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

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

Journal article

Peer reviewed

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, …

International journal of cancer, Vol.148(2), pp.307-319

15/01/2021

DOI: https://doi.org/10.1002/ijc.33206

PMID: 32851660

Abstract

Case-Control Studies

Cholesterol, HDL - blood

Cholesterol, HDL - genetics

Cholesterol, LDL - blood

Cholesterol, LDL - genetics

Endometrial Neoplasms - blood

Endometrial Neoplasms - genetics

Female

Genome-Wide Association Study

Humans

Mendelian Randomization Analysis

Risk

Triglycerides - blood

Triglycerides - genetics

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 ) 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.

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Title: Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer
Creators - without role: Pik-Fang Kho - Queensland University of Technology
Frederic Amant - KU Leuven
Daniela Annibali - KU Leuven
Katie Ashton - University of Newcastle Australia
John Attia - University of Newcastle Australia
Paul L Auer - University of Wisconsin–Milwaukee
Matthias W Beckmann - Friedrich-Alexander-Universität Erlangen-Nürnberg
Amanda Black - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Louise Brinton - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Daniel D Buchanan - University of Melbourne
Stephen J Chanock - National Institutes of Health
Chu Chen - Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
Maxine M Chen - Harvard University
Timothy H T Cheng - Wellcome Centre for Human Genetics
Linda S Cook - Alberta Health Services
Marta Crous-Bous - Harvard University
Kamila Czene - Karolinska Institutet
Immaculata De Vivo - Harvard University
Joe Dennis - University of Cambridge
Thilo Dörk - Medizinische Hochschule Hannover
Sean C Dowdy - Mayo Clinic in Arizona
Alison M Dunning - University of Cambridge
Matthias Dürst - Friedrich Schiller University Jena
Douglas F Easton - University of Cambridge
Arif B Ekici - Friedrich-Alexander-Universität Erlangen-Nürnberg
Peter A Fasching - University of California, Los Angeles
Brooke L Fridley - University of Kansas
Christine M Friedenreich - Alberta Health Services
Montserrat García-Closas - National Institutes of Health
Mia M Gaudet - American Cancer Society
Graham G Giles - Monash University
Ellen L Goode - Mayo Clinic
Maggie Gorman - Wellcome Centre for Human Genetics
Christopher A Haiman - University of Southern California
Per Hall - Karolinska Institutet
Susan E Hankinson - University of Massachusetts Amherst
Alexander Hein - Friedrich-Alexander-Universität Erlangen-Nürnberg
Peter Hillemanns - Medizinische Hochschule Hannover
Shirley Hodgson - St George's, University of London
Erling A Hoivik - University of Bergen
Elizabeth G Holliday - University of Newcastle Australia
David J Hunter - University of Oxford
Angela Jones - Wellcome Centre for Human Genetics
Peter Kraft - Harvard University
Camilla Krakstad - University of Bergen
Diether Lambrechts - KU Leuven
Loic Le Marchand - University of Hawaii System
Xiaolin Liang - Memorial Sloan Kettering Cancer Center
Annika Lindblom - Karolinska Institutet
Jolanta Lissowska - Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland
Jirong Long - Vanderbilt University
Lingeng Lu - Yale University
Anthony M Magliocco - Moffitt Cancer Center
Lynn Martin - University of Birmingham
Mark McEvoy - University of Newcastle Australia
Roger L Milne - Monash University
Miriam Mints - Karolinska Institutet
Rami Nassir - University of California, Davis
Geoffrey Otton - University of Newcastle Australia
Claire Palles - Wellcome Centre for Human Genetics
Loreall Pooler - University of Southern California
Tony Proietto - University of Newcastle Australia
Timothy R Rebbeck - Harvard University
Stefan P Renner - Friedrich-Alexander-Universität Erlangen-Nürnberg
Harvey A Risch - Yale University
Matthias Rübner - Friedrich-Alexander-Universität Erlangen-Nürnberg
Ingo Runnebaum - Friedrich Schiller University Jena
Carlotta Sacerdote - Italian institute for Genomic Medicine
Gloria E Sarto - University of Wisconsin–Madison
Fredrick Schumacher - Case Western Reserve University
Rodney J Scott - University of Newcastle Australia
V Wendy Setiawan - University of Southern California
Mitul Shah - University of Cambridge
Xin Sheng - University of Southern California
Xiao-Ou Shu - Vanderbilt University
Melissa C Southey - Monash University
Emma Tham - Karolinska Institutet
Ian Tomlinson - University of Birmingham
Jone Trovik - University of Bergen
Constance Turman - Harvard University
Jonathan P Tyrer - University of Cambridge
David Van Den Berg - University of Southern California
Zhaoming Wang - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Nicolas Wentzensen - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Lucy Xia - University of Southern California
Yong-Bing Xiang - Shanghai Jiao Tong University
Hannah P Yang - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
Herbert Yu - University of Hawaii System
Wei Zheng - Vanderbilt University
Penelope M Webb - QIMR Berghofer Medical Research Institute
Deborah J Thompson - University of Cambridge
Amanda B Spurdle - QIMR Berghofer Medical Research Institute
Dylan M Glubb - QIMR Berghofer Medical Research Institute
Tracy A O'Mara - QIMR Berghofer Medical Research Institute
Publication Details: International journal of cancer, Vol.148(2), pp.307-319
Grant note: HHSN268201100004I / NHLBI NIH HHS R01 CA054281 / NCI NIH HHS U19-CA148112 / US National Institutes of Health R01 CA105212 / NCI NIH HHS R03 CA080636 / NCI NIH HHS NO1 HD23166 / NIH Grant HHSN268201100004C / WHI NIH HHS U19 CA148537 / NCI NIH HHS U19 CA148065-01 / NCI NIH HHS R03 CA096400 / NCI NIH HHS 100069 / Wellcome Trust MOP-86727 / Canadian Institutes of Health Research (CIHR) HHSN268201100002C / WHI NIH HHS R01 CA058598 / NCI NIH HHS RO1 CA 87538 / NIH Grant R01 CA128978 / NCI NIH HHS C1287/A10710 / Cancer Research UK 29186 / Cancer Research UK P01 CA017054 / NCI NIH HHS C490/A10124 / Cancer Research UK HHSN268201100003C / WHI NIH HHS R01 CA077398 / NCI NIH HHS R01 CA134958 / NCI NIH HHS R01 CA91019 / NIH Grant C5047/A8384 / Cancer Research UK CA128978 / the National Institutes of Health CA54281 / NIH Grant P01 CA087969 / NCI NIH HHS K05 CA136967 / NCI NIH HHS R01 CA091019 / NCI NIH HHS HHSN268201100046C / NHLBI NIH HHS R37 CA054281 / NCI NIH HHS R01 CA087538 / NCI NIH HHS R03 CA128008 / NCI NIH HHS R01 CA122443 / NCI NIH HHS R01 CA108634 / NCI NIH HHS R01 CA074847 / NCI NIH HHS CA1X01HG007491-01 / US National Institutes of Health 085475 / Wellcome Trust 1U19 CA148065 / Post-Cancer GWAS initiative R01-CA149429 / US National Institutes of Health HHSN271201100004C / NIA NIH HHS Wellcome Trust N01 HD023166 / NICHD NIH HHS 090532/Z/09Z / Wellcome Trust C1287/A16563 / Cancer UK Grant 068545/Z/02 / Wellcome Trust P30 CA015083 / NCI NIH HHS R35 CA39779 / NIH Grant R01 CA149429 / NCI NIH HHS HHSN268201100003I / NHLBI NIH HHS U19 CA148065 / NCI NIH HHS C5047/A15007 / Cancer Research UK U19 CA148112 / NCI NIH HHS RO3 CA80636 / NIH Grant UL1 TR001863 / NCATS NIH HHS C5047/A10692 / Cancer Research UK 2R01 CA082838 / NIH Grant C1287/A10118 / Cancer Research UK HHSN268201100002I / NHLBI NIH HHS 1U19 CA148537 / Post-Cancer GWAS initiative HHSN268201100001C / WHI NIH HHS K05 CA092002 / NCI NIH HHS P30 CA15083 / National Cancer Institute of United States Public Health Service RO1 CA75977 / NIH Grant C12292/A11174 / Cancer Research UK P30 CA008748 / NCI NIH HHS UM1 CA186107 / NCI NIH HHS CA128978 / NIH HHS P50 CA136393 / NCI NIH HHS 209057 / Wellcome Trust R01 CA082838 / NCI NIH HHS HHSN268201100001I / NHLBI NIH HHS R01 CA77398 / NIH Grant R01 CA098346 / NCI NIH HHS R01 CA049449 / NCI NIH HHS C1281/A12014 / Cancer Research UK C8197/A16565 / Cancer Research UK R01 CA49449 / NIH Grant
Identifiers: 9930762008331
Academic Unit: Umm Al Qura University
Language: English
Resource Type: Journal article