Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

• Authors: Zhan Su, Laura J Gay, Amy Strange, Claire Palles, Gavin Band, David C Whiteman, Francesco Lescai, Cordelia Langford, Manoj Nanji, Sarah Edkins, Anouk van der Winkel, David Levine, Peter Sasieni, Céline Bellenguez, Kimberley Howarth, Colin Freeman, Nigel Trudgill, Art T Tucker, Matti Pirinen, Maikel P Peppelenbosch, Luc J W van der Laan, Ernst J Kuipers, Joost P H Drenth, Wilbert H Peters, John V Reynolds, Dermot P Kelleher, Ross McManus, Heike Grabsch, Hans Prenen, Raf Bisschops, Kausila Krishnadath, Peter D Siersema, Jantine W P M van Baal, Mark Middleton, Russell Petty, Richard Gillies, Nicola Burch, Pradeep Bhandari, Stuart Paterson, Cathryn Edwards, Ian Penman, Kishor Vaidya, Yeng Ang, Iain Murray, Praful Patel, Weimin Ye, Paul Mullins, Anna H Wu, Nigel C Bird, Helen Dallal, Nicholas J Shaheen, Liam J Murray, Konrad Koss, Leslie Bernstein, Yvonne Romero, Laura J Hardie, Rui Zhang, Helen Winter, Douglas A Corley, Simon Panter, Harvey A Risch, Brian J Reid, Ian Sargeant, Marilie D Gammon, Howard Smart, Anjan Dhar, Hugh McMurtry, Haythem Ali, Geoffrey Liu, Alan G Casson, Wong-Ho Chow, Matt Rutter, Ashref Tawil, Danielle Morris, Chuka Nwokolo, Peter Isaacs, Colin Rodgers, Krish Ragunath, Chris MacDonald, Chris Haigh, David Monk, Gareth Davies, Saj Wajed, David Johnston, Michael Gibbons, Sue Cullen, Nicholas Church, Ruth Langley, Michael Griffin, Derek Alderson, Panos Deloukas, Sarah E Hunt, Emma Gray, Serge Dronov, Simon C Potter, Avazeh Tashakkori-Ghanbaria, Mark Anderson, Claire Brooks, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan P Casas, Aiden Corvin, Audrey Duncanson, Hugh S Markus, Christopher G Mathew, Colin N A Palmer, Robert Plomin, Anna Rautanen, Stephen J Sawcer, Richard C Trembath, Ananth C Viswanathan, Nicholas Wood, Gosia Trynka, Cisca Wijmenga, Jean-Baptiste Cazier, Paul Atherfold, Anna M Nicholson, Nichola L Gellatly, Deborah Glancy, Sheldon C Cooper, David Cunningham, Tore Lind, Julie Hapeshi, David Ferry, Barrie Rathbone, Julia Brown, Sharon Love, Stephen Attwood, Stuart MacGregor, Peter Watson, Scott Sanders, Weronica Ek, Rebecca F Harrison, Paul Moayyedi, John de Caestecker, Hugh Barr, Elia Stupka, Thomas L Vaughan, Leena Peltonen, Chris C A Spencer, Ian Tomlinson, Peter Donnelly, Janusz A Z Jankowski, Esophageal Adenocarcinoma Genetics Consortium, Wellcome Trust Case Control Consortium 2
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 10 Pg. 1131-6 (Oct 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 22961001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Adult
• Aged
• Barrett Esophagus (genetics)
• Case-Control Studies
• Chromosomes, Human, Pair 16
• Female
• Gene Frequency
• Genetic Loci
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Humans
• Linkage Disequilibrium
• Major Histocompatibility Complex
• Male
• Middle Aged
• Models, Genetic
• Polymorphism, Single Nucleotide