Genetic risk score Mendelian randomization shows obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer
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Authors
Painter, Jodie N
O’Mara, Tracy A
Marquart, Louise
Webb, Penelope M
for, the AOCS Group
Attia, John
Medland, Sarah E
Cheng, Timothy
Holliday, Elizabeth G
McEvoy, Mark
Scott, Rodney J
Ahmed, Shahana
Healey, Catherine S
Shah, Mitul
Gorman, Maggie
Martin, Lynn
Hodgson, Shirley
Beckmann, Matthias W
Ekici, Arif B
Fasching, Peter A
Hein, Alexander
Rübner, Matthias
Czene, Kamila
Darabi, Hatef
Hall, Per
Li, Jingmei
Dörk, Thilo
Dürst, Matthias
Hillemanns, Peter
Runnebaum, Ingo
Amant, Frederic
Annibali, Daniela
Depreeuw, Jeroen
Lambrechts, Diether
Neven, Patrick
Cunningham, Julie M
Dowdy, Sean C
Goode, Ellen L
Fridley, Brooke L
Winham, Stacey J
Njølstad, Tormund S
Salvesen, Helga B
Trovik, Jone
Werner, Henrica MJ
Ashton, Katie
Otton, Geoffrey
Proietto, Tony
Mints, Miriam
Tham, Emma
for, RENDOCAS
Bolla, Manjeet K
Michailidou, Kyriaki
Hopper, John L
Peto, Julian
Swerdlow, Anthony J
Burwinkel, Barbara
Brenner, Hermann
Meindl, Alfons
Brauch, Hiltrud
Lindblom, Annika
Chang-Claude, Jenny
Couch, Fergus J
Giles, Graham G
Kristensen, Vessela N
Cox, Angela
Tomlinson, Ian
for, the National Study of Endometrial Cancer Genetics Group NSECG
Spurdle, Amanda B
for, the Australian National Endometrial Cancer Study Group ANECS
Publication Date
2016-08-22Journal Title
Cancer Epidemiology, Biomarkers & Prevention
ISSN
1055-9965
Publisher
American Association for Cancer Research
Language
English
Type
Article
This Version
AM
Metadata
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Painter, J. N., O’Mara, T. A., Marquart, L., Webb, P. M., for, t. A. G., Attia, J., Medland, S. E., et al. (2016). Genetic risk score Mendelian randomization shows obesity measured as body mass index, but not waist:hip ratio, is causal for endometrial cancer. Cancer Epidemiology, Biomarkers & Prevention https://doi.org/10.1158/1055-9965.EPI-16-0147
Abstract
$\textbf{Background:}$ The strongest known risk factor for endometrial cancer (EC) is obesity. To determine whether single nucleotide polymorphisms (SNPs) associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with EC risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and EC in 6,609 cases and 37,926 country-matched controls.
$\textbf{Methods:}$ Logistic regression analysis and fixed-effects meta-analysis were used to test for associations between EC risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for EC was assessed using Mendelian randomization, with BMIwGRS as instrumental variable.
$\textbf{Results:}$ The BMIwGRS was significantly associated with EC risk ($P$=3.4x10$^{-17}$). Scaling the effect of the BMIwGRS on EC risk by its effect on BMI, the EC odds ratio (OR) per 5kg/m$^2$ of genetically predicted BMI was 2.06 (95% confidence interval (CI)=1.89-2.21), larger than the observed effect of BMI on EC risk (OR=1.55, 95% CI 1.44-1.68, per 5kg/m$^2$). The association attenuated but remained significant after adjusting for BMI (OR=1.22, 95% CI=1.10-1.39, $P$=5.3x10$^{-4}$). There was evidence of directional pleiotropy ($P$=1.5x10$^{-4}$). BMI SNP rs2075650 was associated with EC at study-wide significance ($P$<4.0x10$^{-4}$), independent of BMI. EC was not significantly associated with individual WHR SNPs or the WHRwGRS.
$\textbf{Conclusions:}$ BMI, but not WHR, is causally associated with EC risk, with evidence that some BMI-associated SNPs alter EC risk via mechanisms other than measurable BMI.
$\textbf{Impact:}$ The causal association between BMI SNPs and EC has possible implications for EC risk modeling.
Keywords
endometrial cancer, genetic predisposition, risk score analysis, pleiotropy
Sponsorship
NHMRC (Grant ID:1031333), NHMRC Fellowship scheme, Cancer Research UK, Oxford Comprehensive Biomedical Research Centre, Rhodes Trust, Nuffield Department of Medicine, European Community's Seventh Framework Programme (Grant ID: 223175 [HEALTH-F2-2009-223175] [COGS]), Cancer Research UK [C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565], National Institutes of Health [CA128978], Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative], Department of Defence [W81XWH-10-1-0341], Canadian Institutes of Health Research [CIHR] for the CIHR Team in Familial Risks of Breast Cancer, Komen 5Foundation for the Cure, Breast Cancer Research Foundation, Ovarian Cancer Research Fund, NHMRC (Grant ID: 339435), The Cancer Council Queensland (Grant ID: 4196615), Cancer Council Tasmania (Grant IDs: 403031, 457636), Cancer Research UK (Grant ID: C490/A10124), NHMRC (Grant ID: 552402, 1031333), Wellcome Trust ((Grant ID: 076113), Medical Research Council (Grant ID: G0000934), Wellcome Trust (Grant ID: 068545/Z/02), Wellcome Trust (Grant ID: 085475), EU FP7 (Grant ID: CHIBCHA), Wellcome Trust Centre for Human Genetics Core Grant (Grant ID: 090532/Z/09Z), Cancer Research UK, NHMRC, The University of Newcastle, the Gladys M Brawn Senior Research Fellowship scheme, The Vincent Fairfax Family Foundation, Hunter Medical Research Institute, Hunter Area Pathology Service, University of Erlangen (ELAN fund), Verelst Foundation for endometrial cancer, National Cancer Institute of United States Public Health Service [R01 CA122443, P30 CA15083, P50 CA136393, and GAME-ON the NCI Cancer Post-GWAS Initiative U19 CA148112], Fred C and Katherine B Andersen Foundation, Mayo Foundation, Ovarian Cancer Research Fund with support of the Smith family, in memory of Kathryn Sladek Smith, Helse Vest, University of Bergen, Melzer Foundation, The Norwegian Cancer Society (Harald Andersens legat), The Research Council of Norway, Haukeland University Hospital, University of Newcastle, The NBN Children’s Cancer Research Group, Ms Jennie Thomas, Hunter Medical Research Institute, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet [numbers: 20110222, 20110483, 20110141 and DF 07015], The Swedish Labor Market Insurance [number 100069] and The Swedish Cancer Society [number 11 0439], Agency for Science, Technology and Research of Singapore (A*STAR), US National Institutes of Health, Susan G. Komen Breast Cancer Foundation
Funder references
Cancer Research UK (10119)
Cancer Research UK (10124)
Cancer Research UK (A11020)
Cancer Research UK (11021)
Cancer Research UK (16561)
National Cancer Institute (NCI) (R01CA128978)
National Cancer Institute (NCI) (U19CA148537)
National Cancer Institute (NCI) (U19CA148065)
Identifiers
External DOI: https://doi.org/10.1158/1055-9965.EPI-16-0147
This record's URL: https://www.repository.cam.ac.uk/handle/1810/260624
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