Abstract 243: Genetic polymorphisms of diabetes-related genes, their interaction with diabetes status, and breast cancer incidence and mortality: The Long Island Breast Cancer Study Project

Background: Diabetes is associated with increased risk of breast cancer and subsequent mortality; however, whether genetic variants that increase diabetes risk also influence breast cancer has received little attention. Herein, we examined the associations between 143 single nucleotide polymorphisms (SNPs) identified from genome-wide association studies of diabetes risk, and breast cancer incidence and subsequent mortality. For SNPs significantly associated with breast cancer incidence or mortality, we evaluated effect modification by diabetes status. Methods: Caucasian women diagnosed with first primary invasive breast cancer (n=817) and controls (n=1,021) from a population-based case-control study were interviewed to assess diabetes status. Using the National Death Index, women with breast cancer were followed for more than 18 years during which we identified 340 deaths including 139 from breast cancer. Genomic DNA was extracted from blood samples and genotyping was done using high-throughput matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We used logistic regression to estimate age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for breast cancer incidence and used Cox regression to estimate age-adjusted hazard ratios (HRs) and 95% CIs for all-cause and breast cancer-specific mortality. Results: Twelve SNPs were associated with incident breast cancer in additive models, at an alpha of 0.05. The top three most significantly associated SNPs included SLC30A8 rs4876369 (P=0.0034), HHEX rs11187146 (P=0.0086), and CDKN2A/CDKN2B rs1333049 (P=0.0086). Diabetes status modified two SNP-breast cancer incidence associations: SLC30A8 rs4876369 was associated with a 25% increase (OR=1.25, 95% CI=1.02-1.53) in odds of breast cancer among women without diabetes, and with a 330% increase (OR=4.30, 95% CI=1.66-11.17) in odds of breast cancer among women with diabetes (PInteraction=0.0150). IRS2 rs2241745 was inversely associated (OR=0.76, 95% CI=0.61-0.94) with breast cancer among women without diabetes, and associated with a 76% increase (OR=1.76, 95% CI=0.86-3.58) in odds of breast cancer among women with diabetes (PInteraction=0.0283). Three SNPs were associated with all-cause (CDKAL1 rs981042, P=0.0032; HHEX rs1111875, P=0.0361; and INSR rs919275, P=0.0488) and three with breast cancer-specific (CDKN2A/CDKN2B rs3218020, P=0.0225; CDKAL1 rs981042, P=0.0246; and TCF2/HNF1B rs3094508, P=0.0344) mortality in additive models, at