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Mammographic density mediates the protective effect of early-life body size on breast cancer risk

Author

Listed:
  • Marina Vabistsevits

    (MRC Integrative Epidemiology Unit
    Population Health Sciences)

  • George Davey Smith

    (MRC Integrative Epidemiology Unit
    Population Health Sciences)

  • Tom G. Richardson

    (MRC Integrative Epidemiology Unit
    Population Health Sciences)

  • Rebecca C. Richmond

    (MRC Integrative Epidemiology Unit
    Population Health Sciences)

  • Weiva Sieh

    (Department of Population Health Science and Policy
    Department of Epidemiology)

  • Joseph H. Rothstein

    (Department of Population Health Science and Policy
    Department of Epidemiology)

  • Laurel A. Habel

    (Division of Research)

  • Stacey E. Alexeeff

    (Division of Research)

  • Bethan Lloyd-Lewis

    (School of Cellular and Molecular Medicine)

  • Eleanor Sanderson

    (MRC Integrative Epidemiology Unit
    Population Health Sciences)

Abstract

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes. Childhood adiposity has a decreasing effect on DA, while adulthood adiposity increases NDA. Later menarche increases DA/PD, but when accounting for childhood adiposity, this effect is attenuated. Next, we examine the effect of MD on breast cancer risk. DA/PD have a risk-increasing effect on breast cancer across all subtypes. The MD SNPs estimates are heterogeneous, and additional analyses suggest that different mechanisms may be linking MD and breast cancer. Finally, we evaluate the role of MD in the protective effect of childhood adiposity on breast cancer. Mediation MR analysis shows that 56% (95% CIs [32%–79%]) of this effect is mediated via DA. Our finding suggests that higher childhood adiposity decreases mammographic DA, subsequently reducing breast cancer risk. Understanding this mechanism is important for identifying potential intervention targets.

Suggested Citation

  • Marina Vabistsevits & George Davey Smith & Tom G. Richardson & Rebecca C. Richmond & Weiva Sieh & Joseph H. Rothstein & Laurel A. Habel & Stacey E. Alexeeff & Bethan Lloyd-Lewis & Eleanor Sanderson, 2024. "Mammographic density mediates the protective effect of early-life body size on breast cancer risk," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48105-7
    DOI: 10.1038/s41467-024-48105-7
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    1. Kyriaki Michailidou & Sara Lindström & Joe Dennis & Jonathan Beesley & Shirley Hui & Siddhartha Kar & Audrey Lemaçon & Penny Soucy & Dylan Glubb & Asha Rostamianfar & Manjeet K. Bolla & Qin Wang & Jon, 2017. "Association analysis identifies 65 new breast cancer risk loci," Nature, Nature, vol. 551(7678), pages 92-94, November.
    2. Gibran Hemani & Kate Tilling & George Davey Smith, 2017. "Orienting the causal relationship between imprecisely measured traits using GWAS summary data," PLOS Genetics, Public Library of Science, vol. 13(11), pages 1-22, November.
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