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.
Bibliographical noteFunding Information:
This work was primarily funded by National Institutes of Health (R01CA136725). The funders of the study had no role in the design, analysis, or interpretation of the data, nor in writing or publication decisions related to this article.
APT is supported by Travel Fellowships from the European Association for Cancer Research and the University of Queensland and an Early Career Fellowship from the National Health and Medical Research Council of Australia. NJS is supported by a grant (P30 DK034987) from the National Institutes of Health. GL was supported by the Alan B. Brown Chair in Molecular Genomics and by the CCO Chair in Experimental Therapeutics and Population Studies. YR is supported by a grant from the National Institutes of Health (NIDDK 02956), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program, and the Fraternal Order of the Eagles. SM is supported by an Australian National Health and Medical Research Council Career Development Award and the Swedish Ministry of Higher Education. TLV is supported by National Institutes of Health Career Development Award K05CA124911. DCW is supported by a Future Fellowship (FT0990987) from the Australian Research Council.
The Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus (EABE) Registry Consortium is supported in part by the American Digestive Health Foundation “Endoscopic Research Award,” the American College of Gastroenterology “Junior Faculty Development Award,” the Glaxo Wellcome Inc. Institute for Digestive Health “Clinical Research Award,” and the Miles and Shirley Fiterman Center for Digestive Diseases at Mayo Clinic, Rochester, MN. The EABE Registry also has charitable gifts from five industry partners (Affymetrix, AstraZeneca, Santarus, Takeda and Wyeth). Members of the Mayo Clinic Esophageal Adenocarcinoma and Barrett’s Esophagus Registry Consortium (1Mayo Clinic Florida, 2Mayo Clinic Rochester, 3Mayo Clinic Arizona): Sami R.Achem, MD1, Yvonne Romero, MD2, David A. Ahlquist, MD2, Steven R. Alberts,MD2,Jeffrey A. Alexander,MD2,Mark S. Allen,MD2,Amindra S. Arora, MBBChir2, Jonathan B. Ashman, MD, PhD3, Pamela J. Atherton2, Lisa A. Boardman, MD2, Ernest P. Bouras, MD1, Vicki A. Bryhn2, Patrick A. Burch, MD2, George E. Burdick, MD2, Navtej S. Buttar, MD2, John K. Camoriano, MD3, John R. Cangemi, MD1, Stephen D. Cassivi, MD2, Frances K. Cayer1, Amy C. Clayton, MD2, Michael D. Crowell, MD, PhD3, Julie M. Cunningham, PhD2, Mariza de Andrade, PhD2, Piet de Groen, MD2, Giovani De Petris, MD3, Claude Deschamps, MD2, Kenneth R. DeVault, MD1, Robert B. Diasio, MD2, John K. DiBaise, MD3, Eric S. Edell, MD2, Sharon Elcombe2, Charles Erlichman, MD2, Douglas O. Faigel, MD3, Tom R. Fitch, MD3, David E. Fleischer, MD3, Jean C. Fox, MD2, Amy E. Foxx-Orenstein, DO2, Dawn Francis, MD2, Mary B. Fredericksen2, Evanthia Galanis, MD2, Debra M. Geno2, Axel Grothey, MD2, Michael G. Haddock, MD2, Kevin C. Halling, MD, PhD2, Denise M. Harnois, DO1, Tracy W. Hilton1, Timothy Hobday, MD2, Lesley A. Houghton, PhD1, Prasad A. Iyer, MD2, Dawn E. Jaroszewski, MD3, Aminah Jatoi, MD2, Robert B. Jenkins, MD, PhD2, Elizabeth A. Johnson, MD1, Rajni Katipamula, MD2, David A. Katzka, MD2, Sharon F. Kaufman2, Andrew P. Keaveny, MD1, Daniel A. Keller2, George P. Kim, MD1, Benjamin R. Kipp, PhD2, Dora M. Lam-Himlin, MD2, Stephen M. Lange, MD1, Louis Lanza, MD3, Shauna N. Legrand1, Paul J. Limburg, MD2, Wilma L. Lingle, PhD2, Wanguo Liu, PhD2, G. Richard Locke III, MD2, David S. Loeb, MD1, Lori S. Lutzke2, James A. Martenson Jr, MD2 Robert R. McWilliams, MD2, Robert C. Miller, MD2, Joseph A. Murray, MD2, Cuong C. Nguyen, MD3, Francis C. Nichols, III, MD2, John A. Odell, MD1, Rahul Pannala, MD3, Harshita R. Paripati, MD2, Alexander S. Parker, PhD1, Shabana F. Pasha, MD2, Bret T. Petersen, MD2, Gloria M. Petersen, PhD2, Michael F. Picco, MD1, Henry C. Pitot, MD2, J. Fernando Quevedo, MD2, Massimo Raimondo, MD1, Elizabeth Rajan, MD2, Francisco (Pancho) C. Ramirez, MD2, Renee M. Root2, Helen J. Ross, MD3, Joseph Rubin, MD2, Schuyler O. Sanderson, MD2, Daniel J. Sargent, PhD2, Daniel J. Schaid, PhD2, K. Robert Shen, MD2, Qian Shi, PhD2, Frank A. Sinicrope, MD2, Jeff A. Sloan, PhD2, Dan C. Smith, MD1, David I. Smith, PhD2, Thomas C. Smyrk, MD2, Mark E. Stark, MD1, Nicholas Talley, MD, PhD2, Stephen N. Thibodeau, PhD2, Michael D. Van Norstrand, MD, PhD2, Michael B. Wallace, MD1, Kenneth K. Wang, MD2, Richard M. Weinshilboum, MD2, Dennis Wigle, MD, PhD2, Herbert C. Wolfsen, MD1, Louis M. Wong Kee Song, MD2, Timothy A. Woodward, MD1, Tsung-The Wu, MD, PhD2, Harry H. Yoon, MD2, Alan R. Zinsmeister, PhD2.