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

Z Su; LJ Gay; A Strange; C Palles; G Band; DC Whiteman; F Lescai; C Langford; M Nanji; S Edkins; Anouk Winkel; D Levine; P Sasieni; C Bellenguez; K Howarth; C Freeman; N Trudgill; AT Tucker; M Pirinen; Maikel Peppelenbosch; Luc van der Laan; Ernst Kuipers; JPH Drenth; WH Peters; JV Reynolds; DP Kelleher; R McManus; H Grabsch; H Prenen; R Bisschops; K Krishnadath; PD (Peter) Siersema; JWPM van Baal; M Middleton; R Petty; R Gillies; N Burch; P Bhandari; S Paterson; C Edwards; I Penman; K Vaidya; Y Ang; I Murray; P Patel; WM Ye; P Mullins; AH Wu; NC Bird; H Dallal; NJ Shaheen; LJ Murray; K Koss; L Bernstein; Y Romero; LJ Hardie; R Zhang; H Winter; DA Corley; S Panter; HA Risch; BJ Reid; I Sargeant; MD Gammon; H Smart; A Dhar; H McMurtry; H Ali; G Liu; AG Casson; WH Chow; M Rutter; A Tawil; D Morris; C Nwokolo; P Isaacs; C Rodgers; K Ragunath; C MacDonald; C Haigh; D Monk; G Davies; S Wajed; D Johnston; M Gibbons; S Cullen; N Church; R Langley; M Griffin; D Alderson; P Deloukas; SE Hunt; E Gray; S Dronov; SC Potter; A Tashakkori-Ghanbaria; M Anderson; C Brooks; JM Blackwell; E Bramon; MA Brown; JP Casas; A Corvin; A Duncanson; HS Markus; CG Mathew; CNA Palmer; R Plomin; A Rautanen; SJ Sawcer; RC Trembath; AC Viswanathan; N Wood; G Trynka; C Wijmenga; JB Cazier; P Atherfold; AM Nicholson; NL Gellatly; D Glancy; SC Cooper; D Cunningham; T Lind; J Hapeshi; D Ferry; B Rathbone; J Brown; S Love; S Attwood; S Macgregor; P Watson; S Sanders; W Ek; RF Harrison; P Moayyedi; J de Caestecker; H Barr; E Stupka; TL Vaughan; L Peltonen; CCA Spencer; I Tomlinson; P Donnelly; JAZ Jankowski

doi:10.1038/ng.2408

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

Z Su, LJ Gay, A Strange, C Palles, G Band, DC Whiteman, F Lescai, C Langford, M Nanji, S Edkins, Anouk Winkel, D Levine, P Sasieni, C Bellenguez, K Howarth, C Freeman, N Trudgill, AT Tucker, M Pirinen, Maikel PeppelenboschLuc van der Laan, Ernst Kuipers, JPH Drenth, WH Peters, JV Reynolds, DP Kelleher, R McManus, H Grabsch, H Prenen, R Bisschops, K Krishnadath, PD (Peter) Siersema, JWPM van Baal, M Middleton, R Petty, R Gillies, N Burch, P Bhandari, S Paterson, C Edwards, I Penman, K Vaidya, Y Ang, I Murray, P Patel, WM Ye, P Mullins, AH Wu, NC Bird, H Dallal, NJ Shaheen, LJ Murray, K Koss, L Bernstein, Y Romero, LJ Hardie, R Zhang, H Winter, DA Corley, S Panter, HA Risch, BJ Reid, I Sargeant, MD Gammon, H Smart, A Dhar, H McMurtry, H Ali, G Liu, AG Casson, WH Chow, M Rutter, A Tawil, D Morris, C Nwokolo, P Isaacs, C Rodgers, K Ragunath, C MacDonald, C Haigh, D Monk, G Davies, S Wajed, D Johnston, M Gibbons, S Cullen, N Church, R Langley, M Griffin, D Alderson, P Deloukas, SE Hunt, E Gray, S Dronov, SC Potter, A Tashakkori-Ghanbaria, M Anderson, C Brooks, JM Blackwell, E Bramon, MA Brown, JP Casas, A Corvin, A Duncanson, HS Markus, CG Mathew, CNA Palmer, R Plomin, A Rautanen, SJ Sawcer, RC Trembath, AC Viswanathan, N Wood, G Trynka, C Wijmenga, JB Cazier, P Atherfold, AM Nicholson, NL Gellatly, D Glancy, SC Cooper, D Cunningham, T Lind, J Hapeshi, D Ferry, B Rathbone, J Brown, S Love, S Attwood, S Macgregor, P Watson, S Sanders, W Ek, RF Harrison, P Moayyedi, J de Caestecker, H Barr, E Stupka, TL Vaughan, L Peltonen, CCA Spencer, I Tomlinson, P Donnelly, JAZ Jankowski

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

155 Citations (Scopus)

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 x 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 x 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	Undefined/Unknown
Pages (from-to)	1131-+
Journal	Nature Genetics
Volume	44
Issue number	10
DOIs	https://doi.org/10.1038/ng.2408
Publication status	Published - 2012

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Access to Document

10.1038/ng.2408

http://hdl.handle.net/1765/55187

Cite this

Su, Z., Gay, LJ., Strange, A., Palles, C., Band, G., Whiteman, DC., Lescai, F., Langford, C., Nanji, M., Edkins, S., Winkel, A., Levine, D., Sasieni, P., Bellenguez, C., Howarth, K., Freeman, C., Trudgill, N., Tucker, AT., Pirinen, M., ... Jankowski, JAZ. (2012). Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus. Nature Genetics, 44(10), 1131-+. https://doi.org/10.1038/ng.2408

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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 x 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 x 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 = "Z Su and LJ Gay and A Strange and C Palles and G Band and DC Whiteman and F Lescai and C Langford and M Nanji and S Edkins and Anouk Winkel and D Levine and P Sasieni and C Bellenguez and K Howarth and C Freeman and N Trudgill and AT Tucker and M Pirinen and Maikel Peppelenbosch and {van der Laan}, Luc and Ernst Kuipers and JPH Drenth and WH Peters and JV Reynolds and DP Kelleher and R McManus and H Grabsch and H Prenen and R Bisschops and K Krishnadath and Siersema, {PD (Peter)} and {van Baal}, JWPM and M Middleton and R Petty and R Gillies and N Burch and P Bhandari and S Paterson and C Edwards and I Penman and K Vaidya and Y Ang and I Murray and P Patel and WM Ye and P Mullins and AH Wu and NC Bird and H Dallal and NJ Shaheen and LJ Murray and K Koss and L Bernstein and Y Romero and LJ Hardie and R Zhang and H Winter and DA Corley and S Panter and HA Risch and BJ Reid and I Sargeant and MD Gammon and H Smart and A Dhar and H McMurtry and H Ali and G Liu and AG Casson and WH Chow and M Rutter and A Tawil and D Morris and C Nwokolo and P Isaacs and C Rodgers and K Ragunath and C MacDonald and C Haigh and D Monk and G Davies and S Wajed and D Johnston and M Gibbons and S Cullen and N Church and R Langley and M Griffin and D Alderson and P Deloukas and SE Hunt and E Gray and S Dronov and SC Potter and A Tashakkori-Ghanbaria and M Anderson and C Brooks and JM Blackwell and E Bramon and MA Brown and JP Casas and A Corvin and A Duncanson and HS Markus and CG Mathew and CNA Palmer and R Plomin and A Rautanen and SJ Sawcer and RC Trembath and AC Viswanathan and N Wood and G Trynka and C Wijmenga and JB Cazier and P Atherfold and AM Nicholson and NL Gellatly and D Glancy and SC Cooper and D Cunningham and T Lind and J Hapeshi and D Ferry and B Rathbone and J Brown and S Love and S Attwood and S Macgregor and P Watson and S Sanders and W Ek and RF Harrison and P Moayyedi and {de Caestecker}, J and H Barr and E Stupka and TL Vaughan and L Peltonen and CCA Spencer and I Tomlinson and P Donnelly and JAZ Jankowski",

year = "2012",

doi = "10.1038/ng.2408",

language = "Undefined/Unknown",

volume = "44",

pages = "1131--+",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "10",

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Su, Z, Gay, LJ, Strange, A, Palles, C, Band, G, Whiteman, DC, Lescai, F, Langford, C, Nanji, M, Edkins, S, Winkel, A, Levine, D, Sasieni, P, Bellenguez, C, Howarth, K, Freeman, C, Trudgill, N, Tucker, AT, Pirinen, M, Peppelenbosch, M , van der Laan, L , Kuipers, E, 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, WM, 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-+. https://doi.org/10.1038/ng.2408

TY - JOUR

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

AU - Su, Z

AU - Gay, LJ

AU - Strange, A

AU - Palles, C

AU - Band, G

AU - Whiteman, DC

AU - Lescai, F

AU - Langford, C

AU - Nanji, M

AU - Edkins, S

AU - Winkel, Anouk

AU - Levine, D

AU - Sasieni, P

AU - Bellenguez, C

AU - Howarth, K

AU - Freeman, C

AU - Trudgill, N

AU - Tucker, AT

AU - Pirinen, M

AU - Peppelenbosch, Maikel

AU - van der Laan, Luc

AU - Kuipers, Ernst

AU - Drenth, JPH

AU - Peters, WH

AU - Reynolds, JV

AU - Kelleher, DP

AU - McManus, R

AU - Grabsch, H

AU - Prenen, H

AU - Bisschops, R

AU - Krishnadath, K

AU - Siersema, PD (Peter)

AU - van Baal, JWPM

AU - Middleton, M

AU - Petty, R

AU - Gillies, R

AU - Burch, N

AU - Bhandari, P

AU - Paterson, S

AU - Edwards, C

AU - Penman, I

AU - Vaidya, K

AU - Ang, Y

AU - Murray, I

AU - Patel, P

AU - Ye, WM

AU - Mullins, P

AU - Wu, AH

AU - Bird, NC

AU - Dallal, H

AU - Shaheen, NJ

AU - Murray, LJ

AU - Koss, K

AU - Bernstein, L

AU - Romero, Y

AU - Hardie, LJ

AU - Zhang, R

AU - Winter, H

AU - Corley, DA

AU - Panter, S

AU - Risch, HA

AU - Reid, BJ

AU - Sargeant, I

AU - Gammon, MD

AU - Smart, H

AU - Dhar, A

AU - McMurtry, H

AU - Ali, H

AU - Liu, G

AU - Casson, AG

AU - Chow, WH

AU - Rutter, M

AU - Tawil, A

AU - Morris, D

AU - Nwokolo, C

AU - Isaacs, P

AU - Rodgers, C

AU - Ragunath, K

AU - MacDonald, C

AU - Haigh, C

AU - Monk, D

AU - Davies, G

AU - Wajed, S

AU - Johnston, D

AU - Gibbons, M

AU - Cullen, S

AU - Church, N

AU - Langley, R

AU - Griffin, M

AU - Alderson, D

AU - Deloukas, P

AU - Hunt, SE

AU - Gray, E

AU - Dronov, S

AU - Potter, SC

AU - Tashakkori-Ghanbaria, A

AU - Anderson, M

AU - Brooks, C

AU - Blackwell, JM

AU - Bramon, E

AU - Brown, MA

AU - Casas, JP

AU - Corvin, A

AU - Duncanson, A

AU - Markus, HS

AU - Mathew, CG

AU - Palmer, CNA

AU - Plomin, R

AU - Rautanen, A

AU - Sawcer, SJ

AU - Trembath, RC

AU - Viswanathan, AC

AU - Wood, N

AU - Trynka, G

AU - Wijmenga, C

AU - Cazier, JB

AU - Atherfold, P

AU - Nicholson, AM

AU - Gellatly, NL

AU - Glancy, D

AU - Cooper, SC

AU - Cunningham, D

AU - Lind, T

AU - Hapeshi, J

AU - Ferry, D

AU - Rathbone, B

AU - Brown, J

AU - Love, S

AU - Attwood, S

AU - Macgregor, S

AU - Watson, P

AU - Sanders, S

AU - Ek, W

AU - Harrison, RF

AU - Moayyedi, P

AU - de Caestecker, J

AU - Barr, H

AU - Stupka, E

AU - Vaughan, TL

AU - Peltonen, L

AU - Spencer, CCA

AU - Tomlinson, I

AU - Donnelly, P

AU - Jankowski, JAZ

PY - 2012

Y1 - 2012

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 x 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 x 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 x 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 x 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.

U2 - 10.1038/ng.2408

DO - 10.1038/ng.2408

M3 - Article

C2 - 22961001

SN - 1061-4036

VL - 44

SP - 1131-+

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -