Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study.

Abstract

BackgroundCirculating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer (BCa). Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to BCa overlap is unclear.MethodsMendelian Randomisation (MR) was conducted to estimate the relationship between lipids or IGF-I and BCa risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol,LDL-C; high-density lipoprotein cholesterol,HDL-C; triglycerides,TGs), IGF-I and BCa from GLGC/UKBB (N=239,119), CHARGE/UKBB (N=252,547) and BCAC (N=247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bi-directional relationship between lipids and IGF-I in SHIP (N=3,812) and UKBB (N=422,389), and using genetic summary statistics from GLGC (N=188,577) and CHARGE/UKBB (N=469,872).ResultsIn multivariable MR (MVMR) analyses, the OR for BCa per 1-SD increase in HDL-C and TG was 1.08 (95%CI: 1.04,1.13) and 0.94 (95%CI: 0.89,0.98), respectively. The OR for BCa per 1-SD increase in IGF-I was 1.09 (95%CI: 1.04,1.15). MR analyses suggested a bi-directional TG-IGF-I relationship (TG-IGF-I beta per 1-SD: -0.13; 95%CI: -0.23,-0.04; and IGF-I-TG beta per 1-SD: -0.11; 95%CI: -0.18,-0.05). There was little evidence for a causal relationship between HDL-C and LDL-C with IGF-I. In MVMR analyses, associations of TG or IGF-I with BCa were robust to adjustment for IGF-I or TG, respectively.ConclusionsOur findings suggest a causal role of HDL-C, TG and IGF-I in BCa. Observational and MR analyses support an interplay between IGF-I and TG, however, MVMR estimates suggest that TG and IGF-I may act independently to influence BCa.ImpactOur findings should be considered in the development of prevention strategies for BCa, where interventions are known to modify circulating lipids and IGF-I.