Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals KU Leuven, University of Leuven, Leuven, Belgium.
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia.
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
- Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
- Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
- Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
- Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
- University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, Minnesota, USA.
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
- Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
- Department of Biostatistics, Kansas University Medical Center, Kansas City, Kansas, USA.
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, Alberta, Canada.
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
- Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
- Department of Clinical Genetics, St George's, University of London, London, UK.
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway.
- VIB Center for Cancer Biology, Leuven, Belgium.
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
- Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
- Chronic Disease Epidemiology, Yale School of Medicine, New Haven, Connecticut, USA.
- Department of Anatomic Pathology, Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
- Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, USA.
- School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
- Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
- Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
- Center for Cancer Prevention (CPO-Peimonte), Turin, Italy.
- Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
- State Key Laboratory of Oncogene and Related Genes & Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.