Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.
Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus.
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DOI：
10.1053/j.gastro.2014.10.041
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发表时间：
2015-02
期刊：
影响因子：
29.4
通讯作者：
Jankowski J
中科院分区：
文献类型：
--
作者：
Palles C;Chegwidden L;Li X;Findlay JM;Farnham G;Castro Giner F;Peppelenbosch MP;Kovac M;Adams CL;Prenen H;Briggs S;Harrison R;Sanders S;MacDonald D;Haigh C;Tucker A;Love S;Nanji M;deCaestecker J;Ferry D;Rathbone B;Hapeshi J;Barr H;Moayyedi P;Watson P;Zietek B;Maroo N;Gay L;Underwood T;Boulter L;McMurtry H;Monk D;Patel P;Ragunath K;Al Dulaimi D;Murray I;Koss K;Veitch A;Trudgill N;Nwokolo C;Rembacken B;Atherfold P;Green E;Ang Y;Kuipers EJ;Chow W;Paterson S;Kadri S;Beales I;Grimley C;Mullins P;Beckett C;Farrant M;Dixon A;Kelly S;Johnson M;Wajed S;Dhar A;Sawyer E;Roylance R;Onstad L;Gammon MD;Corley DA;Shaheen NJ;Bird NC;Hardie LJ;Reid BJ;Ye W;Liu G;Romero Y;Bernstein L;Wu AH;Casson AG;Fitzgerald R;Whiteman DC;Risch HA;Levine DM;Vaughan TL;Verhaar AP;van den Brande J;Toxopeus EL;Spaander MC;Wijnhoven BP;van der Laan LJ;Krishnadath K;Wijmenga C;Trynka G;McManus R;Reynolds JV;O'Sullivan J;MacMathuna P;McGarrigle SA;Kelleher D;Vermeire S;Cleynen I;Bisschops R;Tomlinson I;Jankowski J
Barrett食管（BE）增加了食管腺癌（EAC）的风险。我们发现BE的风险与染色体6p 21（HLA区域内）和16 q23上的单核苷酸多态性（SNP）相关，其中最接近的蛋白质编码基因是FOXF 1。随后，Barrett和食管腺癌联盟（BEACON）确定了CRTC 1和BARX 1附近以及FOXP 1的100 kb内BE和食管腺癌的风险位点。我们的目的是进一步确定增加BE风险的SNPs，并验证先前报道的相关性。我们进行了一项全基因组关联研究（GWAS），以确定与BE相关的变异，并通过对10，158名BE患者和21，062名对照进行基因分型，进一步分析了BEACON确定的有希望的变异。我们发现了2个以前与BE无关的SNP：rs3072（2p24.1;比值比[OR] = 1.14; 95%CI：1.09-1.18; P = 1.8 × 10−11）和rs 2701108（12q24.21; OR = 0.90; 95%CI：0.86-0.93; P = 7.5 × 10−9）。最接近的蛋白质编码基因分别是GDF 7（rs3072）和TBX 5（rs 2701108），GDF 7编码骨形态发生蛋白途径中的配体，TBX 5编码调节食管和心脏发育的转录因子。我们的数据还支持BE病例中BEACON确定的3个风险SNP（rs 2687201，rs 11789015和rs 10423674）。所有数据的荟萃分析发现了另一个与BE和食管腺癌相关的SNP：rs3784262，在ALDH 1A 2内（OR = 0.90; 95%CI：0.87-0.93; P = 3.72 × 10−9）。我们确定了2个与BE风险相关的基因座，并提供了支持另一个基因座的数据。我们发现与BE风险相关的基因编码参与胸廓、胃和食管发育的转录因子或参与炎症反应的蛋白质。
Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be 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. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. 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 respectively 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. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87–0.93; P = 3.72 × 10−9). We identified 2 loci associated with risk of BE and provided data to support a further locus. 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.
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影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
影响因子：
3.8
作者：
Chak, Amitabh;Ochs-Balcom, Heather;Eng, Charis
通讯作者：
Eng, Charis
影响因子：
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作者：
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通讯作者：
Houlston RS
影响因子：
10.3
作者：
Ek, Weronica E.;Levine, David M.;MacGregor, Stuart
通讯作者：
MacGregor, Stuart
影响因子：
6.4
作者：
Dura, Polat;van Veen, Elke M.;Peters, Wilbert H. M.
通讯作者：
Peters, Wilbert H. M.