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Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer.
Authors
Shahana Ahmed
Frederic Amant
+74 more
Daniela Annibali
AOCS Group
Katie A Ashton
John Attia
Australian National Endometrial Cancer Study Group (ANECS)
Matthias W Beckmann
Manjeet K Bolla
Hiltrud Brauch
Hermann Brenner
Barbara Burwinkel
Jenny Chang-Claude
Timothy Cheng
Fergus J Couch
Angela Cox
Julie M Cunningham
Kamila Czene
Hatef Darabi
Joe Dennis
Jeroen Depreeuw
Sean C Dowdy
Alison M Dunning
Thilo Dörk
Matthias Dürst
Douglas F Easton
Arif B Ekici
Peter A Fasching
for RENDOCAS
Brooke L Fridley
Graham G Giles
Ellen L Goode
Maggie Gorman
Per Hall
Catherine S Healey
Alexander Hein
Peter Hillemanns
Shirley V Hodgson
Elizabeth G Holliday
John L Hopper
Vessela N Kristensen
Diether Lambrechts
Jingmei Li
Annika Lindblom
Louise Marquart
Lynn Martin
Mark McEvoy
Sarah E Medland
Alfons Meindl
Kyriaki Michailidou
Miriam Mints
National Study of Endometrial Cancer Genetics Group (NSECG)
Patrick Neven
Tormund S Njølstad
Tracy A O'Mara
Geoffrey Otton
Jodie N Painter
Julian Peto
Paul DP Pharoah
Anthony Proietto
Ingo B Runnebaum
Matthias Rübner
Helga B Salvesen
Rodney J Scott
Mitul Shah
Amanda B Spurdle
Anthony J Swerdlow
Emma Tham
Deborah J Thompson
Ian Tomlinson
Jone Trovik
Jonathan P Tyrer
Qin Wang
Penelope M Webb
Henrica MJ Werner
Stacey J Winham
Publication date
1 January 2016
Publisher
Cancer Epidemiol Biomarkers Prev
Doi
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on
PubMed
Abstract
BACKGROUND: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist-hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. METHODS: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. RESULTS: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10-17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89-2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10-1.39; P = 5.3 × 10-4). There was evidence of directional pleiotropy (P = 1.5 × 10-4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P < 4.0 × 10-4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. CONCLUSIONS: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. IMPACT: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503-10. ©2016 AACR.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 FoundationThis is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/1055-9965.EPI-16-014
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