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Clin Gastroenterol Hepatol. 2018 Oct;16(10):1598-1606.e4. doi: 10.1016/j.cgh.2018.03.007. Epub 2018 Mar 15.

Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus.

Author information

1
Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
2
Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington.
3
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
4
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
5
Medical Research Council Cancer Unit, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, United Kingdom.
6
Division of Research, Kaiser Permanente Northern California, Oakland, California; San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.
7
Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
8
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; School of Cancer Sciences, King's College London, London, United Kingdom.
9
Division of Epidemiology, LICAMM, School of Medicine, University of Leeds, Leeds, United Kingdom.
10
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
11
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
12
Cancer Research UK, Cambridge Institute, Cambridge, United Kingdom; Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
13
Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
14
Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
15
Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Canada.
16
Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
17
Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.
18
Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.
19
Department of Oncology, Medical School, University of Sheffield, Sheffield, United Kingdom.
20
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
21
Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
22
Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom.
23
Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
24
Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
25
Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas; Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Electronic address: aaron.thrift@bcm.edu.

Abstract

BACKGROUND & AIMS:

Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE.

METHODS:

We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions.

RESULTS:

For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively.

CONCLUSION:

The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

KEYWORDS:

Esophageal Neoplasm; Esophagus; Genetic Variants; Risk Factors

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