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Gastroenterology. 2015 Feb;148(2):367-78. doi: 10.1053/j.gastro.2014.10.041. Epub 2014 Nov 5.

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

Author information

1
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: cpalles@well.ox.ac.uk.
2
Plymouth University Peninsula School of Medicine and Dentistry, Plymouth, Devon, UK.
3
Centre of Biostatistics, Bioinformatics and Biomarkers, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, Devon, UK.
4
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
5
Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
6
Department of Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
7
Department of Pathology, Leicester Royal Infirmary, Leicester, UK.
8
Department of Cellular Pathology, Warwick Hospital, Warwick, UK.
9
Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
10
Department of Gastroenterology, Wansbeck General Hospital, Ashington, Northumberland, UK.
11
William Harvey Research Institute, The Ernest Cooke Vascular & Microvascular Unit, Centre for Clinical Pharmacology, St Bartholomew's Hospital, London, UK.
12
Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK.
13
Centre for Digestive Diseases, Queen Mary University of London, London, UK.
14
Department of Gastroenterology, Leicester General Hospital, Leicester, UK.
15
Department of Oncology, New Cross Hospital, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK.
16
Department for Gastroenterology, Leicester Royal Infirmary, Leicester, UK.
17
Gloucestershire Royal Hospital, Great Western Road, Gloucester, UK.
18
Department of Upper GI Surgery, Gloucestershire, Royal Hospital, Gloucester, UK.
19
Department of Medicine, McMaster HC, Hamilton Ontario, Canada.
20
School of Medicine, Dentistry, and Biomedical Sciences, Centre for Public Health, Queens University Belfast, NI.
21
University of Southampton, Southampton General Hospital, Tremona Road, Southampton, UK.
22
Lancashire Teaching Hospitals NHS Foundation Trust, Royal Preston Hospital, Lancashire, UK.
23
General Surgery, Countess of Chester Hospital, Chester, UK.
24
Southampton University Hospitals NHS Trust, Southampton, UK.
25
Wolfson Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.
26
Worcestershire Acute Hospitals NHS Trust, Alexandra Hospital, Redditch, UK.
27
Department of Gastroenterology, Royal Cornwall Hospital, Truro, Cornwall, UK.
28
Macclesfield General Hospital, Macclefield, Cheshire, UK.
29
Department of Gastroenterology, Sandwell General Hospital, Lyndon, West Bromwich, UK.
30
Department of Gastroenterology, University Hospital of Coventry, Coventry, UK.
31
Department of Gastroenterology, Leeds General Infirmary, Leeds, UK.
32
Department of Clinical Pharmacology University of Oxford, Oxford, UK.
33
School of Biomedical & Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
34
Gastroenterology, Royal Albert Edward Infirmary NHS Trust, Wigan, UK; GI Science Centre, Salford Royal NHS Foundation Trust, University of Manchester, Salford, UK.
35
Department of Gastroenterology and Hepatology, Department of Internal Medicine, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
36
Forth Valley Royal Hospital, Larbert, Scotland, UK.
37
Norfolk and Norwich University Hospitals NHS Foundation Trust, Norfolk and Norwich University Hospital, Norwich, UK.
38
Burnley General Hospital, Burnley, Lancashire, UK.
39
Head of Gastroenterology, University Hospital of Northern BC, Prince George, British Columbia, Canada.
40
Bradford Teaching Hospitals NHS Foundation Trust, Bradford Royal Infirmary, Bradford, UK.
41
Royal United Hospital Bath NHS Trust, Royal United Hospital, Avon, Bath, Somerset, UK.
42
Kettering General Hospital NHS Foundation Trust, Kettering General Hospital, Rothwell Road, Kettering, Northants, UK.
43
York Teaching Hospital NHS Foundation Trust, York, UK.
44
Luton and Dunstable University Hospital NHS Foundation Trust, Luton, Bedfordshire, UK.
45
Department of Thoracic and Upper Gastrointestinal Surgery, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
46
County and Durham and Darlington NHS Foundation Trust, Bishop Auckland, County Durham, UK.
47
Guy's and St Thomas' NHS Foundation Trust, London, UK.
48
Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, UK.
49
Division of Public Health Sciences, Fred Hutchinson Cancer Research Centre, Seattle, Washington.
50
Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, North Carolina.
51
Division of Research and San Francisco Medical Center, Kaiser Permanente Northern California, California.
52
Division of Gastroenterology and Hepatology, UNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
53
Department of Oncology, The Medical School, University of Sheffield, UK.
54
Division of Epidemiology, University of Leeds, Leeds, UK.
55
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
56
Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, North Carolina; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
57
Princess Margaret Cancer Centre, Ontario Cancer Institute, Toronto, ON, Canada.
58
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
59
Registry, On behalf of the Romero; Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.
60
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
61
Department of Surgery, University of Saskatchewan, Saskatoon, Canada.
62
MRC Cancer Cell Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, UK.
63
Cancer Control, QIMR Berghofer Medical Research Institute, Queensland, Australia.
64
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
65
Department of Biostatistics, University of Washington School of Public Health, Seattle, Washington.
66
Department of Gastroenterology, Tergooi Hospital, Hilversum, The Netherlands.
67
Department of Surgery, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands.
68
Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
69
Department of Genetics, University Medical Centre Groningen and University of Groningen, The Netherlands.
70
Department of Clinical Medicine & Institute of Molecular Medicine, Trinity Centre for Health Sciences, Trinity College Dublin, St James's Hospital, Dublin, Ireland.
71
Department of Surgery, Trinity Centre for Health Sciences, Trinity College Dublin, St. James' Hospital, Dublin, Ireland.
72
Gastrointestinal Unit, Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland.
73
Faculty of Medicine, Imperial College London, South Kensington Campus, London, UK.
74
Faculty of Medicine, Imperial College, South Kensington Campus, London, UK.
75
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. Electronic address: iant@well.ox.ac.uk.
76
University Hospitals Coventry & Warwickshire NHS Trust, Warwickshire, England; Warwick Medical School, University of Warwick, Warwickshire, England. Electronic address: J.Jankowski@warwick.ac.uk.

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:

Cancer; EAC; Intestinal Metaplasia; Susceptibility

PMID:
25447851
PMCID:
PMC4315134
DOI:
10.1053/j.gastro.2014.10.041
[Indexed for MEDLINE]
Free PMC Article

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