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

C Palles; L Chegwidden; XZ Li; JM Findlay; G Farnham; FC Giner; Maikel Peppelenbosch; M Kovac; CL Adams; H Prenen; S Briggs; R Harrison; S Sanders; D Macdonald; C Haigh; A Tucker; S Love; M Nanji; J Decaestecker; D Ferry; B Rathbone; J Hapeshi; H Barr; P Moayyedi; P Watson; B Zietek; N Maroo; L Gay; T Underwood; L Boulter; H McMurtry; D Monk; P Patel; K Ragunath; D Al Dulaimi; I Murray; K Koss; A Veitch; N Trudgill; C Nwokolo; B Rembacken; P Atherfold; E Green; Y Ang; Ernst Kuipers; W Chow; S Paterson; S Kadri; I Beales; C Grimley; P Mullins; C Beckett; M Farrant; A Dixon; S Kelly; M Johnson; S Wajed; A Dhar; E Sawyer; R Roylance; L Onstad; MD Gammon; DA Corley; NJ Shaheen; NC Bird; LJ Hardie; BJ Reid; WM Ye; G Liu; Y Romero; L Bernstein; AH Wu; AG Casson; R Fitzgerald; DC Whiteman; HA Risch; DM Levine; TL Vaughan; Auke Verhaar; J van den Brande; EL Toxopeus; MC Spaander; Bas Wijnhoven; Luc van der Laan; K Krishnadath; C Wijmenga; G Trynka; R McManus; JV Reynolds; J O'Sullivan; P MacMathuna; SA McGarrigle; D Kelleher; S Vermeire; I Cleynen; R Bisschops; I Tomlinson; J Jankowski

doi:10.1053/j.gastro.2014.10.041

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

C Palles, L Chegwidden, XZ Li, JM Findlay, G Farnham, FC Giner, Maikel Peppelenbosch, M Kovac, CL Adams, H Prenen, S Briggs, R Harrison, S Sanders, D Macdonald, C Haigh, A Tucker, S Love, M Nanji, J Decaestecker, D FerryB Rathbone, J Hapeshi, H Barr, P Moayyedi, P Watson, B Zietek, N Maroo, L Gay, T Underwood, L Boulter, H McMurtry, D Monk, P Patel, K Ragunath, D Al Dulaimi, I Murray, K Koss, A Veitch, N Trudgill, C Nwokolo, B Rembacken, P Atherfold, E Green, Y Ang, Ernst Kuipers, W Chow, S Paterson, S Kadri, I Beales, C Grimley, P Mullins, C Beckett, M Farrant, A Dixon, S Kelly, M Johnson, S Wajed, A Dhar, E Sawyer, R Roylance, L Onstad, MD Gammon, DA Corley, NJ Shaheen, NC Bird, LJ Hardie, BJ Reid, WM Ye, G Liu, Y Romero, L Bernstein, AH Wu, AG Casson, R Fitzgerald, DC Whiteman, HA Risch, DM Levine, TL Vaughan, Auke Verhaar, J van den Brande, EL Toxopeus, MC Spaander, Bas Wijnhoven, Luc van der Laan, K Krishnadath, C Wijmenga, G Trynka, R McManus, JV Reynolds, J O'Sullivan, P MacMathuna, SA McGarrigle, D Kelleher, S Vermeire, I Cleynen, R Bisschops, I Tomlinson, J Jankowski

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

84 Citations (Scopus)

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 x 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 x 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 x 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	Undefined/Unknown
Pages (from-to)	367-378
Number of pages	12
Journal	Gastroenterology
Volume	148
Issue number	2
DOIs	https://doi.org/10.1053/j.gastro.2014.10.041
Publication status	Published - 2015

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10.1053/j.gastro.2014.10.041

Cite this

Palles, C., Chegwidden, L., Li, XZ., Findlay, JM., Farnham, G., Giner, FC., Peppelenbosch, M., Kovac, M., Adams, CL., Prenen, H., Briggs, S., Harrison, R., Sanders, S., Macdonald, D., Haigh, C., Tucker, A., Love, S., Nanji, M., Decaestecker, J., ... Jankowski, 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

@article{2726e6879c364a31b33450ee7af8539b,

title = "Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett'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 x 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 x 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 x 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.",

author = "C Palles and L Chegwidden and XZ Li and JM Findlay and G Farnham and FC Giner and Maikel Peppelenbosch and M Kovac and CL Adams and H Prenen and S Briggs and R Harrison and S Sanders and D Macdonald and C Haigh and A Tucker and S Love and M Nanji and J Decaestecker and D Ferry and B Rathbone and J Hapeshi and H Barr and P Moayyedi and P Watson and B Zietek and N Maroo and L Gay and T Underwood and L Boulter and H McMurtry and D Monk and P Patel and K Ragunath and {Al Dulaimi}, D and I Murray and K Koss and A Veitch and N Trudgill and C Nwokolo and B Rembacken and P Atherfold and E Green and Y Ang and Ernst Kuipers and W Chow and S Paterson and S Kadri and I Beales and C Grimley and P Mullins and C Beckett and M Farrant and A Dixon and S Kelly and M Johnson and S Wajed and A Dhar and E Sawyer and R Roylance and L Onstad and MD Gammon and DA Corley and NJ Shaheen and NC Bird and LJ Hardie and BJ Reid and WM Ye and G Liu and Y Romero and L Bernstein and AH Wu and AG Casson and R Fitzgerald and DC Whiteman and HA Risch and DM Levine and TL Vaughan and Auke Verhaar and {van den Brande}, J and EL Toxopeus and MC Spaander and Bas Wijnhoven and {van der Laan}, Luc and K Krishnadath and C Wijmenga and G Trynka and R McManus and JV Reynolds and J O'Sullivan and P MacMathuna and SA McGarrigle and D Kelleher and S Vermeire and I Cleynen and R Bisschops and I Tomlinson and J Jankowski",

year = "2015",

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

language = "Undefined/Unknown",

volume = "148",

pages = "367--378",

journal = "Gastroenterology",

issn = "0016-5085",

number = "2",

}

Palles, C, Chegwidden, L, Li, XZ, Findlay, JM, Farnham, G, Giner, FC, Peppelenbosch, M, 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, E, 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, WM, Liu, G, Romero, Y, Bernstein, L, Wu, AH, Casson, AG, Fitzgerald, R, Whiteman, DC, Risch, HA, Levine, DM, Vaughan, TL, Verhaar, A, van den Brande, J, Toxopeus, EL, Spaander, MC, Wijnhoven, B , van der Laan, L, 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 & Jankowski, 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

TY - JOUR

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

AU - Palles, C

AU - Chegwidden, L

AU - Li, XZ

AU - Findlay, JM

AU - Farnham, G

AU - Giner, FC

AU - Peppelenbosch, Maikel

AU - Kovac, M

AU - Adams, CL

AU - Prenen, H

AU - Briggs, S

AU - Harrison, R

AU - Sanders, S

AU - Macdonald, D

AU - Haigh, C

AU - Tucker, A

AU - Love, S

AU - Nanji, M

AU - Decaestecker, J

AU - Ferry, D

AU - Rathbone, B

AU - Hapeshi, J

AU - Barr, H

AU - Moayyedi, P

AU - Watson, P

AU - Zietek, B

AU - Maroo, N

AU - Gay, L

AU - Underwood, T

AU - Boulter, L

AU - McMurtry, H

AU - Monk, D

AU - Patel, P

AU - Ragunath, K

AU - Al Dulaimi, D

AU - Murray, I

AU - Koss, K

AU - Veitch, A

AU - Trudgill, N

AU - Nwokolo, C

AU - Rembacken, B

AU - Atherfold, P

AU - Green, E

AU - Ang, Y

AU - Kuipers, Ernst

AU - Chow, W

AU - Paterson, S

AU - Kadri, S

AU - Beales, I

AU - Grimley, C

AU - Mullins, P

AU - Beckett, C

AU - Farrant, M

AU - Dixon, A

AU - Kelly, S

AU - Johnson, M

AU - Wajed, S

AU - Dhar, A

AU - Sawyer, E

AU - Roylance, R

AU - Onstad, L

AU - Gammon, MD

AU - Corley, DA

AU - Shaheen, NJ

AU - Bird, NC

AU - Hardie, LJ

AU - Reid, BJ

AU - Ye, WM

AU - Liu, G

AU - Romero, Y

AU - Bernstein, L

AU - Wu, AH

AU - Casson, AG

AU - Fitzgerald, R

AU - Whiteman, DC

AU - Risch, HA

AU - Levine, DM

AU - Vaughan, TL

AU - Verhaar, Auke

AU - van den Brande, J

AU - Toxopeus, EL

AU - Spaander, MC

AU - Wijnhoven, Bas

AU - van der Laan, Luc

AU - Krishnadath, K

AU - Wijmenga, C

AU - Trynka, G

AU - McManus, R

AU - Reynolds, JV

AU - O'Sullivan, J

AU - MacMathuna, P

AU - McGarrigle, SA

AU - Kelleher, D

AU - Vermeire, S

AU - Cleynen, I

AU - Bisschops, R

AU - Tomlinson, I

AU - Jankowski, J

PY - 2015

Y1 - 2015

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 x 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 x 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 x 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 x 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 x 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 x 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.

U2 - 10.1053/j.gastro.2014.10.041

DO - 10.1053/j.gastro.2014.10.041

M3 - Article

SN - 0016-5085

VL - 148

SP - 367

EP - 378

JO - Gastroenterology

JF - Gastroenterology

IS - 2

ER -