Cancer Epidemiol Biomarkers Prev. 2021 Sep 28:cebp.0315.2021. doi: 10.1158/1055-9965.EPI-21-0315. Online ahead of print.
ABSTRACT
BACKGROUND: Circulating 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.
METHODS: Mendelian 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).
RESULTS: In multivariable MR(MVMR) analyses, the OR for BCa per 1-SD increase in HDL-C or 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.
CONCLUSIONS: Our 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.
IMPACT: Our findings should be considered in the development of prevention strategies for BCa, where interventions are known to modify circulating lipids and IGF-I.
PMID:34583967 | DOI:10.1158/1055-9965.EPI-21-0315
