Association Between Levels of Sex Hormones and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Shao-Hua Xie, Rui Fang, Mingtao Huang, Juncheng dai, Aaron Thrift, Lesley Anderson, Wong-Ho Chow, Leslie Bernstein, Marilie D Gammon, Harvey A Risch, Nicholas J Shaheen, Brian J Reid, Anna H Wu, Prasad G Iyer, Geoffrey Liu, Douglas A Corley, David C Whiteman, Carlos Caldas, Paul Pharoah, Laura J HardieRebecca C. Fitzgerald, Hongbing Shen, Thomas L Vaughan, Jesper Lagergren

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Background & Aims Esophageal adenocarcinoma (EAC) occurs most frequently in men. We performed a Mendelian randomization analysis to investigate whether genetic factors that regulate levels of sex hormones are associated with risk of EAC or Barrett’s esophagus (BE). Methods We conducted a Mendelian randomization analysis using data from patients with EAC (n = 2488) or BE (n = 3247) and control participants (n = 2127), included in international consortia of genome-wide association studies in Australia, Europe, and North America. Genetic risk scores or single-nucleotide variants were used as instrumental variables for 9 specific sex hormones. Logistic regression provided odds ratios (ORs) with 95% CIs. Results Higher genetically predicted levels of follicle-stimulating hormones were associated with increased risks of EAC and/or BE in men (OR, 1.14 per allele increase; 95% CI, 1.01–1.27) and in women (OR, 1.28; 95% CI, 1.03–1.59). Higher predicted levels of luteinizing hormone were associated with a decreased risk of EAC in men (OR, 0.92 per SD increase; 95% CI, 0.87–0.99) and in women (OR, 0.93; 95% CI, 0.79–1.09), and decreased risks of BE (OR, 0.88; 95% CI, 0.77–0.99) and EAC and/or BE (OR, 0.89; 95% CI, 0.79–1.00) in women. We found no clear associations for other hormones studied, including sex hormone–binding globulin, dehydroepiandrosterone sulfate, testosterone, dihydrotestosterone, estradiol, progesterone, or free androgen index. Conclusions In a Mendelian randomization analysis of data from patients with EAC or BE, we found an association between genetically predicted levels of follicle-stimulating and luteinizing hormones and risk of BE and EAC.

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