Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Nikos Papadimitriou*, Caroline J Bull, Mazda Jenab, David J Hughes, Joshua A Bell, Eleanor Sanderson, Nicholas J Timpson, George Davey Smith, Demetrius Albanes, Peter T Campbell, Sébastien Küry, Loic Le Marchand, Cornelia M Ulrich, Kala Visvanathan, Jane C Figueiredo, Polly A Newcomb, Rish K Pai, Ulrike Peters, Kostas K Tsilidis, Jolanda M A BoerEmma E Vincent, Daniela Mariosa, Marc J Gunter, Tom G Richardson, Neil Murphy

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk.

METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants.

RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05).

CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

Original languageEnglish
Article number5
Pages (from-to)5
JournalBMC Medicine
Volume21
Issue number1
DOIs
Publication statusPublished - 4 Jan 2023

Bibliographical note

Funding Information:
J.A.B. works in a unit funded by the UK MRC (MC_UU_00011/1) and the University of Bristol.

Funding Information:
NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011) and the MRC Integrative Epidemiology Unit (MC_UU_12013/3), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169).

Funding Information:
Information on consortia acknowledgements is included in the Additional file 2 : Acknowledgements. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization.

Funding Information:
C.J.B. is supported by the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009).

Funding Information:
KKT is supported by Cancer Research UK (PPRCPJT\100005)

Funding Information:
E.E.V. is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant program (IIG_2019_2009) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019).

Funding Information:
This work was supported by Cancer Research UK (C18281/A29019)

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

Structured keywords

  • Bristol Population Health Science Institute

Keywords

  • Adult
  • Humans
  • Child
  • Middle Aged
  • Adiposity/genetics
  • Pediatric Obesity
  • Risk Factors
  • Mendelian Randomization Analysis
  • Genome-Wide Association Study
  • Body Mass Index
  • Colonic Neoplasms
  • Polymorphism, Single Nucleotide

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