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Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk... - PubMed - NCBI

2014 Nov 5. pii: S0016-5085(14)01334-1. doi: 10.1053/j.gastro.2014.10.041. [Epub ahead of print]

Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett's Esophagus.

Palles C1, Chegwidden L2, Li X3, Findlay JM1, Farnham G2, Giner FC1, Peppelenbosch MP4, Kovac M1, Adams CL2, Prenen H5, Briggs S1, Harrison R6,Sanders S7, MacDonald D8, Haigh C9, Tucker A10, Love S11, Nanji M12, deCaestecker J13, Ferry D14, Rathbone B15, Hapeshi J16, Barr H17, Zietek B12, Maroo N12, Gay L12, Underwood T18, Boulter L18, McMurtry H19, Monk D20, Patel P21, Ragunath K22, Al Dulaimi D23, Murray I24, Koss K25, Veitch A14, Trudgill N26,Nwokolo C27, Rembacken B28, Atherfold P29, Green E30, Ang Y31, Kuipers EJ32, Chow W33, Paterson S34, Kadri S15, Beales I35, Grimley C36, Mullins P37,Beckett C38, Farrant M39, Dixon A40, Kelly S41, Johnson M42, Wajed S43, Dhar A44, Sawyer E45, Roylance R46, Onstad L47, Gammon MD48, Corley DA49,Shaheen NJ50, Bird NC51, Hardie LJ52, Reid BJ53, Ye W54, Liu G55, Romero Y56, Bernstein L57, Wu AH58, Casson AG59, Fitzgerald R60, Whiteman DC61,Risch HA62, Levine DM63, Vaughan TL47, Verhaar AP4, van den Brande J64, Toxopeus EL65, Spaander MC4, Wijnhoven BP65, van der Laan LJ65,Krishnadath K66, Wijmenga C67, Trynka G67, McManus R68, Reynolds JV69, O'Sullivan J69, MacMathuna P70, McGarrigle SA69, Kelleher D70, Vermeire S5,Cleynen I5, Bisschops R5, Tomlinson I1, Jankowski J71.

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Abstract

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.