Aaron P Thrift1, Nicholas J Shaheen2, Marilie D Gammon2, Leslie Bernstein2, Brian J Reid2, Lynn Onstad2, Harvey A Risch2, Geoffrey Liu2, Nigel C Bird2, Anna H Wu2, Douglas A Corley2, Yvonne Romero2, Stephen J Chanock2, Wong-Ho Chow2, Alan G Casson2, David M Levine2, Rui Zhang2, Weronica E Ek2, Stuart MacGregor2, Weimin Ye2, Laura J Hardie2, Thomas L Vaughan2, David C Whiteman2. 1. Division of Public Health Sciences (APT, LO, TLV) and Division of Human Biology (BJR), Fred Hutchinson Cancer Research Center, Seattle, WA; Cancer Control Group (APT, DCW) and Statistical Genetics (WEE, SM), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Division of Gastroenterology and Hepatology, UNC School of Medicine (NJS) and Department of Epidemiology, School of Public Health (MDG), University of North Carolina, Chapel Hill, NC; Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA (LB); Yale School of Public Health, Department of Chronic Disease Epidemiology, New Haven, CT (HAR); Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada (GL); Department of Oncology, The Medical School, University of Sheffield, Sheffield, UK (NCB); Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA (AHW); Division of Research and Oakland Medical Center, Kaiser Permanente, Oakland, CA (DAC); Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN (YR), on behalf of the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (SJC); Department of Epidemiology, MD Anderson Cancer Center, Houston, TX (WHC); Department of Surgery, University of Saskatchewan, Saskatoon SK, Canada (AGC); Department of Biostatistics, University of Washington School of Public Health, Seattle, WA (DML, RZ); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (WY); Division of Epidemiology, University of Leeds, Leeds, UK (LJH). athrift@fhcrc.org. 2. Division of Public Health Sciences (APT, LO, TLV) and Division of Human Biology (BJR), Fred Hutchinson Cancer Research Center, Seattle, WA; Cancer Control Group (APT, DCW) and Statistical Genetics (WEE, SM), QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Division of Gastroenterology and Hepatology, UNC School of Medicine (NJS) and Department of Epidemiology, School of Public Health (MDG), University of North Carolina, Chapel Hill, NC; Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, CA (LB); Yale School of Public Health, Department of Chronic Disease Epidemiology, New Haven, CT (HAR); Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada (GL); Department of Oncology, The Medical School, University of Sheffield, Sheffield, UK (NCB); Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA (AHW); Division of Research and Oakland Medical Center, Kaiser Permanente, Oakland, CA (DAC); Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN (YR), on behalf of the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry Consortium; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (SJC); Department of Epidemiology, MD Anderson Cancer Center, Houston, TX (WHC); Department of Surgery, University of Saskatchewan, Saskatoon SK, Canada (AGC); Department of Biostatistics, University of Washington School of Public Health, Seattle, WA (DML, RZ); Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden (WY); Division of Epidemiology, University of Leeds, Leeds, UK (LJH).
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 1kg/m(2) 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.
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 1kg/m(2) 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.
Authors: Z F Zhang; R C Kurtz; M Sun; M Karpeh; G P Yu; N Gargon; J S Fein; S K Georgopoulos; S Harlap Journal: Cancer Epidemiol Biomarkers Prev Date: 1996-10 Impact factor: 4.254
Authors: Elfriede Bollschweiler; Eva Wolfgarten; Thomas Nowroth; Ursula Rosendahl; Stefan P Mönig; Arnulf H Hölscher Journal: J Cancer Res Clin Oncol Date: 2002-09-24 Impact factor: 4.553
Authors: Jing Dong; Puya Gharahkhani; Wong-Ho Chow; Marilie D Gammon; Geoffrey Liu; Carlos Caldas; Anna H Wu; Weimin Ye; Lynn Onstad; Lesley A Anderson; Leslie Bernstein; Paul D Pharoah; Harvey A Risch; Douglas A Corley; Rebecca C Fitzgerald; Prasad G Iyer; Brian J Reid; Jesper Lagergren; Nicholas J Shaheen; Thomas L Vaughan; Stuart MacGregor; Sharon Love; Claire Palles; Ian Tomlinson; Ines Gockel; Andrea May; Christian Gerges; Mario Anders; Anne C Böhmer; Jessica Becker; Nicole Kreuser; Rene Thieme; Tania Noder; Marino Venerito; Lothar Veits; Thomas Schmidt; Claudia Schmidt; Jakob R Izbicki; Arnulf H Hölscher; Hauke Lang; Dietmar Lorenz; Brigitte Schumacher; Rupert Mayershofer; Yogesh Vashist; Katja Ott; Michael Vieth; Josef Weismüller; Markus M Nöthen; Susanne Moebus; Michael Knapp; Wilbert H M Peters; Horst Neuhaus; Thomas Rösch; Christian Ell; Janusz Jankowski; Johannes Schumacher; Rachel E Neale; David C Whiteman; Aaron P Thrift Journal: Clin Gastroenterol Hepatol Date: 2019-02-01 Impact factor: 11.382
Authors: Daniela Mariosa; Robert Carreras-Torres; Richard M Martin; Mattias Johansson; Paul Brennan Journal: Int J Epidemiol Date: 2019-06-01 Impact factor: 7.196