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

Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium, Jonathan B. Ashman, Ernest P. Bouras, Stephen D. Cassivi, Michael D. Crowell, Piet De Groen, Charles Erlichman, Tom R. Fitch, David E. Fleischer, Amy E. Foxx-Orenstein, Kevin C. Halling, Lesley A. Houghton, Andrew P. Keaveny, G. Richard Locke, James A. Martenson

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numberdju252
JournalJournal of the National Cancer Institute
Volume106
Issue number11
DOIs
StatePublished - Nov 1 2014

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Barrett Esophagus
Random Allocation
Body Mass Index
Obesity
Adenocarcinoma
Odds Ratio
Confidence Intervals
Propensity Score
Population Control
Metaplasia
Genetic Predisposition to Disease
Gastroesophageal Reflux
Observational Studies
Adenocarcinoma Of Esophagus
Smoking
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium, Ashman, J. B., Bouras, E. P., Cassivi, S. D., Crowell, M. D., De Groen, P., ... Martenson, J. A. (2014). Obesity and risk of esophageal adenocarcinoma and barrett's esophagus: A mendelian randomization study. Journal of the National Cancer Institute, 106(11), [dju252]. https://doi.org/10.1093/jnci/dju252

Obesity and risk of esophageal adenocarcinoma and barrett's esophagus : A mendelian randomization study. / Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium; Ashman, Jonathan B.; Bouras, Ernest P.; Cassivi, Stephen D.; Crowell, Michael D.; De Groen, Piet; Erlichman, Charles; Fitch, Tom R.; Fleischer, David E.; Foxx-Orenstein, Amy E.; Halling, Kevin C.; Houghton, Lesley A.; Keaveny, Andrew P.; Locke, G. Richard; Martenson, James A.

In: Journal of the National Cancer Institute, Vol. 106, No. 11, dju252, 01.11.2014.

Research output: Contribution to journalArticle

Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium, Ashman, JB, Bouras, EP, Cassivi, SD, Crowell, MD, De Groen, P, Erlichman, C, Fitch, TR, Fleischer, DE, Foxx-Orenstein, AE, Halling, KC, Houghton, LA, Keaveny, AP, Locke, GR & Martenson, JA 2014, 'Obesity and risk of esophageal adenocarcinoma and barrett's esophagus: A mendelian randomization study', Journal of the National Cancer Institute, vol. 106, no. 11, dju252. https://doi.org/10.1093/jnci/dju252
Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium, Ashman JB, Bouras EP, Cassivi SD, Crowell MD, De Groen P et al. Obesity and risk of esophageal adenocarcinoma and barrett's esophagus: A mendelian randomization study. Journal of the National Cancer Institute. 2014 Nov 1;106(11). dju252. https://doi.org/10.1093/jnci/dju252
Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium ; Ashman, Jonathan B. ; Bouras, Ernest P. ; Cassivi, Stephen D. ; Crowell, Michael D. ; De Groen, Piet ; Erlichman, Charles ; Fitch, Tom R. ; Fleischer, David E. ; Foxx-Orenstein, Amy E. ; Halling, Kevin C. ; Houghton, Lesley A. ; Keaveny, Andrew P. ; Locke, G. Richard ; Martenson, James A. / Obesity and risk of esophageal adenocarcinoma and barrett's esophagus : A mendelian randomization study. In: Journal of the National Cancer Institute. 2014 ; Vol. 106, No. 11.
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abstract = "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.",
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T1 - Obesity and risk of esophageal adenocarcinoma and barrett's esophagus

T2 - A mendelian randomization study

AU - Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium

AU - Ashman, Jonathan B.

AU - Shaheen, Nicholas J.

AU - Bouras, Ernest P.

AU - Bernstein, Leslie

AU - Reid, Brian J.

AU - Cassivi, Stephen D.

AU - Crowell, Michael D.

AU - Boardman, Lisa Allyn

AU - Buttar, Navtej Singh

AU - De Groen, Piet

AU - Cunningham, Julie M

AU - De Andrade, Mariza

AU - Erlichman, Charles

AU - DiBaise, John D

AU - Fitch, Tom R.

AU - Fleischer, David E.

AU - Foxx-Orenstein, Amy E.

AU - Grothey, Axel F

AU - Harnois, Denise

AU - Hobday, Timothy James

AU - Halling, Kevin C.

AU - Jatoi, Aminah

AU - Jenkins, Robert Brian

AU - Houghton, Lesley A.

AU - Limburg, Paul John

AU - Mc Williams, Robert R

AU - Murray, Joseph A

AU - Nguyen, Cuong C

AU - Pannala, Rahul

AU - Keaveny, Andrew P.

AU - Parker, Alexander

AU - Pasha, Shabana F

AU - Locke, G. Richard

AU - Martenson, James A.

AU - Pitot, Henry Clement

AU - Raimondo, Massimo

AU - Ramirez, Francisco C

AU - Ross, Helen J

AU - Schaid, Daniel J

AU - Shi, Qian D

AU - Sinicrope, Frank A

AU - Sloan, Jeff A

AU - Smith, David I

AU - Thibodeau, Stephen N

AU - Wallace, Michael B

AU - Wang, Kenneth Ke Ning

AU - Weinshilboum, Richard M

AU - Wigle, Dennis A

AU - Wu, Tsung-Teh

AU - Yoon, Harry H

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

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DO - 10.1093/jnci/dju252

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JO - Journal of the National Cancer Institute

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