title: Polymorphisms in Genes of Relevance for Oestrogen and Oxytocin Pathways and Risk of Barrett's Oesophagus and Oesophageal Adenocarcinoma: A Pooled Analysis from the BEACON Consortium.
abstract: BACKGROUND
  The strong male predominance in oesophageal adenocarcinoma (OAC) and Barrett's oesophagus (BO) continues to puzzle. Hormonal influence, e.g. oestrogen or oxytocin, might contribute.
  
  
  METHODS
  This genetic-epidemiological study pooled 14 studies from three continents, Australia, Europe, and North America. Polymorphisms in 3 key genes coding for the oestrogen pathway (receptor alpha (ESR1), receptor beta (ESR2), and aromatase (CYP19A1)), and 3 key genes of the oxytocin pathway (the oxytocin receptor (OXTR), oxytocin protein (OXT), and cyclic ADP ribose hydrolase glycoprotein (CD38)), were analysed using a gene-based approach, versatile gene-based test association study (VEGAS).
  
  
  RESULTS
  Among 1508 OAC patients, 2383 BO patients, and 2170 controls, genetic variants within ESR1 were associated with BO in males (p = 0.0058) and an increased risk of OAC and BO combined in males (p = 0.0023). Genetic variants within OXTR were associated with an increased risk of BO in both sexes combined (p = 0.0035) and in males (p = 0.0012). We followed up these suggestive findings in a further smaller data set, but found no replication. There were no significant associations between the other 4 genes studied and risk of OAC, BO, separately on in combination, in males and females combined or in males only.
  
  
  CONCLUSIONS
  Genetic variants in the oestrogen receptor alpha and the oxytocin receptor may be associated with an increased risk of BO or OAC, but replication in other large samples are needed.
authors.affiliation: Upper Gastrointestinal Surgery, Department of Molecular medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Lagergren
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden.
authors.forename: Weronica E
authors.initials: WE
authors.lastname: Ek
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Levine
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.affiliation: Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, United States of America.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.affiliation: Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Casson
authors.affiliation: Yale School of Public Health, New Haven, Connecticut, United States of America.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Division of Gastroenterology and Hepatology, UNC School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
authors.affiliation: Department of Oncology, The Medical School, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Bird
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Reid
authors.affiliation: Kaiser Permanente Northern California, Division of Research, Oakland, California, United States of America.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Corley
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.affiliation: Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, United States of America.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
authors.affiliation: Department of Public Health, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Pharoah
authors.affiliation: Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
authors.affiliation: Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Cancer Control Group, Queensland Institute of Medical Research, Herston, Queensland, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Whiteman
authors.affiliation: Department of Pharmacology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Westberg
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Nyren
authors.affiliation: Upper Gastrointestinal Surgery, Department of Molecular medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Jesper
authors.initials: J
authors.lastname: Lagergren
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics; D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics*; D001141:Aromatase / Q000235:genetics; D001471:Barrett Esophagus / Q000453:epidemiology / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D010121:Oxytocin / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018045:Receptors, Oxytocin / Q000235:genetics*; D012737:Sex Factors
chemical_list: C506487:ESR1 protein, human; C000600034:ESR2 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008562:Membrane Glycoproteins; C569600:OXTR protein, human; D018045:Receptors, Oxytocin; D010121:Oxytocin; D001141:Aromatase; C561410:CYP19A1 protein, human; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1