Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer
Authors: Kho Pik‐Fang , Amant Frederic , Annibali Daniela , Ashton Katie , Attia John , Auer Paul L. , Beckmann Matthias W. , Black Amanda , Brinton Louise , Buchanan Daniel D. , Chanock Stephen J. , Chen Chu , Chen Maxine M. , Cheng Timothy H. T. , Cook Linda S. , Crous‐Bous Marta , Czene Kamila , De Vivo Immaculata , Dennis Joe , Dörk Thilo , Dowdy Sean C. , Dunning Alison M. , Dürst Matthias , Easton Douglas F. , Ekici Arif B. , Fasching Peter A. , Fridley Brooke L. , Friedenreich Christine M. , García‐Closas Montserrat , Gaudet Mia M. , Giles Graham G. , Goode Ellen L. , Gorman Maggie , Haiman Christopher A. , Hall Per , Hankinson Susan E. , Hein Alexander , Hillemanns Peter , Hodgson Shirley , Hoivik Erling A. , Holliday Elizabeth G. , Hunter David J. , Jones Angela , Kraft Peter , Krakstad Camilla , Lambrechts Diether , Le Marchand Loic , Liang Xiaolin , Lindblom Annika , Lissowska Jolanta , Long Jirong , Lu Lingeng , Magliocco Anthony M. , Martin Lynn , McEvoy Mark , Milne Roger L. , Mints Miriam , Nassir Rami , Otton Geoffrey , Palles Claire , Pooler Loreall , Proietto Tony , Rebbeck Timothy R. , Renner Stefan P. , Risch Harvey A. , Rübner Matthias , Runnebaum Ingo , Sacerdote Carlotta , Sarto Gloria E. , Schumacher Fredrick , Scott Rodney J. , Setiawan V. Wendy , Shah Mitul , Sheng Xin , Shu Xiao‐Ou , Southey Melissa C. , Tham Emma , Tomlinson Ian , Trovik Jone , Turman Constance , Tyrer Jonathan P. , Van Den Berg David , Wang Zhaoming , Wentzensen Nicolas , Xia Lucy , Xiang Yong‐Bing , Yang Hannah P. , Yu Herbert , Zheng Wei , Webb Penelope M. , Thompson Deborah J. , Spurdle Amanda B. , Glubb Dylan M. , O'Mara Tracy A. 
Published: July 2020

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.