title: MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium.
abstract: Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Buas
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Lynn
authors.initials: L
authors.lastname: Onstad
authors.affiliation: Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Levine
authors.affiliation: Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, United States of America.
authors.forename: Harvey A
authors.initials: HA
authors.lastname: Risch
authors.affiliation: Department of Epidemiology, MD Anderson Cancer Center, Houston, TX, United States of America.
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.affiliation: Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada, M5G 2M9.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre and University of Cambridge, Cambridge, United Kingdom.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fitzgerald
authors.affiliation: Department of Populations 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 Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ye
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 Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America; The Romero Registry, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Romero
authors.affiliation: Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Casson
authors.affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California, United States of America; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California, United States of America.
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, United States of America.
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, United States of America.
authors.forename: Anna H
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, North Carolina, United States of America.
authors.forename: Marilie D
authors.initials: MD
authors.lastname: Gammon
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; 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: Division of Epidemiology, University of Leeds, Leeds, United Kingdom.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Hardie
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, United States of America.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, 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, United States of America; Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington, United States of America.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Vaughan
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D000368:Aged; D001471:Barrett Esophagus / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D004947:Esophagus / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005764:Gastroesophageal Reflux / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009765:Obesity / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D012907:Smoking / Q000235:genetics / Q000473:pathology; D044465:White People
chemical_list: D035683:MicroRNAs