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

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Details zur Publikation

Autor(en): 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 PA, 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
Zeitschrift: Cancer Epidemiology Biomarkers & Prevention
Jahr der Veröffentlichung: 2016
Band: 25
Heftnummer: 11
Seitenbereich: 1503-1510
ISSN: 1055-9965


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.


FAU-Autoren / FAU-Herausgeber

Beckmann, Matthias Prof. Dr.
Lehrstuhl für Geburtshilfe und Frauenheilkunde
Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut
Fasching, Peter PD Dr.
Professur für Translationale Frauenheilkunde und Geburtshilfe
Hein, Alexander PD Dr.
Frauenklinik
Rübner, Matthias Dr. rer. nat.
Frauenklinik


Autor(en) der externen Einrichtung(en)
Deutsches Krebsforschungszentrum (DKFZ)
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Friedrich-Schiller-Universität Jena
Hannover Medical School / Medizinische Hochschule Hannover (MHH)
John Hunter Hospital
Karolinska Institute
Karolinska University Hospital / Karolinska Universitetssjukhuset
Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven
London School of Hygiene and Tropical Medicine
Mayo Clinic
Oslo University Hospital / Oslo Universitetssykehus
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Ruprecht-Karls-Universität Heidelberg
St George's, University of London (SGUL) / St George's Hospital Medical School
Technische Universität München (TUM)
The Institute of Cancer Research (ICR)
The University of Melbourne
University of Bergen
University of Cambridge
University of Kansas (KU)
University of Newcastle (UoN)
University of Oxford
University of Sheffield


Zitierweisen

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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Zuletzt aktualisiert 2018-09-10 um 07:26