Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer

Painter JN, O'Mara TA, Marquart L, Webb PM, Attia J, Medland SE, Cheng T, Dennis J, Holliday EG, Mcevoy M, Scott RJ, Ahmed S, Healey CS, Shah M, Gorman M, Martin L, Hodgson SV, Beckmann M, Ekici AB, Fasching P, Hein A, Rübner M, Czene K, Darabi H, Hall P, Li J, Doerk T, Duerst M, Hillemanns P, Runnebaum IB, Amant F, Annibali D, Depreeuw J, Lambrechts D, Neven P, Cunningham JM, Dowdy SC, Goode EL, Fridley BL, Winham SJ, Njolstad TS, Salvesen HB, Trovik J, Werner HMJ, Ashton KA, Otton G, Proietto A, Mints M, Tham E, Bolla MK, Michailidou K, Wang Q, Tyrer JP, Hopper JL, Peto J, Swerdlow AJ, Burwinkel B, Brenner H, Meindl A, Brauch H, Lindblom A, Chang-Claude J, Couch FJ, Giles G, Kristensen VN, Cox A, Pharoah PDP, Tomlinson I, Dunning AM, Easton DF, Thompson DJ, Spurdle AB (2016)

Publication Type: Journal article

Publication year: 2016

Journal

Book Volume: 25

Pages Range: 1503-1510

Journal Issue: 11

DOI: 10.1158/1055-9965.EPI-16-0147

Abstract

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.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.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/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 endometrial cancer risk (OR = 1.55; 95% CI, 1.44-1.68, per 5 kg/m(2)). 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.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.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 with CRIS profile

Involved external institutions

St George's, University of London (SGUL) / St George's Hospital Medical School United Kingdom (GB) Friedrich-Schiller-Universität Jena Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Karolinska Institute Sweden (SE) Mayo Clinic United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Cambridge United Kingdom (GB) University of Oxford United Kingdom (GB) University of Sheffield United Kingdom (GB) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) The University of Melbourne Australia (AU) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Technische Universität München (TUM) Germany (DE) Ruprecht-Karls-Universität Heidelberg Germany (DE) The Institute of Cancer Research (ICR) United Kingdom (GB) London School of Hygiene and Tropical Medicine United Kingdom (GB) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) University of Newcastle (UoN) Australia (AU) John Hunter Hospital Australia (AU) University of Bergen / Universitetet i Bergen Norway (NO) University of Kansas (KU) United States (USA) (US) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE)

How to cite

APA:

Painter, J.N., O'Mara, T.A., Marquart, L., Webb, P.M., Attia, J., Medland, S.E.,... Spurdle, A.B. (2016). Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer. Cancer Epidemiology Biomarkers & Prevention, 25(11), 1503-1510. https://dx.doi.org/10.1158/1055-9965.EPI-16-0147

MLA:

Painter, Jodie N., et al. "Genetic Risk Score Mendelian Randomization Shows that Obesity Measured as Body Mass Index, but not Waist:Hip Ratio, Is Causal for Endometrial Cancer." Cancer Epidemiology Biomarkers & Prevention 25.11 (2016): 1503-1510.

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