Deciphering how early life adiposity influences breast cancer risk using Mendelian randomization

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Abstract

Studies suggest that adiposity in childhood may reduce the risk of breast cancer in later life. The biological mechanism underlying this effect is unclear but is likely to be independent of body size in adulthood. Using a Mendelian randomization framework, we investigate 18 hypothesised mediators of the protective effect of childhood adiposity on later-life breast cancer, including hormonal, reproductive, physical, and glycaemic traits. Our results indicate that, while most of the hypothesised mediators are affected by childhood adiposity, only IGF-1 (OR: 1.08 [1.03: 1.15]), testosterone (total/free/bioavailable ~ OR: 1.12 [1.05: 1.20]), age at menopause (OR: 1.05 [1.03: 1.07]), and age at menarche (OR: 0.92 [0.86: 0.99], direct effect) influence breast cancer risk. However, multivariable Mendelian randomization analysis shows that the protective effect of childhood body size remains unaffected when accounting for these traits (ORs: 0.59-0.67). This suggests that none of the investigated potential mediators strongly contribute to the protective effect of childhood adiposity on breast cancer risk individually. It is plausible, however, that several related traits could collectively mediate the effect when analysed together, and this work provides a compelling foundation for investigating other mediating pathways in future studies.
Original languageEnglish
Article number337
Pages (from-to)337
Number of pages11
JournalCommunications Biology
Volume5
Issue number1
Early online date8 Apr 2022
DOIs
Publication statusE-pub ahead of print - 8 Apr 2022

Bibliographical note

Funding Information:
B.L.L. is supported by the University of Bristol Vice-Chancellor’s fellowship, Academy of Medical Sciences, Elizabeth Blackwell Institute for Health Research (University of Bristol) and the Wellcome Trust Institutional Strategic Support Fund; R.C.R. is a de Pass Vice Chancellor’s research fellow at the University of Bristol; M.V. is supported by the University of Bristol Alumni Fund (Professor Sir Eric Thomas Scholarship). M.V., G.D.S., E.S., T.G.R., R.C.R. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol supported by Medical Research Council (MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/4). This work is also supported by a Cancer Research UK programme grant (the Integrative Cancer Epidemiology Programme) (C18281/A19169). This research has been conducted using the UK Biobank Resource under application number 15825. 

Funding Information:
B.L.L. is supported by the University of Bristol Vice-Chancellor?s fellowship, Academy of Medical Sciences, Elizabeth Blackwell Institute for Health Research (University of Bristol) and the Wellcome Trust Institutional Strategic Support Fund; R.C.R. is a de Pass Vice Chancellor?s research fellow at the University of Bristol; M.V. is supported by the University of Bristol Alumni Fund (Professor Sir Eric Thomas Scholarship). M.V., G.D.S., E.S., T.G.R., R.C.R. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol supported by Medical Research Council (MC_UU_00011/1, MC_UU_00011/5 and MC_UU_00011/4). This work is also supported by a Cancer Research UK programme grant (the Integrative Cancer Epidemiology Programme) (C18281/A19169). This research has been conducted using the UK Biobank Resource under application number 15825. ?

Publisher Copyright:
© 2022, The Author(s).

Structured keywords

  • ICEP
  • breast cancer
  • mendelian randomization
  • childhood adiposity

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