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 Dörk; Sean 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

doi:10.1002/ijc.33206

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 journal › Article › peer-review

2 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 language	English (US)
Pages (from-to)	307-319
Number of pages	13
Journal	International Journal of Cancer
Volume	148
Issue number	2
DOIs	https://doi.org/10.1002/ijc.33206
State	Published - Jan 15 2021

Keywords

HDL cholesterol
LDL cholesterol
Mendelian randomization
endometrial cancer risk
triglycerides

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1002/ijc.33206

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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. (2021). Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer. International Journal of Cancer, 148(2), 307-319. https://doi.org/10.1002/ijc.33206

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 2021, 'Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer', International Journal of Cancer, vol. 148, no. 2, pp. 307-319. https://doi.org/10.1002/ijc.33206

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title = "Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer",

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.",

keywords = "HDL cholesterol, LDL cholesterol, Mendelian randomization, endometrial cancer risk, triglycerides",

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

note = "Publisher Copyright: {\textcopyright} 2020 Union for International Cancer Control",

year = "2021",

month = jan,

day = "15",

doi = "10.1002/ijc.33206",

language = "English (US)",

volume = "148",

pages = "307--319",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

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TY - JOUR

T1 - Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer

AU - Kho, Pik Fang

AU - Amant, Frederic

AU - Annibali, Daniela

AU - Ashton, Katie

AU - Attia, John

AU - Auer, Paul L.

AU - Beckmann, Matthias W.

AU - Black, Amanda

AU - Brinton, Louise

AU - Buchanan, Daniel D.

AU - Chanock, Stephen J.

AU - Chen, Chu

AU - Chen, Maxine M.

AU - Cheng, Timothy H.T.

AU - Cook, Linda S.

AU - Crous-Bous, Marta

AU - Czene, Kamila

AU - De Vivo, Immaculata

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dowdy, Sean C.

AU - Dunning, Alison M.

AU - Dürst, Matthias

AU - Easton, Douglas F.

AU - Ekici, Arif B.

AU - Fasching, Peter A.

AU - Fridley, Brooke L.

AU - Friedenreich, Christine M.

AU - García-Closas, Montserrat

AU - Gaudet, Mia M.

AU - Giles, Graham G.

AU - Goode, Ellen L.

AU - Gorman, Maggie

AU - Haiman, Christopher A.

AU - Hall, Per

AU - Hankinson, Susan E.

AU - Hein, Alexander

AU - Hillemanns, Peter

AU - Hodgson, Shirley

AU - Hoivik, Erling A.

AU - Holliday, Elizabeth G.

AU - Hunter, David J.

AU - Jones, Angela

AU - Kraft, Peter

AU - Krakstad, Camilla

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Liang, Xiaolin

AU - Lindblom, Annika

AU - Lissowska, Jolanta

AU - Long, Jirong

AU - Lu, Lingeng

AU - Magliocco, Anthony M.

AU - Martin, Lynn

AU - McEvoy, Mark

AU - Milne, Roger L.

AU - Mints, Miriam

AU - Nassir, Rami

AU - Otton, Geoffrey

AU - Palles, Claire

AU - Pooler, Loreall

AU - Proietto, Tony

AU - Rebbeck, Timothy R.

AU - Renner, Stefan P.

AU - Risch, Harvey A.

AU - Rübner, Matthias

AU - Runnebaum, Ingo

AU - Sacerdote, Carlotta

AU - Sarto, Gloria E.

AU - Schumacher, Fredrick

AU - Scott, Rodney J.

AU - Setiawan, V. Wendy

AU - Shah, Mitul

AU - Sheng, Xin

AU - Shu, Xiao Ou

AU - Southey, Melissa C.

AU - Tham, Emma

AU - Tomlinson, Ian

AU - Trovik, Jone

AU - Turman, Constance

AU - Tyrer, Jonathan P.

AU - Van Den Berg, David

AU - Wang, Zhaoming

AU - Wentzensen, Nicolas

AU - Xia, Lucy

AU - Xiang, Yong Bing

AU - Yang, Hannah P.

AU - Yu, Herbert

AU - Zheng, Wei

AU - Webb, Penelope M.

AU - Thompson, Deborah J.

AU - Spurdle, Amanda B.

AU - Glubb, Dylan M.

AU - O'Mara, Tracy A.

PY - 2021/1/15

Y1 - 2021/1/15

N2 - 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.

AB - 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.

KW - HDL cholesterol

KW - LDL cholesterol

KW - Mendelian randomization

KW - endometrial cancer risk

KW - triglycerides

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U2 - 10.1002/ijc.33206

DO - 10.1002/ijc.33206

M3 - Article

C2 - 32851660

AN - SCOPUS:85089080614

SN - 0020-7136

VL - 148

SP - 307

EP - 319

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 2

ER -

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

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