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• W2014858975 abstract "Barrett's esophagus (BE) is a common premalignant lesion affecting ≥2% of the population in the West.1Ronkainen J. Aro P. Storskrubb T. et al.Prevalence of Barrett esophagus in the general population: an endoscopic study.Gastroenterology. 2005; 129: 1825-1831Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar The economic impact of the condition is huge and has a well-established risk (between 2.5 and 6.5 per 1000 patient-years) of progressing to esophageal adenocarcinoma. The prognosis of these tumors is still poor (≈10% 5-year survival) and is directly associated with the stage at diagnosis2Jankowski J. Barr H. Wang K. et al.Diagnosis and management of Barrett's oesophagus.Brit Med J. 2010; 10 (c4551): 341Google Scholar, 3Bennett C. Vakil N. Bergman J. et al.Consensus statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process.Gastroenterology. 2012; 143: 336-346Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar; in the United States, ≥$100,000 dollars are spent to detect each cancer.4Gupta N. Bansal A. Wani S.B. et al.Endoscopy for upper GI cancer screening in the general population: a cost-utility analysis.Gastrointest Endosc. 2011; 74: 610-624Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar BE involves a metaplastic change in the midst of chronic mucosal inflammation in response to refluxed gastroduodenal contents.2Jankowski J. Barr H. Wang K. et al.Diagnosis and management of Barrett's oesophagus.Brit Med J. 2010; 10 (c4551): 341Google Scholar Until recently, reflux and BE were thought to be solely an acquired disease, but family and twin studies have implicated a genetic component to the disease predisposition.5Mohammed I. Cherkas L.F. Riley S.A. et al.Genetic influences in gastro-oesophageal reflux disease: a twin study.Gut. 2003; 52: 1085-1089Crossref PubMed Scopus (209) Google Scholar, 6Chak A. Ochs-Balcom H. Falk G. et al.Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction.Cancer Epidemiol Biomarkers Prev. 2006; 15 (1668–1667)Crossref PubMed Scopus (89) Google Scholar Of all reflux disease, 43% is heritable based on concordance data for gastroesophageal reflux and symptomatic BE in twins,5Mohammed I. Cherkas L.F. Riley S.A. et al.Genetic influences in gastro-oesophageal reflux disease: a twin study.Gut. 2003; 52: 1085-1089Crossref PubMed Scopus (209) Google Scholar, 6Chak A. Ochs-Balcom H. Falk G. et al.Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction.Cancer Epidemiol Biomarkers Prev. 2006; 15 (1668–1667)Crossref PubMed Scopus (89) Google Scholar although the sibling relative risk is only modestly increased (odds ratio [OR], 1.58).7Romero Y. Cameron A.J. Schaid D.J. et al.Barrett's esophagus: prevalence in symptomatic relatives.Am J Gastroenterol. 2002; 97: 1127-1132Crossref PubMed Google Scholar Furthermore duplex and multiplex kindreds have a younger age of onset compared with nonfamilial cases (57, 62, and 63 years, respectively).8Chak A. Chen Y. Vengoechea J. et al.Variation in age at cancer diagnosis in familial versus nonfamilial Barrett's esophagus.Cancer Epidemiol Biomarkers Prev. 2012; 21: 376-383Crossref PubMed Scopus (23) Google Scholar There is, however, a real need to improve the understanding of the early pathogenesis, both to allow early detection biomarkers to aid risk stratification strategies and to help in the targeting of new treatment strategies. In the last 5 years, genome-wide association studies (GWAS) have been undertaken in many polygenic diseases, and have provided important insights into basic pathogenetic mechanisms. Following studies from the UK WTCCC1 team, this strategy has been remarkably successful in many common gastrointestinal and hepatobiliary diseases including colon cancer, gall stone diseases, primary sclerosing cholangitis, and primary biliary cirrhosis.9Wellcome Trust Case Control ConsortiumGenome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.Nature. 2007; 447: 661-678Crossref PubMed Scopus (7849) Google Scholar, 10Anderson C.A. Massey D.C. Barrett J.C. et al.Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship.Gastroenterology. 2009; 136: 523-529Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar Studies in immune-mediated diseases have been especially successful, with remarkable insights in inflammatory bowel disease and celiac disease continuing to emerge.10Anderson C.A. Massey D.C. Barrett J.C. et al.Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship.Gastroenterology. 2009; 136: 523-529Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 11Dubois P.C. Trynka G. Franke L. et al.Multiple common variants for celiac disease influencing immune gene expression.Nat Genet. 2010; 42 (Erratum in: Nat Genet 2010;42:465): 295-302Crossref PubMed Scopus (736) Google Scholar It is clear that chronic inflammatory diseases of the colon, intestine, stomach, and now esophagus share genetic determinants with several other immune-mediated illnesses like psoriasis and rheumatoid arthritis, and with diabetes types 1 and 2.12Cho J.H. Brant S.R. Recent insights into the genetics of inflammatory bowel disease.Gastroenterology. 2011; 140: 1704-1712Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 13Lees C.W. Barrett J.C. Parkes M. et al.New IBD genetics: common pathways with other diseases.Gut. 2011; 60: 1739-1753Crossref PubMed Scopus (424) Google Scholar, 14Zhernakova A. van Diemen C.C. Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases.Nat Rev Genet. 2009; 10: 43-55Crossref PubMed Scopus (416) Google Scholar, 15Barrett J.C. Hansoul S. Nicolae D.L. et al.Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.Nat Genet. 2008; 40: 955-962Crossref PubMed Scopus (2171) Google Scholar In the majority of cases, the contribution of any single locus to hereditability appears modest (ORs between 1.1 and 1.5).12Cho J.H. Brant S.R. Recent insights into the genetics of inflammatory bowel disease.Gastroenterology. 2011; 140: 1704-1712Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 13Lees C.W. Barrett J.C. Parkes M. et al.New IBD genetics: common pathways with other diseases.Gut. 2011; 60: 1739-1753Crossref PubMed Scopus (424) Google Scholar, 14Zhernakova A. van Diemen C.C. Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases.Nat Rev Genet. 2009; 10: 43-55Crossref PubMed Scopus (416) Google Scholar, 15Barrett J.C. Hansoul S. Nicolae D.L. et al.Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.Nat Genet. 2008; 40: 955-962Crossref PubMed Scopus (2171) Google Scholar The recent analyses of BE have now provided further intriguing clues as to disease pathogenesis. The discovery phase of this GWA study was based on the cohort of patients recruited into the aspirin esomeprazole chemoprevention trial (AspECT), a randomized, controlled trial using stringent inclusion criteria for BE.15Barrett J.C. Hansoul S. Nicolae D.L. et al.Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease.Nat Genet. 2008; 40: 955-962Crossref PubMed Scopus (2171) Google Scholar Subsequently, 5 replication phases were based on standard case controls from various consortia including the EsophAGeal GenEtic Consortia (EAGLE). The overall study involved approximately 8000 cases and approximately 18,000 controls, and reassuringly replicated on different genotyping methodology platforms. Two novel determinants achieving confirmed genome-wide significance were identified, one in the human leukocyte antigen (HLA) region and another related to esophageal mesodermal structure.16The Esophageal Adenocarcinoma Genetics Consortium; The Wellcome Trust Case Control Consortium 2Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.Nat Genet. 2012; 44: 1131-1136Crossref PubMed Scopus (143) Google Scholar The highly significant association with the 6p21 region (RS9257809) (Figure 1) in the HLA region (P = 4.09 × 10−9) was an unexpected new finding in BE, although it accounted for <5% of the estimated genetic risk (OR, 1.21). Intriguingly, the data raise the possibility that complex genetic susceptibility may contribute, in part, to the marked male to female gender bias (4:1) in disease incidence, because the OR for rs9257809 for males was 1.38 (95% confidence interval [CI], 1.25–1.53; 1.11 in women [95% CI, 0.95–1.30]), indicating a gender selection for disease predisposition. Furthermore, if several genes had similar small effects it would be cumulative. In addition, geographical differences in allelic frequencies in the UK were evident, with the HLA-encoded risk alleles more common in Scotland compared with Southern England, proportional to the prevalence of diagnosed BE. However, the Scottish population was only 10% of the UK sample so the statistical power to probe further was limited. The second highly significant genetic locus implicated by the BE GWAS, achieving genome-wide significance at 16q24 (RS 9936833; P = 2.74 × 10−10) (Figure 1) is noteworthy for its proximity to the transcription factor FOXF1. FOXF1 is part of the Forkhead gene family of transcription factors, which controls mesodermal development of the gastrointestinal tract. Crucially, deletion of the entire function of FOXF1 in humans and FOXF1 knockout mice results in esophageal atresia, tracheoesophageal fistula, and esophageal wall alterations.17Shaw-Smith C. Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature.Eur J Med Genet. 2010; 53: 6-13Crossref PubMed Scopus (81) Google Scholar It will be interesting to assess whether this gene may be involved in the genesis of BE through a relationship with subtle structural changes resulting in hiatus hernias, also known to have a genetic predisposition. Abrogation in the muscle layers, as well as abnormal mucin content and glandular structures have been implicated in both diseases.18Dutta H.K. Mathur M. Bhatnagar V. A histopathological study of esophageal atresia and tracheoesophageal fistula.J Pediatr Surg. 2000; 35: 438-441Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar The OR for increasing susceptibility to BE for the present variant is once again low, at 1.14 (95% CI, 1.10–1.19). One potentially important holistic (Figure 1) feature of the report is the discovery of the extent of shared genetic determinants between altered body shape in the form of obesity and BE. In the top 40 genes associated with BE, 29 were also implicated in obesity, most predisposing to an increased body mass index or increased hip-to-waist ratio through functional alterations. These associations, which are shared with cardiac disease, may explain in part the heightened mortality from ischemic heart disease in patients with BE.19Moayyedi P. Burch N. Akhtar-Danesh N. et al.Mortality rates in patients with Barrett's oesophagus.Aliment Pharmacol Ther. 2008; 27: 316-320Crossref PubMed Scopus (74) Google Scholar Furthermore, there are many small effects by many other genes, as the best predictive model using an en masse analyses indicated 1710 genes added together was hugely significant (7.07 × 10−11). As in other gastrointestinal diseases, the initial excitement of these discoveries in BE is to stimulate new directions for translational and therapeutic research (Table 1). From a biological perspective, we need to characterize the specific mutations within these loci and the overall contribution of each mutation to understand their exact function in the evolution of the esophagitis–metaplasia–adenocarcinoma sequence as well as to elucidate gene environment interactions and signalling pathways, especially FOXF1 and wnt signalling. In this regard, the pathways identified by the genetic studies may represent targets of epigenetic alteration in the upper gastrointestinal tract. Smoking and dietary factors are increasingly implicated as epigenetic factors involved in immune as well as nonimmune cell regulation of gene expression.Table 1Gastrointestinal Diseases With Polygenic TraitsHiatal herniaREBarrett's esophagusUlcerative colitisCrohn's diseaseFamily clustering, (λs)5–105–1031525–35HeritabilityaHeritability of phenotype from genome: <5, low; >10, moderate; >25, very high.?10%5%30%40%–70%Male:Female1:11:14:11:11:1EthnicityW and AW and AWcW and AW and APrevalencebPrevalence in population.20%10%2%0.25%0.15%Genes identified as causal,cGenes (%) that cause the phenotype rather than associated with the disease (noncasual). (%)???20%30%Top associationsdTop gene.16q24?16q24 and 6p21DRB1NOD2GWA > 10−8 targetseNumber of genes with strongest level of statistical proof.1?2133140A, Asian; λs, % risk of having second child affected; RE, Reflux esophagitis; W, white; Wc, white Caucasian.a Heritability of phenotype from genome: <5, low; >10, moderate; >25, very high.b Prevalence in population.c Genes (%) that cause the phenotype rather than associated with the disease (noncasual).d Top gene.e Number of genes with strongest level of statistical proof. Open table in a new tab A, Asian; λs, % risk of having second child affected; RE, Reflux esophagitis; W, white; Wc, white Caucasian. From the perspective of moving to clinical translation, the challenges are evident, and reflect those in other complex diseases ORs > 5 are optimal for clinical decision making,20Pillay N. Plagnol V. Tarpey P.S. et al.A common single-nucleotide variant in T is strongly associated with chordoma.Nat Genet. 2012; 44: 1185-1187Crossref PubMed Scopus (95) Google Scholar and the single nucleotide polymorphisms (SNPs) discovered in the present study do not represent biomarkers predictive of progression from reflux disease to BE. However, fine mapping and next generation sequencing may detect stronger associations with loci of interest, as exemplified by experience with NOD2 variation in Crohn's disease, and in other diseases (Table 1).21Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3320) Google Scholar, 22Lees C.W. Barrett J.C. Parkes M. et al.New IBD genetics: common pathways with other diseases.Gut. 2011; 60: 1739-1753Crossref PubMed Scopus (473) Google Scholar Furthermore, pathway analyses of many SNPs of small effect may allow elucidation of the key functional drivers of disease, and in turn lead to biomarker discovery, or key areas for therapeutic intervention.23Satsangi J. Kennedy N.A. Henderson P. et al.Exploring the hidden heritability of inflammatory bowel disease.Gut. 2011; 60: 1447-1448Crossref PubMed Scopus (6) Google Scholar However, the main success is that, before this GWAS, we would never have imagined BE potentially as an immune-mediated disease, emphasizing how little we really know. The authors thank Sarah Williamson for help with the production of the figure and the EsophAGeal GenEtic Consortia (EAGLE) Trial Management Group for helpful comments." @default.
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• W2014858975 title "Barrett's Esophagus: Evolutionary Insights From Genomics" @default.
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