title: A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett's esophagus.
abstract: BACKGROUND
  Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear.
  
  
  METHODS
  We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma.
  
  
  RESULTS
  The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index.
  
  
  CONCLUSIONS
  Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1.
  
  
  CONCLUSIONS
  The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington. jdai@fredhutch.org tvaughan@u.washington.edu.
authors.forename: James Y
authors.initials: JY
authors.lastname: Dai
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jean
authors.initials: J
authors.lastname: de Dieu Tapsoba
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Buas
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Onstad
authors.affiliation: Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington.
authors.forename: David M
authors.initials: DM
authors.lastname: Levine
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.
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.
authors.forename: Leslie
authors.initials: L
authors.lastname: Bernstein
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ye
authors.affiliation: 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
authors.affiliation: Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Bird
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California. San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Corley
authors.affiliation: Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Shaheen
authors.affiliation: Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Reid
authors.affiliation: Division of Epidemiology, University of Leeds, Leeds, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.affiliation: Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington. jdai@fredhutch.org tvaughan@u.washington.edu.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics; D001471:Barrett Esophagus / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000502:physiology; D005764:Gastroesophageal Reflux / Q000150:complications / Q000235:genetics*; D056426:Genetic Loci / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006720:Homozygote; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology; D012307:Risk Factors
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D005819:Genetic Markers; D012097:Repressor Proteins