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Cancer Epidemiol Biomarkers Prev. 2015 Nov;24(11):1739-47. doi: 10.1158/1055-9965.EPI-15-0507. Epub 2015 Sep 16.

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

Author information

1
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington. jdai@fredhutch.org tvaughan@u.washington.edu.
2
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
3
Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington.
4
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
5
Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.
6
Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.
7
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
8
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Division of Cancer Studies, King's College London, London, United Kingdom.
9
Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom.
10
Division of Research, Kaiser Permanente Northern California, Oakland, California. San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.
11
Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
12
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
13
Division of Epidemiology, University of Leeds, Leeds, United Kingdom.
14
Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
15
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington. jdai@fredhutch.org tvaughan@u.washington.edu.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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 rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) 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.

CONCLUSION:

Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1.

IMPACT:

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

PMID:
26377193
PMCID:
PMC4816532
DOI:
10.1158/1055-9965.EPI-15-0507
[Indexed for MEDLINE]
Free PMC Article

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