Abstract 1201: A mendelian randomization study for the potential causal effect of genetically driven insulin resistance on invasive breast cancer
Authors: Han Sihao , Mancuso Nicholas , Zhang Zuofeng , Papp Jeanette , Sobel Eric , Yao Jiemin , Jung Su Yon 
Published: September 2020

Abstract
Objectives
Insulin resistance (IR), traditionally measured by fasting blood levels of glucose (FG) and fasting insulin (FI), has been considered a potential risk factor for breast cancer development. However, findings from previous epidemiologic studies of the relationships between IR and breast cancer were inconsistent, partially due to selection bias, confounding, short time exposure to biomarkers, measurement errors, and reverse causation. We tried to address those challenges by using a Mendelian Randomization (MR) method where FG and FI were analyzed via genetic instrumental variables. Our study aimed to examine the potential causal effect of genetically driven IR on breast cancer development and hoped to understand the underlying mechanisms between IR and breast cancer.
Methods
We conducted a two-sample MR analysis using the most updated publicly available data from a genome-wide association study (GWAS) of Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC), Breast Cancer Association Consortium (BCAC), and Atlas of GWAS Summary Statistics (ATLAS), focusing on European women. We utilized different datasets for breast cancer outcomes to complement MR analyses with the inverse-variance weighted method. To determine the extent of pleiotropic signal, we applied Cochran's Q test and the MR-Egger regression analysis. Given obesity and diabetes's established role for breast cancer, we excluded those related single-nucleotide polymorphisms (SNPs) from the MR analysis.
Results
Of 44 SNPs associated with IR, 38 FG SNPs showed slightly positive effects on breast cancer risk across datasets (OncoArray/iCOGS, odds ratio (OR) = 1.002, 95% confidence interval (CI): 0.831- 1.209; ATLAS-General: OR = 1.146, 95% CI: 0.507 - 2.592; ATLAS-GEEA: OR = 1.034, 95% CI: 0.748 - 1.429; ATLAS-GEEAB: OR = 1.029, 95% CI: 0.747 - 1.416). After excluding SNPs associated with diabetes and obesity, the directions of the association between FG and breast cancer in the OncoArray/iCOGS datasets changed but not in the ATLAS-General dataset. Similarly, 6 FI SNPs had a positive association with breast cancer across the datasets. No significant directional pleiotropy was observed.
Conclusions
Our findings indicate a marginal association between genetically driven IR and breast cancer risk suggesting complex evidence for causal association. Our study may support the potential value of interventions to lower IR, thus reducing breast cancer risk.
Citation Format: Sihao Han, Nicholas Mancuso, Zuofeng Zhang, Jeanette Papp, Eric Sobel, Jiemin Yao, Su Yon Jung. A mendelian randomization study for the potential causal effect of genetically driven insulin resistance on invasive breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1201.