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

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 (Pcombined=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 (Pcombined=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.

SUBMITTER: Su Z

PROVIDER: S-EPMC3459818 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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

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

Nature genetics 20120909 10

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 ...[more]

PMID: 22961001

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Project description:As the premalignant lesion of human esophageal adenocarcinoma (EAC), Barrett's esophagus (BE) is characterized by intestinal metaplasia in the normal esophagus (NE). Gene expression profiling with microarray and serial analysis of gene expression (SAGE) may help us understand the potential molecular mechanism of human BE.We analyzed three microarray datasets (two cDNA arrays and one oligonucleotide array) and one SAGE dataset with statistical tools, significance analysis of microarrays (SAM) and SAGE(Poisson), to identify individual genes differentially expressed in BE. Gene set enrichment analysis (GSEA) was used to identify a priori defined sets of genes that were differentially expressed. These gene sets were grouped according to either certain signaling pathways (GSEA curated), or the presence of consensus binding sequences of known transcription factors (GSEA motif). Immunohistochemical staining (IHC) was used to validate differential gene expression.Both SAM and SAGE(Poisson) identified 68 differentially expressed genes (55 BE genes and 13 NE genes) with an arbitrary cutoff ratio (> or =4-fold). With IHC on matched pairs of NE and BE tissues from 6 patients, these genes were grouped into 6 categories: category I (25 genes only expressed in BE), category II (5 genes only expressed in NE), category III (8 genes expressed more in BE than in NE), and category IV (2 genes expressed more in NE than in BE). Differential expression of the remaining genes was not confirmed by IHC either due to false discovery (category V), or lack of proper antibodies (category VI). Besides individual genes, the TGFbeta pathway and several transcription factors (CDX2, HNF1, and HNF4) were identified by GSEA as enriched pathways and motifs in BE. Apart from 9 target genes known to be up-regulated in BE, IHC staining confirmed up-regulation of 19 additional CDX1 and CDX2 target genes in BE.Our data suggested an important role of CDX1 and CDX2 in the development of BE. The IHC-confirmed gene list will lead to future studies on the molecular mechanism of BE.

Project description:BACKGROUND & AIMS:Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS:We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS:For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION:The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

Dataset Information

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

Publications

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

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