title: Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk.
abstract: Barrett's esophagus, with gastroesophageal reflux disease and obesity as risk factors, predisposes to esophageal adenocarcinoma (EAC). Recently a British genome wide association study identified two Barrett's esophagus susceptibility loci mapping within the major histocompatibility complex (MHC; rs9257809) and closely to the Forkhead-F1 (FOXF1; rs9936833) coding gene. An interesting issue is whether polymorphisms associated with Barrett's esophagus, are also implicated in esophageal carcinoma (EC), and more specifically EAC genesis. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from surveillance programs. Our hypothesis: Barrett associated MHC and FOXF1 variants modify EC risk in Caucasians. In a Dutch case-control study, 431 patients with EC and 605 healthy controls were included. Polymorphisms at chromosomes 6p21 (MHC) and 16q24 (FOXF1) were determined by means of real-time polymerase chain reaction (RT-PCR). Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals. The FOXF1 rs9936833 variant C allele was associated with an increased EAC susceptibility; OR, [95% CI]; 1.21, [0.99-1.47]. A sex-stratified analysis revealed a similar association in males; 1.24 [1.00-1.55]. The variant MHC rs9257809 G allele as well as the MHC heterozygous AG genotype significantly increased ESCC risk; 1.76 [1.16-2.66] and 1.74 [1.08-2.80], respectively. Sex-stratification showed that the variant G allele was especially present in female patients; 2.32 [1.04-5.20]. In conclusion, this study provides evidence that MHC rs9257809 and FOXF1 rs9936833 variants, associated with Barrett's esophagus, also increase ESCC and EAC susceptibility in Caucasians. FOX proteins are transcription factors involved in organogenesis of the GI tract, while MHC haplotypes are strongly associated with smoking behavior, a crucial risk factor for ESCC. Assessing the individual genetic susceptibility can help identify high risk patients more prone to benefit from (Barrett) surveillance programs.
authors.affiliation: Department of Gastroenterology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. p.dura@mdl.umcn.nl
authors.forename: Polat
authors.initials: P
authors.lastname: Dura
authors.forename: Elke M
authors.initials: EM
authors.lastname: van Veen
authors.forename: Jody
authors.initials: J
authors.lastname: Salomon
authors.forename: Rene H M
authors.initials: RH
authors.lastname: te Morsche
authors.forename: Hennie M J
authors.initials: HM
authors.lastname: Roelofs
authors.forename: Jon O
authors.initials: JO
authors.lastname: Kristinsson
authors.forename: Theo
authors.initials: T
authors.lastname: Wobbes
authors.forename: Ben J M
authors.initials: BJ
authors.lastname: Witteman
authors.forename: Adriaan C I T L
authors.initials: AC
authors.lastname: Tan
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.forename: Wilbert H M
authors.initials: WH
authors.lastname: Peters
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology; D000368:Aged; D001471:Barrett Esophagus / Q000150:complications / Q000235:genetics*; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005764:Gastroesophageal Reflux / Q000150:complications; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000150:complications; D020641:Polymorphism, Single Nucleotide; D012907:Smoking
chemical_list: C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors
keywords: Barrett's esophagus; FOXF1; MHC; esophageal cancer; genetic polymorphism; rs9257809; rs9936833