, Tashakkori-Ghanbaria, A, Anderson, M, Brooks, C, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Duncanson, A, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Viswanathan, AC, Wood, N, Trynka, G, Wijmenga, C, Cazier, JB, Atherfold, P, Nicholson, AM, Gellatly, NL, Glancy, D, Cooper, SC, Cunningham, D, Lind, T, Hapeshi, J, Ferry, D, Rathbone, B, Brown, J, Love, S, Attwood, S, MacGregor, S, Watson, P, Sanders, S, Ek, W, Harrison, RF, Moayyedi, P, De Caestecker, J, Barr, H, Stupka, E, Vaughan, TL, Peltonen, L, Spencer, CCA, Tomlinson, I, Donnelly, P & Jankowski, JAZ 2012, 'Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus', Nature Genetics, vol. 44, no. 10, pp. 1131-1136. https://doi.org/10.1038/ng.2408

@article{03e665810d4842a5bced3315393f0f06,

title = "Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus",

abstract = "Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P combined = 4.09 × 10-9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P combined = 2.74 × 10-10; OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.",

author = "Zhan Su and Gay, {Laura J.} and Amy Strange and Claire Palles and Gavin Band and Whiteman, {David C.} and Francesco Lescai and Cordelia Langford and Manoj Nanji and Sarah Edkins and {Van Der Winkel}, Anouk and David Levine and Peter Sasieni and C{\'e}line Bellenguez and Kimberley Howarth and Colin Freeman and Nigel Trudgill and Tucker, {Art T.} and Matti Pirinen and Peppelenbosch, {Maikel P.} and {Van Der Laan}, {Luc J.W.} and Kuipers, {Ernst J.} and Drenth, {Joost P.H.} and Peters, {Wilbert H.} and Reynolds, {John V.} and Kelleher, {Dermot P.} and Ross McManus and Heike Grabsch and Hans Prenen and Raf Bisschops and Kausila Krishnadath and Siersema, {Peter D.} and {Van Baal}, {Jantine W.P.M.} and Mark Middleton and Russell Petty and Richard Gillies and Nicola Burch and Pradeep Bhandari and Stuart Paterson and Cathryn Edwards and Ian Penman and Kishor Vaidya and Yeng Ang and Iain Murray and Praful Patel and Weimin Ye and Paul Mullins and Wu, {Anna H.} and Bird, {Nigel C.} and Helen Dallal and Shaheen, {Nicholas J.} and Murray, {Liam J.} and Konrad Koss and Leslie Bernstein and Yvonne Romero and Hardie, {Laura J.} and Rui Zhang and Helen Winter and Corley, {Douglas A.} and Simon Panter and Risch, {Harvey A.} and Reid, {Brian J.} and Ian Sargeant and Gammon, {Marilie D.} and Howard Smart and Anjan Dhar and Hugh McMurtry and Haythem Ali and Geoffrey Liu and Casson, {Alan G.} and Chow, {Wong Ho} and Matt Rutter and Ashref Tawil and Danielle Morris and Chuka Nwokolo and Peter Isaacs and Colin Rodgers and Krish Ragunath and Chris MacDonald and Chris Haigh and David Monk and Gareth Davies and Saj Wajed and David Johnston and Michael Gibbons and Sue Cullen and Nicholas Church and Ruth Langley and Michael Griffin and Derek Alderson and Panos Deloukas and Hunt, {Sarah E.} and Emma Gray and Serge Dronov and Potter, {Simon C.} and Avazeh Tashakkori-Ghanbaria and Mark Anderson and Claire Brooks and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Audrey Duncanson and Markus, {Hugh S.} and Mathew, {Christopher G.} and Palmer, {Colin N.A.} and Robert Plomin and Anna Rautanen and Sawcer, {Stephen J.} and Trembath, {Richard C.} and Viswanathan, {Ananth C.} and Nicholas Wood and Gosia Trynka and Cisca Wijmenga and Cazier, {Jean Baptiste} and Paul Atherfold and Nicholson, {Anna M.} and Gellatly, {Nichola L.} and Deborah Glancy and Cooper, {Sheldon C.} and David Cunningham and Tore Lind and Julie Hapeshi and David Ferry and Barrie Rathbone and Julia Brown and Sharon Love and Stephen Attwood and Stuart MacGregor and Peter Watson and Scott Sanders and Weronica Ek and Harrison, {Rebecca F.} and Paul Moayyedi and {De Caestecker}, John and Hugh Barr and Elia Stupka and Vaughan, {Thomas L.} and Leena Peltonen and Spencer, {Chris C.A.} and Ian Tomlinson and Peter Donnelly and Jankowski, {Janusz A.Z.}",

note = "Funding Information: We acknowledge the individuals with Barrett{\textquoteright}s esophagus who participated in the study and the physicians who helped in recruitment. We thank the many research nurses who also helped recruit, including S. Prew. We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute{\textquoteright}s Sample and Genotyping Facilities for technical assistance. We also thank J. Barrett for design of the Immunochip array. Funding for this study was provided by the WTCCC2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/ 03/Z, 090532/Z/09/Z and 075491/Z/04/B). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. D.C.W. is supported by a Future Fellowship from the Australian Research Council. S.M. is supported by an Australian National Health & Medical Research Council (NHMRC) Career Development Award. C.C.A.S. was supported by a Wellcome Trust Fellowship (097364/Z/11/Z). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the UK Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls, funded by the Wellcome Trust, and the People of the British Isles collection, funded by the Wellcome Trust. This work was also supported by the Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project (grant C548/A5675) and Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project (grant MGAG1G7R); Cancer Research UK (AspECT, grants C548/A4584 and D9612L00090, and Histological AssessmeNt Determining EpitheliaL Response (HANDEL), grant C548/A9085); AstraZeneca UK educational grant; University Hospitals of Leicester R and D grant; and AspECT (T91 5211 University of Oxford grant HDRMJQ0). The Barrett{\textquoteright}s and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) within the BEACON Consortium was supported by US National Institutes of Health grant R01CA13672501. We acknowledge the Dublin Centre for Clinical Research (funded by the Health Research Board and the Wellcome Trust) for support in sample collection and the Irish Blood Transfusion Service and TCD DNA Biobank for provision of control samples. R.M. is supported by the Science Foundation Ireland grant 09/IN.1/B2640.",

year = "2012",

month = oct,

doi = "10.1038/ng.2408",

language = "English (US)",

volume = "44",

pages = "1131--1136",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

TY - JOUR

T1 - Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

AU - Su, Zhan

AU - Gay, Laura J.

AU - Strange, Amy

AU - Palles, Claire

AU - Band, Gavin

AU - Whiteman, David C.

AU - Lescai, Francesco

AU - Langford, Cordelia

AU - Nanji, Manoj

AU - Edkins, Sarah

AU - Van Der Winkel, Anouk

AU - Levine, David

AU - Sasieni, Peter

AU - Bellenguez, Céline

AU - Howarth, Kimberley

AU - Freeman, Colin

AU - Trudgill, Nigel

AU - Tucker, Art T.

AU - Pirinen, Matti

AU - Peppelenbosch, Maikel P.

AU - Van Der Laan, Luc J.W.

AU - Kuipers, Ernst J.

AU - Drenth, Joost P.H.

AU - Peters, Wilbert H.

AU - Reynolds, John V.

AU - Kelleher, Dermot P.

AU - McManus, Ross

AU - Grabsch, Heike

AU - Prenen, Hans

AU - Bisschops, Raf

AU - Krishnadath, Kausila

AU - Siersema, Peter D.

AU - Van Baal, Jantine W.P.M.

AU - Middleton, Mark

AU - Petty, Russell

AU - Gillies, Richard

AU - Burch, Nicola

AU - Bhandari, Pradeep

AU - Paterson, Stuart

AU - Edwards, Cathryn

AU - Penman, Ian

AU - Vaidya, Kishor

AU - Ang, Yeng

AU - Murray, Iain

AU - Patel, Praful

AU - Ye, Weimin

AU - Mullins, Paul

AU - Wu, Anna H.

AU - Bird, Nigel C.

AU - Dallal, Helen

AU - Shaheen, Nicholas J.

AU - Murray, Liam J.

AU - Koss, Konrad

AU - Bernstein, Leslie

AU - Romero, Yvonne

AU - Hardie, Laura J.

AU - Zhang, Rui

AU - Winter, Helen

AU - Corley, Douglas A.

AU - Panter, Simon

AU - Risch, Harvey A.

AU - Reid, Brian J.

AU - Sargeant, Ian

AU - Gammon, Marilie D.

AU - Smart, Howard

AU - Dhar, Anjan

AU - McMurtry, Hugh

AU - Ali, Haythem

AU - Liu, Geoffrey

AU - Casson, Alan G.

AU - Chow, Wong Ho

AU - Rutter, Matt

AU - Tawil, Ashref

AU - Morris, Danielle

AU - Nwokolo, Chuka

AU - Isaacs, Peter

AU - Rodgers, Colin

AU - Ragunath, Krish

AU - MacDonald, Chris

AU - Haigh, Chris

AU - Monk, David

AU - Davies, Gareth

AU - Wajed, Saj

AU - Johnston, David

AU - Gibbons, Michael

AU - Cullen, Sue

AU - Church, Nicholas

AU - Langley, Ruth

AU - Griffin, Michael

AU - Alderson, Derek

AU - Deloukas, Panos

AU - Hunt, Sarah E.

AU - Gray, Emma

AU - Dronov, Serge

AU - Potter, Simon C.

AU - Tashakkori-Ghanbaria, Avazeh

AU - Anderson, Mark

AU - Brooks, Claire

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Duncanson, Audrey

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas

AU - Trynka, Gosia

AU - Wijmenga, Cisca

AU - Cazier, Jean Baptiste

AU - Atherfold, Paul

AU - Nicholson, Anna M.

AU - Gellatly, Nichola L.

AU - Glancy, Deborah

AU - Cooper, Sheldon C.

AU - Cunningham, David

AU - Lind, Tore

AU - Hapeshi, Julie

AU - Ferry, David

AU - Rathbone, Barrie

AU - Brown, Julia

AU - Love, Sharon

AU - Attwood, Stephen

AU - MacGregor, Stuart

AU - Watson, Peter

AU - Sanders, Scott

AU - Ek, Weronica

AU - Harrison, Rebecca F.

AU - Moayyedi, Paul

AU - De Caestecker, John

AU - Barr, Hugh

AU - Stupka, Elia

AU - Vaughan, Thomas L.

AU - Peltonen, Leena

AU - Spencer, Chris C.A.

AU - Tomlinson, Ian

AU - Donnelly, Peter

AU - Jankowski, Janusz A.Z.

N1 - Funding Information: We acknowledge the individuals with Barrett’s esophagus who participated in the study and the physicians who helped in recruitment. We thank the many research nurses who also helped recruit, including S. Prew. We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute’s Sample and Genotyping Facilities for technical assistance. We also thank J. Barrett for design of the Immunochip array. Funding for this study was provided by the WTCCC2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/ 03/Z, 090532/Z/09/Z and 075491/Z/04/B). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. D.C.W. is supported by a Future Fellowship from the Australian Research Council. S.M. is supported by an Australian National Health & Medical Research Council (NHMRC) Career Development Award. C.C.A.S. was supported by a Wellcome Trust Fellowship (097364/Z/11/Z). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the UK Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls, funded by the Wellcome Trust, and the People of the British Isles collection, funded by the Wellcome Trust. This work was also supported by the Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project (grant C548/A5675) and Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project (grant MGAG1G7R); Cancer Research UK (AspECT, grants C548/A4584 and D9612L00090, and Histological AssessmeNt Determining EpitheliaL Response (HANDEL), grant C548/A9085); AstraZeneca UK educational grant; University Hospitals of Leicester R and D grant; and AspECT (T91 5211 University of Oxford grant HDRMJQ0). The Barrett’s and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) within the BEACON Consortium was supported by US National Institutes of Health grant R01CA13672501. We acknowledge the Dublin Centre for Clinical Research (funded by the Health Research Board and the Wellcome Trust) for support in sample collection and the Irish Blood Transfusion Service and TCD DNA Biobank for provision of control samples. R.M. is supported by the Science Foundation Ireland grant 09/IN.1/B2640.

PY - 2012/10

Y1 - 2012/10

N2 - Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P combined = 4.09 × 10-9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P combined = 2.74 × 10-10; OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

AB - Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P combined = 4.09 × 10-9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P combined = 2.74 × 10-10; OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

UR - http://www.scopus.com/inward/record.url?scp=84866937862&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866937862&partnerID=8YFLogxK

U2 - 10.1038/ng.2408

DO - 10.1038/ng.2408

M3 - Article

C2 - 22961001

AN - SCOPUS:84866937862

SN - 1061-4036

VL - 44

SP - 1131

EP - 1136

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

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