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

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, AOCS Group, for RENDOCAS, National Study of Endometrial Cancer Genetics Group (NSECG), Australian National Endometrial Cancer Study Group (ANECS)
• Journal: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 25 Issue 11 Pg. 1503-1510 (11 2016) ISSN: 1538-7755 [Electronic] United States
• PMID: 27550749 (Publication Type: Journal Article, Meta-Analysis, Multicenter Study, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: ©2016 American Association for Cancer Research.

Topics

• Body Mass Index
• Endometrial Neoplasms (etiology, genetics)
• Female
• Genetic Predisposition to Disease
• Humans
• Mendelian Randomization Analysis
• Obesity (complications, genetics)
• Polymorphism, Single Nucleotide
• Waist-Hip Ratio