Genetic Predisposition to Metabolically Unfavourable Adiposity and Prostate Cancer Risk: A Mendelian Randomization Analysis

Overview

Journal Cancer Med

Specialty Oncology

Date 2023 Jun 12

PMID 37305903

Authors

Aurora Perez-Cornago

Karl Smith-Byrne

Emma Hazelwood

Cody Z Watling

Susan Martin

Timothy Frayling

Sarah Lewis

Richard M Martin

Hanieh Yaghootkar

Ruth C Travis

Timothy J Key

Affiliations

Soon will be listed here.

Abstract

Background: The associations of adiposity with aggressive prostate cancer risk are unclear. Using two-sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer.

Methods: We examined the association of these genetically predicted adiposity-related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases).

Results: In inverse-variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61-1.19), 0.80 (0.53-1.23) and 0.97 (0.88-1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer.

Conclusions: We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies.

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Genetic predisposition to metabolically unfavourable adiposity and prostate cancer risk: A Mendelian randomization analysis.

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References

Harrison S, Tilling K, Turner E, Martin R, Lennon R, Athene Lane J . Systematic review and meta-analysis of the associations between body mass index, prostate cancer, advanced prostate cancer, and prostate-specific antigen. Cancer Causes Control. 2020; 31(5):431-449. PMC: 7105428. DOI: 10.1007/s10552-020-01291-3. View

Freedland S, Platz E, Presti Jr J, Aronson W, Amling C, Kane C . Obesity, serum prostate specific antigen and prostate size: implications for prostate cancer detection. J Urol. 2006; 175(2):500-4. DOI: 10.1016/S0022-5347(05)00162-X. View

Burgess S, Thompson S . Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017; 32(5):377-389. PMC: 5506233. DOI: 10.1007/s10654-017-0255-x. View

Martin S, Tyrrell J, Thomas E, Bown M, Wood A, Beaumont R . Disease consequences of higher adiposity uncoupled from its adverse metabolic effects using Mendelian randomisation. Elife. 2022; 11. PMC: 8789289. DOI: 10.7554/eLife.72452. View

Wu L, Wang J, Cai Q, Cavazos T, Emami N, Long J . Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk: A Transcriptome-Wide Association Study in Over 140,000 European Descendants. Cancer Res. 2019; 79(13):3192-3204. PMC: 6606384. DOI: 10.1158/0008-5472.CAN-18-3536. View

Hemani G, Zheng J, Elsworth B, Wade K, Haberland V, Baird D . The MR-Base platform supports systematic causal inference across the human phenome. Elife. 2018; 7. PMC: 5976434. DOI: 10.7554/eLife.34408. View

Conti D, Darst B, Moss L, Saunders E, Sheng X, Chou A . Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction. Nat Genet. 2021; 53(1):65-75. PMC: 8148035. DOI: 10.1038/s41588-020-00748-0. View

Watts E, Perez-Cornago A, Fensom G, Smith-Byrne K, Noor U, Andrews C . Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia. Int J Cancer. 2022; 151(7):1033-1046. PMC: 7613289. DOI: 10.1002/ijc.34116. View

Perez-Cornago A, Dunneram Y, Watts E, Key T, Travis R . Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies. BMC Med. 2022; 20(1):143. PMC: 9069769. DOI: 10.1186/s12916-022-02336-x. View

10.

Burgess S, Foley C, Allara E, Staley J, Howson J . A robust and efficient method for Mendelian randomization with hundreds of genetic variants. Nat Commun. 2020; 11(1):376. PMC: 6969055. DOI: 10.1038/s41467-019-14156-4. View

11.

Martin S, Cule M, Basty N, Tyrrell J, Beaumont R, Wood A . Genetic Evidence for Different Adiposity Phenotypes and Their Opposing Influences on Ectopic Fat and Risk of Cardiometabolic Disease. Diabetes. 2021; 70(8):1843-1856. DOI: 10.2337/db21-0129. View

12.

Davey Smith G, Ebrahim S . 'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?. Int J Epidemiol. 2003; 32(1):1-22. DOI: 10.1093/ije/dyg070. View

13.

Perez-Cornago A, Appleby P, Pischon T, Tsilidis K, Tjonneland A, Olsen A . Tall height and obesity are associated with an increased risk of aggressive prostate cancer: results from the EPIC cohort study. BMC Med. 2017; 15(1):115. PMC: 5508687. DOI: 10.1186/s12916-017-0876-7. View

14.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

15.

Watts E, Appleby P, Albanes D, Black A, Chan J, Chen C . Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men. PLoS One. 2017; 12(12):e0187741. PMC: 5744924. DOI: 10.1371/journal.pone.0187741. View

16.

Albanes D, Weinstein S, Wright M, Mannisto S, Limburg P, Snyder K . Serum insulin, glucose, indices of insulin resistance, and risk of prostate cancer. J Natl Cancer Inst. 2009; 101(18):1272-9. PMC: 2744728. DOI: 10.1093/jnci/djp260. View

17.

Verbanck M, Chen C, Neale B, Do R . Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018; 50(5):693-698. PMC: 6083837. DOI: 10.1038/s41588-018-0099-7. View

18.

Genkinger J, Wu K, Wang M, Albanes D, BLACK A, van den Brandt P . Measures of body fatness and height in early and mid-to-late adulthood and prostate cancer: risk and mortality in The Pooling Project of Prospective Studies of Diet and Cancer. Ann Oncol. 2020; 31(1):103-114. PMC: 8195110. DOI: 10.1016/j.annonc.2019.09.007. View

19.

Ma J, Li H, Giovannucci E, Mucci L, Qiu W, Nguyen P . Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol. 2008; 9(11):1039-47. PMC: 2651222. DOI: 10.1016/S1470-2045(08)70235-3. View

20.

Censin J, Peters S, Bovijn J, Ferreira T, Pulit S, Magi R . Causal relationships between obesity and the leading causes of death in women and men. PLoS Genet. 2019; 15(10):e1008405. PMC: 6812754. DOI: 10.1371/journal.pgen.1008405. View