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 MW, Black A, Brinton L, Buchanan DD, Chanock SJ, Chen C, Chen MM, Cheng THT, 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 PA, 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 SP, 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
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.