Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer
Year: 2016
Type: article
Study design: Observational Study
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.
Authors: Jodie N. Painter, Tracy A. O'Mara, Louise Marquart, Penelope M. Webb, John Attia, Sarah E. Medland, Timothy Cheng, Joe Dennis, Elizabeth G. Holliday, Mark McEvoy, Rodney J. Scott, Shahana Ahmed, Catherine S. Healey, Mitul Shah, Maggie Gorman, Lynn Martin, Shirley V. Hodgson, Matthias W. Beckmann, Arif B. Ekici, Peter A. Fasching, Alexander Hein, Matthias Rübner, Kamila Czene, Hatef Darabi, Per Hall, Jingmei Li, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B. Runnebaum, Frederic Amant, Daniela Annibali, Jeroen Depreeuw, Diether Lambrechts, Patrick Neven, Julie M. Cunningham, Sean C. Dowdy, Ellen L. Goode, Brooke L. Fridley, Stacey J. Winham, Tormund S. Njølstad, Helga B. Salvesen, Jone Trovik, Henrica M.J. Werner, Katie A. Ashton, Geoffrey Otton, Anthony Proietto, Miriam Mints, Emma Tham, Manjeet K. Bolla, Kyriaki Michailidou, Qin Wang, Jonathan P. Tyrer, John L. Hopper, Julian Peto, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Jenny Chang-Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Paul D.P. Pharoah, Ian Tomlinson, Alison M. Dunning, Douglas F. Easton, Deborah J. Thompson, Amanda B. Spurdle
Institutions: QIMR Berghofer Medical Research Institute, John Hunter Hospital, Hunter Medical Research Institute, University of Newcastle Australia, Centre for Human Genetics, University of Oxford, University of Cambridge, University of London, St George's, University of London, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, University of California, Los Angeles, Karolinska Institutet, Medizinische Hochschule Hannover, Jena University Hospital, Friedrich Schiller University Jena, KU Leuven, Universitair Ziekenhuis Leuven, Mayo Clinic, University of Kansas Medical Center, Haukeland University Hospital, University of Bergen, Karolinska University Hospital, The University of Melbourne, London School of Hygiene & Tropical Medicine, Institute of Cancer Research, German Cancer Research Center, Heidelberg University, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung, Technical University of Munich, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, University of Tübingen, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, Cancer Council Victoria, Monash University, University of Oslo, Akershus University Hospital, University of Sheffield
Language: English
Topic: Cancer Risks and Factors
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: A genome-wide association study for breast cancer in BRCA1 mutation carriers, G1791794685, WTCCC2 core activities, G2718683818, G2899816875, G3041146491, G3097030853, G3445821079, Elucidating Loci Involved in Prostate Cancer Suceptibility, G4119975330, A national DNA control series for genetic case-control studies based on the British 1958 birth cohort, G5865683244, G6283257732, G6433449787, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7378152860, Genetic Variation in the NF-kappaB Pathway and Ovarian Cancer Etiology, G8199793763, The genetics of weight, BMI, adiposity and obesity, Mayo Clinic Comprehensive Cancer Center Support Grant, Moffitt Cancer Center Support Grant
OpenAlex ID: W2509920873