Obesity and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: A Mendelian Randomization Study

• Published in: JNCI : Journal of the National Cancer Institute Vol. 106; no. 11; p. 1
• Main Authors: THRIFT, Aaron P, SHAHEEN, Nicholas J, CORLEY, Douglas A, ROMERO, Yvonne, CHANOCK, Stephen J, CHOW, Wong-Ho, CASSON, Alan G, LEVINE, David M, RUI ZHANG, EK, Weronica E, MACGREGOR, Stuart, WEIMIN YE, GAMMON, Marilie D, HARDIE, Laura J, VAUGHAN, Thomas L, WHITEMAN, David C, BERNSTEIN, Leslie, REID, Brian J, ONSTAD, Lynn, RISCH, Harvey A, LIU, Geoffrey, BIRD, Nigel C, WU, Anna H
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 01.11.2014; Oxford Publishing Limited (England)
• Subjects: Adenocarcinoma - epidemiology; Adenocarcinoma - genetics; Adult; Aged; Barrett Esophagus - complications; Barrett Esophagus - epidemiology; Barrett Esophagus - genetics; Biological and medical sciences; Body Mass Index; Confidence intervals; Esophageal cancer; Esophageal Neoplasms - epidemiology; Esophageal Neoplasms - genetics; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Genetic Predisposition to Disease; Genetics; Genome-Wide Association Study; Humans; Male; Medical sciences; Medicin och hälsovetenskap; Mendelian Randomization Analysis; Metabolic diseases; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Obesity; Obesity - complications; Obesity - epidemiology; Obesity - genetics; Polymorphism, Single Nucleotide; Precancerous Conditions - epidemiology; Precancerous Conditions - genetics; Predictive Value of Tests; Risk Assessment; Risk Factors; Tumors; Obesity; Premalignant lesion; Esophageal disease; Nutrition disorder; Risk; Malignant tumor; Esophagus cancer; Randomization; Cancerology; Risk factor; Barrett's esophagus; Digestive diseases; Esophagus adenocarcinoma; Nutritional status; Cancer
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/dju252

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. 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. 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. 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.