Title

Obesity and risk of esophageal adenocarcinoma and barrett's esophagus: A mendelian randomization study

Authors

Aaron P. Thrift, Fred Hutchinson Cancer Research Center
Nicholas J. Shaheen, UNC School of Medicine
Marilie D. Gammon, The University of North Carolina at Chapel Hill
Leslie Bernstein, City of Hope National Med Center
Brian J. Reid, Fred Hutchinson Cancer Research Center
Lynn Onstad, Fred Hutchinson Cancer Research Center
Harvey A. Risch, Yale University
Geoffrey Liu, University of Toronto
Nigel C. Bird, The Sheffield Medical School
Anna H. Wu, Keck School of Medicine of USC
Douglas A. Corley, Kaiser Permanente Division of Research
Yvonne Romero, Mayo Clinic
Stephen J. Chanock, National Cancer Institute (NCI)
Wong Ho Chow, University of Texas MD Anderson Cancer Center
Alan G. Casson, University of Saskatchewan, College of Medicine
David M. Levine, University of Washington, Seattle
Rui Zhang, University of Washington, Seattle
Weronica E. Ek, QIMR Berghofer Medical Research Institute
Stuart MacGregor, QIMR Berghofer Medical Research Institute
Weimin Ye, Karolinska Institutet
Laura J. Hardie, University of Leeds
Thomas L. Vaughan, Fred Hutchinson Cancer Research Center
David C. Whiteman, QIMR Berghofer Medical Research Institute
Sami R. Achem, Mayo Clinic
David A. Ahlquist, Mayo Clinic in Rochester, Minnesota
Steven R. Alberts, Mayo Clinic in Rochester, Minnesota
Jeffrey A. Alexander, Mayo Clinic in Rochester, Minnesota
Mark S. Allen, Mayo Clinic in Rochester, Minnesota
Amindra S. Arora, Mayo Clinic in Rochester, Minnesota
Jonathan B. Ashman, Mayo Clinic
Pamela J. Atherton, Mayo Clinic in Rochester, Minnesota
Lisa A. Boardman, Mayo Clinic in Rochester, Minnesota

Document Type

Journal Article

Publication Date

11-1-2014

Journal

Journal of the National Cancer Institute

Volume

106

Issue

11

DOI

10.1093/jnci/dju252

Abstract

© The Author 2014. Background Data from observational studies suggest that body mass index (BMI) is causally related to esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE). However, the relationships may be affected by bias and confounding. Methods We used data from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study: 999 patients with EAC, 2061 patients with BE, and 2169 population controls. We applied the two-stage control function instrumental variable method of the Mendelian randomization approach to estimate the unbiased, unconfounded effect of BMI on risk of EAC and BE. This was performed using a genetic risk score, derived from 29 genetic variants shown to be associated with BMI, as an instrument for lifetime BMI. A higher score indicates propensity to obesity. All tests were two-sided. Results The genetic risk score was not associated with potential confounders, including gastroesophageal reflux symptoms and smoking. In the instrumental variable analyses (IV), EAC risk increased by 16% (IV-odds ratio [OR] = 1.16, 95% confidence interval [CI] = 1.01 to 1.33) and BE risk increased by 12% (IV-OR = 1.12, 95% CI = 1.00 to 1.25) per 1 kg/m2 increase in BMI. BMI was statistically significantly associated with EAC and BE in conventional epidemiologic analyses. Conclusions People with a high genetic propensity to obesity have higher risks of esophageal metaplasia and neoplasia than people with low genetic propensity. These analyses provide the strongest evidence to date that obesity is independently associated with BE and EAC, and is not due to confounding or bias inherent in conventional epidemiologic analyses.

Share

COinS