Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

• Main Authors: Palles, Claire (Author), Chegwidden, Laura (Author), Li, Xinzhong (Author), Findlay, John M (Author), Farnham, Garry (Author), Giner, Francesc Castro (Author), Peppelenbosch, Maikel P (Author), Kovac, Michal (Author), Adams, Claire L (Author), Prenen, Hans (Author), Briggs, Sarah (Author), Harrison, Rebecca (Author), Sanders, Scott (Author), MacDonald, David (Author), Haigh, Chris (Author), Tucker, Art (Author), Love, Sharon (Author), Nanji, Manoj (Author), deCaestecker, John (Author), Ferry, David (Author), Rathbone, Barrie (Author), Hapeshi, Julie (Author), Barr, Hugh (Author), Zietek, Barbara (Author), Maroo, Neera (Author), Gay, Laura (Author), Underwood, Tim (Author), Boulter, Lisa (Author), McMurtry, Hugh (Author), Monk, David (Author), Patel, Praful (Author), Ragunath, Krish (Author), Al Dulaimi, David (Author), Murray, Iain (Author), Koss, Konrad (Author), Veitch, Andrew (Author), Trudgill, Nigel (Author), Nwokolo, Chuka (Author), Rembacken, Bjorn (Author), Atherfold, Paul (Author), Green, Elaine (Author), Ang, Yeng (Author), Kuipers, Ernst J (Author), Chow, Wu (Author), Paterson, Stuart (Author), Kadri, Sudarshan (Author), Beales, Ian (Author), Grimley, Charles (Author), Mullins, Paul (Author), Beckett, Conrad (Author), Farrant, Mark (Author), Dixon, Andrew (Author), Kelly, Sean (Author), Johnson, Matthew (Author), Wajed, Shahjehan (Author), Dhar, Anjan (Author), Sawyer, Elinor (Author), Roylance, Rebecca (Author), Onstad, Lynn (Author), Gammon, Marilie D (Author), Corley, Douglas A (Author), Shaheen, Nicholas J (Author), Bird, Nigel C (Author), Hardie, Laura J (Author), Reid, Brian J (Author), Ye, Weimin (Author), Liu, Geoffrey (Author), Romero, Yvonne (Author), Bernstein, Leslie (Author), Wu, Anna H (Author), Casson, Alan G (Author), Fitzgerald, Rebecca (Author), Whiteman, David C (Author), Risch, Harvey A (Author), Levine, David M (Author), Vaughan, Tom L (Author), Verhaar, Auke P (Author), van den Brande, Jan (Author), Toxopeus, Eelke L (Author), Spaander, Manon C (Author), Wijnhoven, Bas P L (Author), van der Laan, Luc J W (Author), Krishnadath, Kausilia (Author), Wijmenga, Cisca (Author), Trynka, Gosia (Author), McManus, Ross (Author), Reynolds, John V (Author), O'Sullivan, Jacintha (Author), MacMathuna, Padraic (Author), McGarrigle, Sarah A (Author), Kelleher, Dermot (Author), Vermeire, Severine (Author), Cleynen, Isabelle (Author), Bisschops, Raf (Author), Tomlinson, Ian (Author), Jankowski, Janusz (Author)
• Format: Article
• Language: English
• Published: 2015-02.
• Subjects: Article
• Online Access: Get fulltext

 Background & aims: Barrett's esophagus (BE) increases risk for esophageal adenocarcinoma (EAC). Increased risk for BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma in CRTC1 and BARX1, and within 100 kb FOXP1. We aimed to identify SNPs that increased risk for BE in a genome-wide association study (GWAS) and to validate previously reported associations. Methods: we performed a GWAS to identify variants associated with BE and further analyzed promising variants identified by the BEACON. We performed genotype analysis of 10,158 patients with BE and 21,062 controls. Results: we identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10?11) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10?9). The closest protein-coding genes were GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. We also identified 3 SNPS already identified by the BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, near ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10?9). Conclusions: we identified 2 loci associated with risk for BE and provide data to support a locus previously associated with risk in the BEACON. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response