The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

Neil M Davies, Tom R Gaunt, Sarah J Lewis, Jeffrey M P Holly, Jenny L Donovan, Freddie C Hamdy, John P Kemp, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna Schleutker, Børge G Nordestgaard, Ruth C TravisDavid Neal, Nora Pashayan, Kay-Tee Khaw, Janet L Stanford, William J Blot, Stephen Thibodeau, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Park, Radka Kaneva, Jyotsna Batra, Manuel R Teixeira, Hardev Pandha, Mark Lathrop, George Davey Smith, Richard M Martin, the PRACTICAL Consortium

Research output: Contribution to journalArticle (Academic Journal)

36 Citations (Scopus)
316 Downloads (Pure)

Abstract

Background

Epidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality.

Methods

We conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies.

Results

The genetic risk scores explained 6.31 and 1.46 % of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95 % CI 0.96, 1.00; p = 0.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95 % CI 0.97, 1.01; p = 0.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneity = 0.03).

Conclusions

We found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

Original languageEnglish
Pages (from-to)1603-1616
Number of pages14
JournalCancer Causes and Control
Volume26
Early online date19 Sep 2015
DOIs
Publication statusPublished - Nov 2015

Structured keywords

  • ICEP

Keywords

  • Height
  • Body mass index
  • Prostate cancer
  • Mendelian randomization
  • Single nucleotide polymorphisms
  • Instrumental variables analysis

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  • Projects

    IEU Theme 3

    Windmeijer, F., Tilling, K. M. & Tilling, K. M.

    1/06/1331/03/18

    Project: Research

    MRC UoB UNITE Unit - Programme 1

    Davey Smith, G.

    1/06/1331/03/18

    Project: Research

    IEU Theme 2

    Flach, P. A., Gaunt, T. R. & Gaunt, T. R.

    1/06/1331/03/18

    Project: Research

    Cite this

    Davies, N. M., Gaunt, T. R., Lewis, S. J., Holly, J. M. P., Donovan, J. L., Hamdy, F. C., Kemp, J. P., Eeles, R., Easton, D., Kote-Jarai, Z., Al Olama, A. A., Benlloch, S., Muir, K., Giles, G. G., Wiklund, F., Gronberg, H., Haiman, C. A., Schleutker, J., Nordestgaard, B. G., ... the PRACTICAL Consortium (2015). The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium. Cancer Causes and Control, 26, 1603-1616. https://doi.org/10.1007/s10552-015-0654-9