Abstract
BACKGROUND: The potential links between triglyceride-glucose (TyG) related indicators and breast cancer incidence after menopause have been less well studied, and the joint associations between genetic risk, TyG related indicators, and breast cancer are unknown. METHODS: Simple surrogate indicators of insulin resistance including TyG, TyG-waist circumference (TyG-WC), TyG-waist to height ratio (TyG-WHtR), TyG-waist to hip ratio (TyG-WHR), TyG-body mass index (TyG-BMI). Genetic susceptibility in breast cancer was estimated by categorizing polygenic risk scores (PRS). For estimating the associations, we used Cox proportional hazards regression modeling. Correlation shapes were evaluated using restricted cubic splines (RCS). Mediation analyses for assessing the role of sex hormone-binding globulin (SHBG), C-reactive protein (CRP), testosterone, and glycosylated hemoglobin (HbA1c) in mediating the associations were conducted. RESULTS: The study included 83,873 UK biobank participants who were followed for a median of 13.8 years, with 3,561 new cases of postmenopausal breast cancer. Genetic risk and TyG related indicators were monotonically related to breast cancer, with additive but not multiplicative interactions between them. The highest quartiles of TyG, TyG-WC, TyG-WHtR, TyG-WHR, and TyG-BMI were significantly associated with increased breast cancer risk with hazard ratio (95% confidence interval) were 1.12 (1.01-1.25), 1.35 (1.23-1.49), 1.16 (1.05-1.28), 1.22(1.12-1.33), and 1.31 (1.19-1.44), respectively. TyG-WC was nonlinearly linked to breast cancer (P for nonlinear = 0.006). Individuals with high genetic risk and high TyG related indicators exhibited a substantially elevated breast cancer risk by 4- to 5-fold compared with reference group. The associations were mainly mediated by SHBG, CRP, and testosterone, with mediation proportions ranging from 10.24% to 68.29%. CONCLUSIONS: TyG related factors are linked to incident postmenopausal breast cancer, and the combined effects with genetic risk significantly optimize risk stratification. High levels of TyG related indicators may amplify the influence of genetic factors on postmenopausal breast cancer. TRIAL REGISTRATION: Not applicable.