Investigation of the interplay between circulating lipids and IGF-I and relevance to breast cancer risk: an observational and mendelian randomization study

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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 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 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 bi-directional TG–IGF-I relationship (TG–IGF-I β per 1-SD: −0.13; 95% CI, −0.23 to −0.04; and IGF-I–TG β 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.
Original languageEnglish
Pages (from-to)2207-2216
Number of pages10
JournalCancer Epidemiology, Biomarkers and Prevention
Issue number12
Publication statusPublished - Dec 2021

Bibliographical note

Funding Information:
This work was specifically supported by the Medical Research Council (MRC) Integrative Epidemiology Unit (IEU) (MC_UU_12013/3), and by a Cancer Research UK Programme Grant (The Integrative Cancer Epidemiology Programme, ICEP; C18281/A29019). This research was funded in part by the Wellcome Trust (202802/Z/ 16/Z). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. V.Y. Tan, K.M. Biernacka, C.M. Perks, J.M.P. Holly, and N.J. Timpson are supported by ICEP (C18281/A19169). N.J. Timpson is a Wellcome Trust Investigator (202802/Z/16/Z) and works within the University of Bristol NIHR Biomedical Research Centre (BRC). L.J. Corbin was supported by NJT’s Wellcome Trust Investigator grant (202802/Z/16/Z). N.J. Timpson and L.J. Corbin work in the MRC IEU at the University of Bristol, which was supported by the MRC (MC_UU_00011) and the University of Bristol. T. Dudding received support from Wellcome (grant ref. 201268/Z/16/Z) and is now funded by the NIHR as an Academic Clinical Fellow. Q. Qi was supported by a Scientist Development Award (K01HL129892) from the NHLBI. R.C. Kaplan was supported by the National Heart, Lung and Blood Institute of the NIH (HL105756). J.I. Rotter was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR001881, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania, and the network “Greifswald Approach to Individualized Medicine (GANI_MED)” funded by the Federal Ministry of Education and Research (grant no. 03IS2061A). This publication is the work of the authors who will serve as guarantors for the contents of this paper. Quality Control filtering of the UK Biobank data were conducted by R. Mitchell, G. Hemani, T. Dudding, and L. Paternoster as described in the published protocol (doi:10.5523/bris.3074krb6t2frj29yh2b03⨯3wxj).

Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research

Structured keywords

  • ICEP


  • Breast cancer
  • Insulin-like growth factors,
  • lipids


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