Shao-Hua Xie1, Rui Fang2, Mingtao Huang2, Juncheng Dai3, Aaron P Thrift4, Lesley A Anderson5, Wong-Ho Chow6, Leslie Bernstein7, Marilie D Gammon8, Harvey A Risch9, Nicholas J Shaheen10, Brian J Reid11, Anna H Wu12, Prasad G Iyer13, Geoffrey Liu14, Douglas A Corley15, David C Whiteman16, Carlos Caldas17, Paul D Pharoah18, Laura J Hardie19, Rebecca C Fitzgerald20, Hongbing Shen3, Thomas L Vaughan11, Jesper Lagergren21. 1. Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: shaohua.xie@ki.se. 2. Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China. 3. Department of Epidemiology and Biostatistics, International Joint Research Center on Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China; Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China. 4. Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas; Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas. 5. Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom. 6. Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas. 7. Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. 8. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina. 9. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut. 10. Division of Gastroenterology and Hepatology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina. 11. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. 12. Department of Preventive Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California. 13. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota. 14. Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada. 15. Division of Research, Kaiser Permanente Northern California, Oakland, California. 16. Cancer Control, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, Queensland, Australia. 17. Cancer Research UK, Cambridge Institute, Cambridge, United Kingdom. 18. Department of Oncology, University of Cambridge, Cambridge, United Kingdom; Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 19. Division of Epidemiology, Leeds Institute of Cardiovascular and Metabolic Medicine, School of Medicine, University of Leeds, Leeds, United Kingdom. 20. Medical Research Council Cancer Unit, Hutchison-Medical Research Council Research Centre, University of Cambridge, Cambridge, United Kingdom. 21. Upper Gastrointestinal Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom.
Abstract
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.
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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