Abstract B76: Evidence of a causal association between fasting insulin concentrations and endometrial cancer: A Mendelian randomization analysis

Abstract

Abstract Introduction: Epidemiological studies have consistently demonstrated an association between type 2 diabetes (T2D) and increased endometrial cancer risk. Compensatory hyperinsulinemia, resulting from insulin resistance in T2D, is a leading hypothesis for this association. This study utilized genetic risk scores for T2D and fasting insulin concentrations (FI) to determine whether a genetic predisposition to T2D or elevated FI is associated with an increased risk of endometrial cancer. Methods: Genetic variants associated with T2D or FI at genome-wide significance thresholds (5 × 10−8) from genome-wide association study (GWAS) meta-analyses were included as risk score variants. Forty-nine T2D and eighteen FI variants were tested for their association with endometrial cancer in 1,287 cases and 8,273 controls from the United Kingdom and Australia. A weighted risk score method was implemented to determine the risk of endometrial cancer per genetically predicted increase in the risk of T2D or FI. An unweighted per-allele method was also used to determine the risk of endometrial cancer per T2D risk or FI increasing allele. Risk score variants associated with body mass index (BMI) at Bonferroni-corrected significance thresholds in GWAS meta-analyses were removed in sensitivity analyses, as BMI is a potential confounding factor. Results: The T2D risk score was not significantly associated with endometrial cancer using either the weighted (odds ratio [OR]=0.99, 95% confidence interval [CI], 0.98-1.01; P=0.278) or per-allele (OR=1.00; 95% CI, 0.99-1.02; P=0.567) methods. However, the weighted FI risk score demonstrated a significantly increased risk of endometrial cancer (OR, 1.16; 95% CI, 1.01-1.34; P=0.035) per genetically predicted 0.1 unit elevation in log FI. Additionally, in the unweighted method a borderline statistically significant association per FI risk score allele was observed (OR, 1.02; 95% CI, 1.00-1.04; P=0.058). Removal of variants associated with BMI did not appreciably attenuate the magnitude of the observed effect in either the weighted (OR=1.15) or unweighted per-allele (OR=1.02) methods for the FI risk score analysis. Conclusion: This is the first study to examine the effect of FI on endometrial cancer risk using a Mendelian randomization approach and provides evidence to support a causal relationship between elevated FI and increased endometrial cancer risk that has not been previously shown. Citation Format: Kevin T. Nead, Robert A. Scott, Stephen A. Sharp, Adam S. Butterworth, Deborah J. Thompson, Toby Johnson, Amanda B. Spurdle, Paul D. Pharoah, Claudia Langenberg, Douglas F. Easton, Nick J. Wareham. Evidence of a causal association between fasting insulin concentrations and endometrial cancer: A Mendelian randomization analysis. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B76.