Genetic risk score mendelian randomization shows that obesity measured as body mass index, but not waist: hip ratio, is causal for endometrial cancer

Jodie N Painter, Tracy A O'Mara, Louise Marquart, Penelope M Webb, John R 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. FaschingAlexander Hein, Matthias Rübner, Kamila Czene, Hatef Darabi, Per Hall, Jingmei Li, Thilo Dörk, Matthias Dürst, Peter Hillemanns, Ingo B Runnebaum, Frederic J 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 Birgitte Salvesen, Jone Trovik, Henrica Maria Johanna 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 P Tomlinson, Alison M Dunning, Douglas F Easton, Deborah J Thompson, Amanda B Spurdle

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26 Citations (Scopus)


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 metaanalysis were used to test for associations between endometrial cancer risk and (i) individual BMI orWHRSNPs, (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.

Original languageEnglish
Pages (from-to)1503-1510
Number of pages8
JournalCancer Epidemiology, Biomarkers & Prevention
Issue number11
Publication statusPublished - 1 Nov 2016

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