title: Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.
abstract: Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA.
  
  
  
  We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk.
  
  
  
  We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36MGST1SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci forMGST1. Three such variants were associated with similar elevations in OA risk.
  
  
  
  This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants inMGST1influence disease susceptibility.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Buas
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Qianchuan
authors.initials: Q
authors.lastname: He
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Johnson
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Onstad
authors.affiliation: Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Levine
authors.affiliation: Department of Medicine, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Thrift
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute Brisbane, Queensland, Australia.
authors.forename: Puya
authors.initials: P
authors.lastname: Gharahkhani
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Palles
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Division of Cancer Studies, King's College London, UK.
authors.forename: Jesper
authors.initials: J
authors.lastname: Lagergren
authors.affiliation: Medical Research Council (MRC) MRC Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ye
authors.affiliation: Cancer Research UK, Cambridge Institute, Cambridge, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Oncology, Medical School, University of Sheffield, Sheffield, UK.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Bird
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
authors.affiliation: Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.affiliation: Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.affiliation: Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds, UK.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.affiliation: Department of Oncology, University of Cambridge, Cambridge, UK.|Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Prassad
authors.initials: P
authors.lastname: Iyer
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.|San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, USA.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Corley
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.affiliation: Department of Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.affiliation: University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Chegwidden
authors.affiliation: Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: Love
authors.affiliation: Department of General Surgery, North Tyneside General Hospital, North Shields, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Attwood
authors.affiliation: Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Moayyedi
authors.affiliation: Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David
authors.initials: D
authors.lastname: MacDonald
authors.affiliation: Department of Pathology, Leicester Royal Infirmary, Leicester, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Harrison
authors.affiliation: Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Watson
authors.affiliation: Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK.
authors.forename: Hugh
authors.initials: H
authors.lastname: Barr
authors.affiliation: Department of Gastroenterology, Leicester General Hospital, Leicester, UK.
authors.forename: John
authors.initials: J
authors.lastname: deCaestecker
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, University of Oxford, Oxford, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
authors.affiliation: UClan Medical School, West Lakes Campus, Rm 127 Lindow Centre, Cumbria, UK.
authors.forename: Janusz
authors.initials: J
authors.lastname: Jankowski
authors.affiliation: Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: Queensland Institute of Medical Research Berghofer Medical Research Institute Brisbane, Queensland, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Madeleine
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D001471:Barrett Esophagus / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics*; D005260:Female; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D005982:Glutathione Transferase / Q000235:genetics*; D006680:HLA Antigens / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016207:Cytokines; D006680:HLA Antigens; D016328:NF-kappa B; D011451:Prostaglandin-Endoperoxide Synthases; C122107:microsomal glutathione S-transferase-I; D005982:Glutathione Transferase
keywords: BARRETT'S OESOPHAGUS; GENETIC POLYMORPHISMS; INFLAMMATION; OESOPHAGEAL CANCER