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

The Esophageal Adenocarcinoma Genetics Consortium,; The Wellcome Trust Case Control Consortium 2,; Su, Zhan; Gay, Laura J; Strange, Amy; Palles, Claire; Band, Gavin; Whiteman, David C; Lescai, Francesco; Langford, Cordelia; Nanji, Manoj; Koss, Konrad; Bernstein, Leslie; Romero, Yvonne; Hardie, Laura J; Zhang, Ruixin; Winter, Helen; Corley, Douglas A; Panter, Simon; Risch, Harvey A; Reid, Brian J; Blackwell, Jenefer M; Sargeant, Ian; Gammon, Marilie D; Smart, Howard; Dhar, Anjan; McMurtry, Hugh; Ali, Haythem; Liu, Geoffrey; Casson, Alan G; Chow, Wong-Ho; Rutter, Matt; Bramon, Elvira; Tawil, Ashref; Morris, Danielle; Nwokolo, Chuka; Isaacs, Peter; Rodgers, Colin; Ragunath, Krish; Macdonald, Chris; Haigh, Chris; Monk, David; Davies, Gareth; Brown, Matthew A; Wajed, Saj; Johnston, David; Gibbons, Michael; Cullen, Sue; Church, Nicholas; Langley, Ruth; Griffin, Michael; Alderson, Derek; Deloukas, Panos; Hunt, Sarah E; Casas, Juan P; Gray, Emma; Dronov, Serge; Potter, Simon C; Tashakkori-Ghanbaria, Avazeh; Anderson, Mark; Brooks, Claire; Corvin, Aiden; Duncanson, Audrey; Markus, Hugh S; Mathew, Christopher G; Palmer, Colin NA; Plomin, Robert; Edkins, Sarah; Rautanen, Anna; Sawcer, Stephen J; Trembath, Richard C; Viswanathan, Ananth C; Wood, Nicholas; Trynka, Gosia; Wijmenga, Cisca; Cazier, Jean-Baptiste; Atherfold, Paul; Nicholson, Anna M; van der Winkel, Anouk; Gellatly, Nichola L; Glancy, Deborah; Cooper, Sheldon C; Cunningham, David; Lind, Tore; Hapeshi, Julie; Ferry, David; Rathbone, Barrie; Brown, Julia; Love, Sharon; Levine, David; Attwood, Stephen; Macgregor, Stuart; Watson, Peter; Sanders, Scott; Ek, Weronica; Harrison, Rebecca F; Moayyedi, Paul; de Caestecker, John; Barr, Hugh; Stupka, Elia; Sasieni, Peter; Vaughan, Thomas L; Peltonen, Leena; Spencer, Chris CA; Tomlinson, Ian; Donnelly, Peter; Jankowski, Janusz AZ; Bellenguez, Céline; Howarth, Kimberley; Freeman, Colin; Trudgill, Nigel; Tucker, Art T; Pirinen, Matti; Peppelenbosch, Maikel P; van der Laan, Luc JW; Kuipers, Ernst J; Drenth, Joost PH; Peters, Wilbert H; Reynolds, John V; Kelleher, Dermot P; McManus, Ross; Grabsch, Heike; Prenen, Hans; Bisschops, Raf; Krishnadath, Kausila; Siersema, Peter D; van Baal, Jantine WPM; Middleton, Mark; Petty, Russell; Gillies, Richard; Burch, Nicola; Bhandari, Pradeep; Paterson, Stuart; Edwards, Cathryn; Penman, Ian; Vaidya, Kishor; Ang, Yeng; Murray, Iain; Patel, Praful; Ye, Weimin; Mullins, Paul; Wu, Anna H; Bird, Nigel C; Dallal, Helen; Shaheen, Nicholas J; Murray, Liam J

doi:10.1038/ng.2408

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

Author:

The Esophageal Adenocarcinoma Genetics Consortium,

The Wellcome Trust Case Control Consortium 2, ; Su, Zhan ; Gay, Laura J ; Strange, Amy ; Palles, Claire ; Band, Gavin ; Whiteman, David C ; Lescai, Francesco ; Langford, Cordelia ; Nanji, Manoj ; Koss, Konrad ; Bernstein, Leslie ; Romero, Yvonne ; Hardie, Laura J ; Zhang, Ruixin ; Winter, Helen ; Corley, Douglas A ; Panter, Simon ; Risch, Harvey A ; Reid, Brian J ; Blackwell, Jenefer M ; Sargeant, Ian ; Gammon, Marilie D ; Smart, Howard ; Dhar, Anjan ; McMurtry, Hugh ; Ali, Haythem ; Liu, Geoffrey ; Casson, Alan G ; Chow, Wong-Ho ; Rutter, Matt ; Bramon, Elvira ; Tawil, Ashref ; Morris, Danielle ; Nwokolo, Chuka ; Isaacs, Peter ; Rodgers, Colin ; Ragunath, Krish ; Macdonald, Chris ; Haigh, Chris ; Monk, David ; Davies, Gareth ; Brown, Matthew A ; Wajed, Saj ; Johnston, David ; Gibbons, Michael ; Cullen, Sue ; Church, Nicholas ; Langley, Ruth ; Griffin, Michael ; Alderson, Derek ; Deloukas, Panos ; Hunt, Sarah E ; Casas, Juan P ; Gray, Emma ; Dronov, Serge ; Potter, Simon C ; Tashakkori-Ghanbaria, Avazeh ; Anderson, Mark ; Brooks, Claire ; Corvin, Aiden ; Duncanson, Audrey ; Markus, Hugh S ; Mathew, Christopher G ; Palmer, Colin NA ; Plomin, Robert ; Edkins, Sarah ; Rautanen, Anna ; Sawcer, Stephen J ; Trembath, Richard C ; Viswanathan, Ananth C ; Wood, Nicholas ; Trynka, Gosia ; Wijmenga, Cisca ; Cazier, Jean-Baptiste ; Atherfold, Paul ; Nicholson, Anna M ; van der Winkel, Anouk ; Gellatly, Nichola L ; Glancy, Deborah ; Cooper, Sheldon C ; Cunningham, David ; Lind, Tore ; Hapeshi, Julie ; Ferry, David ; Rathbone, Barrie ; Brown, Julia ; Love, Sharon ; Levine, David ; Attwood, Stephen ; Macgregor, Stuart ; Watson, Peter ; Sanders, Scott ; Ek, Weronica ; Harrison, Rebecca F ; Moayyedi, Paul ; de Caestecker, John ; Barr, Hugh ; Stupka, Elia ; Sasieni, Peter ; Vaughan, Thomas L ; Peltonen, Leena ; Spencer, Chris CA ; Tomlinson, Ian ; Donnelly, Peter ; Jankowski, Janusz AZ ; Bellenguez, Céline ; Howarth, Kimberley ; Freeman, Colin ; Trudgill, Nigel ; Tucker, Art T ; Pirinen, Matti ; Peppelenbosch, Maikel P ; van der Laan, Luc JW ; Kuipers, Ernst J ; Drenth, Joost PH ; Peters, Wilbert H ; Reynolds, John V ; Kelleher, Dermot P ; McManus, Ross ; Grabsch, Heike ; Prenen, Hans ; Bisschops, Raf ; Krishnadath, Kausila ; Siersema, Peter D ; van Baal, Jantine WPM ; Middleton, Mark ; Petty, Russell ; Gillies, Richard ; Burch, Nicola ; Bhandari, Pradeep ; Paterson, Stuart ; Edwards, Cathryn ; Penman, Ian ; Vaidya, Kishor ; Ang, Yeng ; Murray, Iain ; Patel, Praful ; Ye, Weimin ; Mullins, Paul ; Wu, Anna H ; Bird, Nigel C ; Dallal, Helen ; Shaheen, Nicholas J ; Murray, Liam J

Keywords:

Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GASTROESOPHAGEAL-REFLUX DISEASE, GENOME-WIDE ASSOCIATION, SUSCEPTIBILITY LOCI, RISK-FACTORS, ADENOCARCINOMA, CANCER, MANAGEMENT, MORTALITY, DIAGNOSIS, GENETICS, Adult, Aged, Barrett Esophagus, 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, Esophageal Adenocarcinoma Genetics Consortium, Wellcome Trust Case Control Consortium 2, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 3001 Agricultural biotechnology, 3102 Bioinformatics and computational biology, 3105 Genetics

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 (P(combined) = 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 (P(combined) = 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.