Data from A Newly Identified Susceptibility Locus near <i>FOXP1</i> Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

Abstract

<div>Abstract<p><b>Background:</b> Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure–disease associations is unclear.</p><p><b>Methods:</b> We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma.</p><p><b>Results:</b> The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of <i>rs2687201</i> (nominal <i>P</i> = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of <i>rs2687201</i> were 6.17 (4.91–7.56), 3.56 (2.85–4.44), and 3.97 (2.47–6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index.</p><p><b>Conclusion:</b> Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of <i>rs2687201</i>, which lies approximately 75 kb downstream of the transcription factor gene <i>FOXP1</i>.</p><p><b>Impact:</b> The novel gene–exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma. <i>Cancer Epidemiol Biomarkers Prev; 24(11); 1739–47. ©2015 AACR</i>.</p></div>