Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data

Autoři: Julia Schröder aff001;  Vitalia Schüller aff002;  Andrea May aff003;  Christian Gerges aff004;  Mario Anders aff005;  Jessica Becker aff001;  Timo Hess aff001;  Nicole Kreuser aff008;  René Thieme aff008;  Kerstin U. Ludwig aff001;  Tania Noder aff005;  Marino Venerito aff009;  Lothar Veits aff010;  Thomas Schmidt aff011;  Claudia Fuchs aff012;  Jakob R. Izbicki aff013;  Arnulf H. Hölscher aff012;  Dani Dakkak aff014;  Boris Jansen-Winkeln aff008;  Yusef Moulla aff008;  Orestis Lyros aff008;  Stefan Niebisch aff008;  Matthias Mehdorn aff008;  Hauke Lang aff015;  Dietmar Lorenz aff016;  Brigitte Schumacher aff014;  Rupert Mayershofer aff017;  Yogesh Vashist aff013;  Katja Ott aff011;  Michael Vieth aff010;  Josef Weismüller aff020;  Elisabeth Mangold aff001;  Markus M. Nöthen aff001;  Susanne Moebus aff021;  Michael Knapp aff002;  Horst Neuhaus aff004;  Thomas Rösch aff005;  Christian Ell aff003;  Ines Gockel aff008;  Johannes Schumacher aff007;  Anne C. Böhmer aff001
Působiště autorů: Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany aff001;  Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany aff002;  Department of Medicine II, Sana Klinikum, Offenbach, Germany aff003;  Department of Internal Medicine II, Evangelisches Krankenhaus, Düsseldorf, Germany aff004;  Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany aff005;  Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany aff006;  Center for Human Genetics, University Hospital Marburg, Marburg, Germany aff007;  Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany aff008;  Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany aff009;  Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany aff010;  Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany aff011;  Department of General, Visceral, and Cancer Surgery, University of Cologne, Cologne, Germany aff012;  Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany aff013;  Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany aff014;  Department of General, Visceral, and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany aff015;  Department of General, Visceral, and Thoracic Surgery, Klinikum Darmstadt, Darmstadt, Germany aff016;  Gastroenterologie am Burgweiher, Bonn, Germany aff017;  Kantonsspital Aarau, Aarau, Switzerland aff018;  Department of General, Visceral, and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany aff019;  Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany aff020;  Centre of Urban Epidemiology, Institute of Medical Informatics, Biometry, and Epidemiology, University of Essen, Essen, Germany aff021
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0227072


Esophageal adenocarcinoma (EA) and its precancerous condition Barrett’s esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10−8) and novel candidate loci (5×10−8 ≤ P ≤ 5×10−5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10−7 and rs1540, Pcombined = 4.16×10−6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.

Klíčová slova:

Gene expression – Gene regulation – Genetic loci – Genetics of disease – Genome-wide association studies – Molecular genetics – Replication studies


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