Obesity and risk of esophageal adenocarcinoma and barrett's esophagus

A mendelian randomization study

Aaron P. Thrift, Nicholas J. Shaheen, Marilie D. Gammon, Leslie Bernstein, Brian J. Reid, Lynn Onstad, Harvey A. Risch, Geoffrey Liu, Nigel C. Bird, Anna H. Wu, Douglas A. Corley, Yvonne Romero, Stephen J. Chanock, Wong Ho Chow, Alan G. Casson, David M. Levine, Rui Zhang, Weronica E. Ek, Stuart MacGregor, Weimin Ye & 31 others Laura J. Hardie, Thomas L. Vaughan, David C. Whiteman, Sami R. Achem, David A. Ahlquist, Steven R. Alberts, Jeffrey A. Alexander, Mark S. Allen, Amindra S. Arora, Jonathan B. Ashman, Pamela J. Atherton, Lisa A. Boardman, Ernest P. Bouras, Vicki A. Bryhn, Patrick A. Burch, George E. Burdick, Navtej S. Buttar, John K. Camoriano, John R. Cangemi, Stephen D. Cassivi, Frances K. Cayer, Amy C. Clayton, Michael D. Crowell, Julie M. Cunningham, Mariza De Andrade, Piet De Groen, Giovani De Petris, Claude Deschamps, Kenneth R. DeVault, Robert B. Diasio, Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

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

Thrift, A. P., Shaheen, N. J., Gammon, M. D., Bernstein, L., Reid, B. J., Onstad, L., ... Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium (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. / Thrift, Aaron P.; Shaheen, Nicholas J.; Gammon, Marilie D.; Bernstein, Leslie; Reid, Brian J.; Onstad, Lynn; Risch, Harvey A.; Liu, Geoffrey; Bird, Nigel C.; Wu, Anna H.; Corley, Douglas A.; Romero, Yvonne; Chanock, Stephen J.; Chow, Wong Ho; Casson, Alan G.; Levine, David M.; Zhang, Rui; Ek, Weronica E.; MacGregor, Stuart; Ye, Weimin; Hardie, Laura J.; Vaughan, Thomas L.; Whiteman, David C.; Achem, Sami R.; Ahlquist, David A.; Alberts, Steven R.; Alexander, Jeffrey A.; Allen, Mark S.; Arora, Amindra S.; Ashman, Jonathan B.; Atherton, Pamela J.; Boardman, Lisa A.; Bouras, Ernest P.; Bryhn, Vicki A.; Burch, Patrick A.; Burdick, George E.; Buttar, Navtej S.; Camoriano, John K.; Cangemi, John R.; Cassivi, Stephen D.; Cayer, Frances K.; Clayton, Amy C.; Crowell, Michael D.; Cunningham, Julie M.; De Andrade, Mariza; De Groen, Piet; De Petris, Giovani; Deschamps, Claude; DeVault, Kenneth R.; Diasio, Robert B.; Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium.

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

Research output: Contribution to journalArticle

Thrift, AP, Shaheen, NJ, Gammon, MD, Bernstein, L, Reid, BJ, Onstad, L, Risch, HA, Liu, G, Bird, NC, Wu, AH, Corley, DA, Romero, Y, Chanock, SJ, Chow, WH, Casson, AG, Levine, DM, Zhang, R, Ek, WE, MacGregor, S, Ye, W, Hardie, LJ, Vaughan, TL, Whiteman, DC, Achem, SR, Ahlquist, DA, Alberts, SR, Alexander, JA, Allen, MS, Arora, AS, Ashman, JB, Atherton, PJ, Boardman, LA, Bouras, EP, Bryhn, VA, Burch, PA, Burdick, GE, Buttar, NS, Camoriano, JK, Cangemi, JR, Cassivi, SD, Cayer, FK, Clayton, AC, Crowell, MD, Cunningham, JM, De Andrade, M, De Groen, P, De Petris, G, Deschamps, C, DeVault, KR, Diasio, RB & Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium 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
Thrift, Aaron P. ; Shaheen, Nicholas J. ; Gammon, Marilie D. ; Bernstein, Leslie ; Reid, Brian J. ; Onstad, Lynn ; Risch, Harvey A. ; Liu, Geoffrey ; Bird, Nigel C. ; Wu, Anna H. ; Corley, Douglas A. ; Romero, Yvonne ; Chanock, Stephen J. ; Chow, Wong Ho ; Casson, Alan G. ; Levine, David M. ; Zhang, Rui ; Ek, Weronica E. ; MacGregor, Stuart ; Ye, Weimin ; Hardie, Laura J. ; Vaughan, Thomas L. ; Whiteman, David C. ; Achem, Sami R. ; Ahlquist, David A. ; Alberts, Steven R. ; Alexander, Jeffrey A. ; Allen, Mark S. ; Arora, Amindra S. ; Ashman, Jonathan B. ; Atherton, Pamela J. ; Boardman, Lisa A. ; Bouras, Ernest P. ; Bryhn, Vicki A. ; Burch, Patrick A. ; Burdick, George E. ; Buttar, Navtej S. ; Camoriano, John K. ; Cangemi, John R. ; Cassivi, Stephen D. ; Cayer, Frances K. ; Clayton, Amy C. ; Crowell, Michael D. ; Cunningham, Julie M. ; De Andrade, Mariza ; De Groen, Piet ; De Petris, Giovani ; Deschamps, Claude ; DeVault, Kenneth R. ; Diasio, Robert B. ; Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium. / 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.
@article{f239936d73dd4262b44a97de477d6b4c,
title = "Obesity and risk of esophageal adenocarcinoma and barrett's esophagus: A mendelian randomization study",
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.",
author = "Thrift, {Aaron P.} and Shaheen, {Nicholas J.} and Gammon, {Marilie D.} and Leslie Bernstein and Reid, {Brian J.} and Lynn Onstad and Risch, {Harvey A.} and Geoffrey Liu and Bird, {Nigel C.} and Wu, {Anna H.} and Corley, {Douglas A.} and Yvonne Romero and Chanock, {Stephen J.} and Chow, {Wong Ho} and Casson, {Alan G.} and Levine, {David M.} and Rui Zhang and Ek, {Weronica E.} and Stuart MacGregor and Weimin Ye and Hardie, {Laura J.} and Vaughan, {Thomas L.} and Whiteman, {David C.} and Achem, {Sami R.} and Ahlquist, {David A.} and Alberts, {Steven R.} and Alexander, {Jeffrey A.} and Allen, {Mark S.} and Arora, {Amindra S.} and Ashman, {Jonathan B.} and Atherton, {Pamela J.} and Boardman, {Lisa A.} and Bouras, {Ernest P.} and Bryhn, {Vicki A.} and Burch, {Patrick A.} and Burdick, {George E.} and Buttar, {Navtej S.} and Camoriano, {John K.} and Cangemi, {John R.} and Cassivi, {Stephen D.} and Cayer, {Frances K.} and Clayton, {Amy C.} and Crowell, {Michael D.} and Cunningham, {Julie M.} and {De Andrade}, Mariza and {De Groen}, Piet and {De Petris}, Giovani and Claude Deschamps and DeVault, {Kenneth R.} and Diasio, {Robert B.} and {Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium}",
year = "2014",
month = "11",
day = "1",
doi = "10.1093/jnci/dju252",
language = "English (US)",
volume = "106",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Obesity and risk of esophageal adenocarcinoma and barrett's esophagus

T2 - A mendelian randomization study

AU - Thrift, Aaron P.

AU - Shaheen, Nicholas J.

AU - Gammon, Marilie D.

AU - Bernstein, Leslie

AU - Reid, Brian J.

AU - Onstad, Lynn

AU - Risch, Harvey A.

AU - Liu, Geoffrey

AU - Bird, Nigel C.

AU - Wu, Anna H.

AU - Corley, Douglas A.

AU - Romero, Yvonne

AU - Chanock, Stephen J.

AU - Chow, Wong Ho

AU - Casson, Alan G.

AU - Levine, David M.

AU - Zhang, Rui

AU - Ek, Weronica E.

AU - MacGregor, Stuart

AU - Ye, Weimin

AU - Hardie, Laura J.

AU - Vaughan, Thomas L.

AU - Whiteman, David C.

AU - Achem, Sami R.

AU - Ahlquist, David A.

AU - Alberts, Steven R.

AU - Alexander, Jeffrey A.

AU - Allen, Mark S.

AU - Arora, Amindra S.

AU - Ashman, Jonathan B.

AU - Atherton, Pamela J.

AU - Boardman, Lisa A.

AU - Bouras, Ernest P.

AU - Bryhn, Vicki A.

AU - Burch, Patrick A.

AU - Burdick, George E.

AU - Buttar, Navtej S.

AU - Camoriano, John K.

AU - Cangemi, John R.

AU - Cassivi, Stephen D.

AU - Cayer, Frances K.

AU - Clayton, Amy C.

AU - Crowell, Michael D.

AU - Cunningham, Julie M.

AU - De Andrade, Mariza

AU - De Groen, Piet

AU - De Petris, Giovani

AU - Deschamps, Claude

AU - DeVault, Kenneth R.

AU - Diasio, Robert B.

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84986910367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84986910367&partnerID=8YFLogxK

U2 - 10.1093/jnci/dju252

DO - 10.1093/jnci/dju252

M3 - Article

VL - 106

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 11

M1 - dju252

ER -