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

Pik Fang Kho, Frederic Amant, Daniela Annibali, Katie Ashton, John Attia, Paul L. Auer, Matthias W. Beckmann, Amanda Black, Louise Brinton, Daniel D. Buchanan, Stephen J. Chanock, Chu Chen, Maxine M. Chen, Timothy H.T. Cheng, Linda S. Cook, Marta Crous-Bous, Kamila Czene, Immaculata De Vivo, Joe Dennis, Thilo DörkSean C. Dowdy, Alison M. Dunning, Matthias Dürst, Douglas F. Easton, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Christine M. Friedenreich, Montserrat García-Closas, Mia M. Gaudet, Graham G. Giles, Ellen L. Goode, Maggie Gorman, Christopher A. Haiman, Per Hall, Susan E. Hankinson, Alexander Hein, Peter Hillemanns, Shirley Hodgson, Erling A. Hoivik, Elizabeth G. Holliday, David J. Hunter, Angela Jones, Peter Kraft, Camilla Krakstad, Diether Lambrechts, Loic Le Marchand, Xiaolin Liang, Annika Lindblom, Jolanta Lissowska, Jirong Long, Lingeng Lu, Anthony M. Magliocco, Lynn Martin, Mark McEvoy, Roger L. Milne, Miriam Mints, Rami Nassir, Geoffrey Otton, Claire Palles, Loreall Pooler, Tony Proietto, Timothy R. Rebbeck, Stefan P. Renner, Harvey A. Risch, Matthias Rübner, Ingo Runnebaum, Carlotta Sacerdote, Gloria E. Sarto, Fredrick Schumacher, Rodney J. Scott, V. Wendy Setiawan, Mitul Shah, Xin Sheng, Xiao Ou Shu, Melissa C. Southey, Emma Tham, Ian Tomlinson, Jone Trovik, Constance Turman, Jonathan P. Tyrer, David Van Den Berg, Zhaoming Wang, Nicolas Wentzensen, Lucy Xia, Yong Bing Xiang, Hannah P. Yang, Herbert Yu, Wei Zheng, Penelope M. Webb, Deborah J. Thompson, Amanda B. Spurdle, Dylan M. Glubb, Tracy A. O'Mara

Research output: Contribution to journalArticle

1 Scopus citations

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.

Original languageEnglish (US)
JournalInternational Journal of Cancer
DOIs
StateAccepted/In press - 2020

Keywords

  • HDL cholesterol
  • LDL cholesterol
  • Mendelian randomization
  • endometrial cancer risk
  • triglycerides

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kho, P. F., Amant, F., Annibali, D., Ashton, K., Attia, J., Auer, P. L., Beckmann, M. W., Black, A., Brinton, L., Buchanan, D. D., Chanock, S. J., Chen, C., Chen, M. M., Cheng, T. H. T., Cook, L. S., Crous-Bous, M., Czene, K., De Vivo, I., Dennis, J., ... O'Mara, T. A. (Accepted/In press). 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