Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

Kho PF, Amant F, Annibali D, Ashton K, Attia J, Auer PL, Beckmann M, Black A, Brinton L, Buchanan DD, Chanock SJ, Chen C, Chen MM, Cheng TH, Cook LS, Crous-Bous M, Czene K, De Vivo I, Dennis J, Dörk T, Dowdy SC, Dunning AM, Dürst M, Easton DF, Ekici AB, Fasching P, Fridley BL, Friedenreich CM, García-Closas M, Gaudet MM, Giles GG, Goode EL, Gorman M, Haiman CA, Hall P, Hankinson SE, Hein A, Hillemanns P, Hodgson S, Hoivik EA, Holliday EG, Hunter DJ, Jones A, Kraft P, Krakstad C, Lambrechts D, Le Marchand L, Liang X, Lindblom A, Lissowska J, Long J, Lu L, Magliocco AM, Martin L, McEvoy M, Milne RL, Mints M, Nassir R, Otton G, Palles C, Pooler L, Proietto T, Rebbeck TR, Renner S, Risch HA, Rübner M, Runnebaum I, Sacerdote C, Sarto GE, Schumacher F, Scott RJ, Setiawan VW, Shah M, Sheng X, Shu XO, Southey MC, Tham E, Tomlinson I, Trovik J, Turman C, Tyrer JP, Van Den Berg D, Wang Z, Wentzensen N, Xia L, Xiang YB, Yang HP, Yu H, Zheng W, Webb PM, Thompson DJ, Spurdle AB, Glubb DM, O'Mara TA (2020)

Publication Type: Journal article

Publication year: 2020

Journal

DOI: 10.1002/ijc.33206

Abstract

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.

Authors with CRIS profile

Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) The University of Melbourne Australia (AU) University of Kansas Medical Center United States (USA) (US) Alberta Health Services (AHS) Canada (CA) National Cancer Institute (NCI) United States (USA) (US) American Cancer Society United States (USA) (US) Melbourne School of Population and Global Health Australia (AU) Mayo Clinic United States (USA) (US) Wellcome Centre for Human Genetics United Kingdom (GB) Keck School of Medicine of USC United States (USA) (US) Karolinska Institute Sweden (SE) Brigham and Women's Hospital (BWH) United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB) University of Bergen / Universitetet i Bergen Norway (NO) John Hunter Hospital Australia (AU) Harvard T.H. Chan School of Public Health United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) University of Hawaiʻi at Mānoa United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Vanderbilt University Medical Center United States (USA) (US) Yale School of Medicine United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) University of Birmingham United Kingdom (GB) University of Newcastle (UoN) Australia (AU) Fred Hutchinson Cancer Research Center United States (USA) (US) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) University of Cambridge United Kingdom (GB) Friedrich-Schiller-Universität Jena Germany (DE) University of California Davis (UCDAVIS) United States (USA) (US) Reference Centre for Epidemiology and Cancer Prevention in Piemonte (CPO Piemonte) / Centro di Riferimento per l'Epidemiologia e la Prevenzione Oncologica in Piemonte Italy (IT) University of Wisconsin - Madison United States (USA) (US) Case Western Reserve University United States (USA) (US) Shanghai Jiao Tong University / 上海交通大学 China (CN)

How to cite

APA:

Kho, P.F., Amant, F., Annibali, D., Ashton, K., Attia, J., Auer, P.L.,... O'Mara, T.A. (2020). Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer. International Journal of Cancer. https://doi.org/10.1002/ijc.33206

MLA:

Kho, Pik Fang, et al. "Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer." International Journal of Cancer (2020).

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