Dataset Information

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

ABSTRACT:

Background & aims

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.

Methods

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.

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 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)).

Conclusions

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.

SUBMITTER: Palles C

PROVIDER: S-EPMC4315134 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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

Palles Claire C Chegwidden Laura L Li Xinzhong X Findlay John M JM Farnham Garry G Castro Giner Francesc F Peppelenbosch Maikel P MP Kovac Michal M Adams Claire L CL Prenen Hans H Briggs Sarah S Harrison Rebecca R Sanders Scott S MacDonald David D Haigh Chris C Tucker Art A Love Sharon S Nanji Manoj M deCaestecker John J Ferry David D Rathbone Barrie B Hapeshi Julie J Barr Hugh H Moayyedi Paul P Watson Peter P Zietek Barbara B Maroo Neera N Gay Laura L Underwood Tim T Boulter Lisa L McMurtry Hugh H Monk David D Patel Praful P Ragunath Krish K Al Dulaimi David D Murray Iain I Koss Konrad K Veitch Andrew A Trudgill Nigel N Nwokolo Chuka C Rembacken Bjorn B Atherfold Paul P Green Elaine E Ang Yeng Y Kuipers Ernst J EJ Chow Wu W Paterson Stuart S Kadri Sudarshan S Beales Ian I Grimley Charles C Mullins Paul P Beckett Conrad C Farrant Mark M Dixon Andrew A Kelly Sean S Johnson Matthew M Wajed Shahjehan S Dhar Anjan A Sawyer Elinor E Roylance Rebecca R Onstad Lynn L Gammon Marilie D MD Corley Douglas A DA Shaheen Nicholas J NJ Bird Nigel C NC Hardie Laura J LJ Reid Brian J BJ Ye Weimin W Liu Geoffrey G Romero Yvonne Y Bernstein Leslie L Wu Anna H AH Casson Alan G AG Fitzgerald Rebecca R Whiteman David C DC Risch Harvey A HA Levine David M DM Vaughan Tom L TL Verhaar Auke P AP van den Brande Jan J Toxopeus Eelke L EL Spaander Manon C MC Wijnhoven Bas P L BP van der Laan Luc J W LJ Krishnadath Kausilia K Wijmenga Cisca C Trynka Gosia G McManus Ross R Reynolds John V JV O'Sullivan Jacintha J MacMathuna Padraic P McGarrigle Sarah A SA Kelleher Dermot D Vermeire Severine S Cleynen Isabelle I Bisschops Raf R Tomlinson Ian I Jankowski Janusz J

Gastroenterology 20141105 2

<h4>Background & aims</h4>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 ...[more]

PMID: 25447851

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Project description:Background & aimsObesity is associated with Barrett's esophagus (BE) and with changes in circulating levels of adipokines (leptin and adiponectin) and cytokines. Although studies have reported that adipokines and inflammatory cytokines are necessary for the development of BE, their role is controversial.MethodsWe performed a case-control study; cases (n = 141) were patients who underwent esophagogastroduodenoscopy and were found to have BE, which was based on endoscopy and histology, and controls (n = 139) were primary care patients eligible for screening colonoscopies who agreed to undergo esophagogastroduodenoscopy. We examined the association between BE and circulating levels of adipokines and cytokines (interleukin [IL]-1β, IL-6, IL-8, IL-10, and IL-12p70; tumor necrosis factor-α; and interferon-γ). Cases and controls were compared by calculating odds ratios (ORs) and 95% confidence intervals (CIs) and using unadjusted and multiple logistic regression, adjusting for age, sex, race, waist-hip ratio, use of proton pump inhibitors and nonsteroidal anti-inflammatory drugs, and Helicobacter pylori infection.ResultsThe adjusted ORs for BE were 2.62 (95% CI, 1.0-6.8), 5.18 (95% CI, 1.7-15.7), and 8.02 (95% CI, 2.79-23.07) for the highest quintile vs the lowest quintile of levels of IL-12p70, IL-8, and leptin, respectively, but the OR was not significant for IL-6 (2.39; 95% CI, 0.84-6.79). The adjusted OR for BE was 0.14 for highest quintile of IL-10 compared with lowest quintile (95% CI, 0.05-0.35) and 0.03 for IL-1β ≥ median vs none detected (95% CI, 0.006-0.13). Higher levels of IL-8 and leptin and lower levels of IL-10 and IL-1β were associated with the presence of long-segment (≥3 cm) and short-segment BE. There were no differences between cases and controls in levels of interferon-γ, tumor necrosis factor-α, adiponectin, or insulin.ConclusionsBE is associated with circulating inflammatory cytokines and leptin and low levels of anti-inflammatory cytokines. These findings could partly explain the effect of obesity on BE.

Project description:Background and aimsBarrett's esophagus (BE) is the precursor lesion for esophageal adenocarcinoma (EAC). To detect EAC in early stage, patients with BE undergo endoscopic surveillance. Surveillance cohorts largely consist of nondysplastic BE (NDBE) patients with a low annual progression risk (<0.5%). Predictive biomarkers for malignant progression of NDBE could improve efficacy of surveillance. Biomarker research has mostly focused on aberrant protein expression on BE epithelial cells. Moreover, insight in cell signaling driving malignant transformation is unknown. This study uses a data-driven approach to analyze tumor-stroma interaction in NDBE which progressed to high-grade dysplasia or EAC.MethodsIn this case-control study, we performed RNA sequencing analysis on index NDBE biopsies from 6 patients who, during long-term follow-up, progressed and 7 who did not progress to high-grade dysplasia/EAC. For control samples, squamous and duodenum tissues from BE patients were analyzed. For validation, we used quantitative PCR.ResultsSignificant differences in BE transcriptomic profiles between progressors and nonprogressors were found by principal component and differential expression analyses. Ingenuity pathway analysis indicated that 8 cell signaling pathways were significantly upregulated in the progressors, and 14 pathways were significantly downregulated. The most interesting finding was the upregulation of the xenobiotic metabolism pregnane X receptor signaling pathway in the progressor cohort, while of the downregulated pathways in progressors, several were related to the immune system.ConclusionThese novel transcriptomic insights are fundamental for developing (chemo-)preventive therapies. These could be therapies, which protect against toxins, including biles, responsible for pregnane X receptor activation or which enhance protective immune mechanisms. The identified RNA markers are promising biomarkers for improving risk stratification in surveillance programs.

Dataset Information

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

Background & aims

Methods

Results

Conclusions

Publications

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

Similar Datasets

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