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

Tan, Vanessa Y.; Bull, Caroline J.; Biernacka, Kalina M.; Teumer, Alexander; Richardson, Tom G.; Sanderson, Eleanor; Corbin, Laura J.; Dudding, Tom; Qi, Qibin; Kaplan, Robert C.; Rotter, Jerome; Friedrich, Nele; Voelker, Uwe; Mayerle, Julia; Perks, Claire M.; Holly, Jeff M. P. und Timpson, Nicholas J. (2021): Investigation of the Interplay between Circulating Lipids and IGF-I and Relevance to Breast Cancer Risk: An Observational and Mendelian Randomization Study. In: Cancer Epidemiology Biomarkers & Prevention, Bd. 30, Nr. 12: S. 2207-2216

Abstract

Background: Circulating lipids and insulin-like growth factor 1 (IGF-I) have been reliably associated with breast cancer. Observational studies suggest an interplay between lipids and IGF-I, however, whether these relationships are causal and if pathways from these phenotypes to breast cancer overlap is unclear. Methods: Mendelian randomization (MR) was conducted to estimate the relationship between lipids or IGF-I and breast cancer risk using genetic summary statistics for lipids (low-density lipoprotein cholesterol, LDL-C;high-density lipoprotein cholesterol, HDL-C;triglycerides, TGs), IGF-I and breast cancer from GLGC/UKBB (N - 239,119), CHARGE/UKBB (N = 252,547), and Breast Cancer Association Consortium (N - 247,173), respectively. Cross-sectional observational and MR analyses were conducted to assess the bidirectional 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 (M V MR) analyses, the OR for breast cancer per 1-SD increase in HDL-C and TG was 1.08 [95% confidence interval (CI), 1.04-1.13] and 0.94 (95% CI, 0.89-0.98), respectively. The OR for breast cancer per 1-SD increase in IGF-I was 1.09 (95% CI, 1.04-1.15). MR analyses suggested a bidirectional TG-IGF-I relationship (TG-IGF-I beta per 1-SD: -0.13;95% CI, -0.23 to -0.04;and IGF-I-TG beta per 1-SD: -0.11;95% CI, -0.18 to -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 breast cancer 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 breast cancer. 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 breast cancer. Impact: Our findings should be considered in the development of prevention strategies for breast cancer, where interventions are known to modify circulating lipids and IGF-I.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1055-9965
• Sprache: Englisch