Cancer Epidemiology Biomarkers and Prevention. 2015 Sep 16. pii: cebp.0507.2015. [Epub ahead of print]

A newly identified susceptibility locus near FOXP1 modifies the association of gastroesophageal reflux with Barrett’s esophagus.

Dai JY, Tapsoba JD, Buas MF, Onstad LE, Levine DM, Risch HA, Chow JW, Bernstein L, Ye W, Lagergren J, Bird NC, Corley DA, Shaheen NJ, Wu AH, Reid BJ, Hardie LJ, Whiteman DC, Vaughan TL.


BACKGROUND: Important risk factors for esophageal adenocarcinoma (EA) and its precursor, Barrett’s esophagus (BE) include gastroesophageal reflux disease, obesity, and cigarette-smoking. Recently, genome-wide association studies have identified seven germline single nucleotide polymorphisms (SNPs) that are associated with risk of BE and EA. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear.

METHODS: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1516 EA case patients, 2416 BE case patients, and 2187 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 odds ratios for these risk factors stratified by SNP genotype, separately for BE and EA.

RESULTS: The odds ratio for BE associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal p-value=0.0005, false discovery rate=0.042). Odds ratios (95% confidence intervals) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 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.fig2

CONCLUSIONS: Reflux symptoms are more strongly associated with BE risk among persons homozygous for the major allele of rs2687201, which lies ~75 kb downstream of the transcription factor gene FOXP1.

IMPACT: The novel gene-exposure interaction discovered in this study provides new insights to the etiology of esophageal adenocarcinoma.

Copyright © 2015, American Association for Cancer Research.