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EPIDEMIOLOGY AND POPULATION HEALTH

Adiposity and cancer: a Mendelian randomization analysis in the UK biobank

Abstract

Background

Observational and Mendelian randomization (MR) studies link obesity and cancer, but it remains unclear whether these depend upon related metabolic abnormalities.

Methods

We used information from 321,472 participants in the UK biobank, including 30,561 cases of obesity-related cancer. We constructed three genetic instruments reflecting higher adiposity together with either “unfavourable” (82 SNPs), “favourable” (24 SNPs) or “neutral” metabolic profile (25 SNPs). We looked at associations with 14 types of cancer, previously suggested to be associated with obesity.

Results

All genetic instruments had a strong association with BMI (p < 1 × 10−300 for all). The instrument reflecting unfavourable adiposity was also associated with higher CRP, HbA1c and adverse lipid profile, while instrument reflecting metabolically favourable adiposity was associated with lower HbA1c and a favourable lipid profile. In MR-inverse-variance weighted analysis unfavourable adiposity was associated with an increased risk of non-hormonal cancers (OR = 1.22, 95% confidence interval [CI]:1.08, 1.38), but a lower risk of hormonal cancers (OR = 0.80, 95%CI: 0.72, 0.89). From individual cancers, MR analyses suggested causal increases in the risk of multiple myeloma (OR = 1.36, 95%CI: 1.09, 1.70) and endometrial cancer (OR = 1.77, 95%CI: 1.16, 2.68) by greater genetically instrumented unfavourable adiposity but lower risks of breast and prostate cancer (OR = 0.72, 95%CI: 0.61, 0.83 and OR = 0.81, 95%CI: 0.68, 0.97, respectively). Favourable or neutral adiposity were not associated with the odds of any individual cancer.

Conclusions

Higher adiposity associated with a higher risk of non-hormonal cancer but a lower risk of some hormone related cancers. Presence of metabolic abnormalities might aggravate the adverse effects of higher adiposity on cancer. Further studies are warranted to investigate whether interventions on adverse metabolic health may help to alleviate obesity-related cancer risk.

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Data availability

All data will be available to approved users of the UK Biobank upon application. This study uses a reporting checklist for observational studies i.e., Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines (Supplementary Table 9).

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Acknowledgements

We extend sincere thanks to the participants of the UK Biobank, who made this work possible. This study was conducted using the UK Biobank Resource under application number 20175.

Funding

This work was supported by grants from Tour de Cure (RSP-013-18/19) and National Health and Medical Research Council, Australia (GT1157281).

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Authors

Contributions

MA wrote the original draft, conducted data management and statistical analyses. AM advised on statistical analysis. EH developed concept and design, drafted the manuscript and funded the study. All authors interpreted data, revised the manuscript and approved the final version.

Corresponding author

Correspondence to Elina Hyppönen.

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Competing interests

Professor Hyppönen has received grants from the National Health and Medical Research Council, Australian Research Council, Tour de Cure, Medical Research Future Fund. The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The rest of the authors (MA, AM, SHL, V-PM and TB) declare no potential competing interest.

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Ahmed, M., Mulugeta, A., Lee, S.H. et al. Adiposity and cancer: a Mendelian randomization analysis in the UK biobank. Int J Obes 45, 2657–2665 (2021). https://doi.org/10.1038/s41366-021-00942-y

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