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 Travis; David 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

doi:10.1007/s10552-015-0654-9

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 journal › Article (Academic Journal) › peer-review

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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 language	English
Pages (from-to)	1603-1616
Number of pages	14
Journal	Cancer Causes and Control
Volume	26
Early online date	19 Sept 2015
DOIs	https://doi.org/10.1007/s10552-015-0654-9
Publication status	Published - Nov 2015

Research Groups and Themes

ICEP

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1007/s10552-015-0654-9

art_3A10.1007_2Fs10552_015_0654_9Final published version, 505 KBLicence: CC BY

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IEU Theme 2
Flach, P. A. (Principal Investigator), Gaunt, T. R. (Principal Investigator) & Gaunt, T. R. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 1
Davey Smith, G. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
IEU Theme 3
Windmeijer, F. (Principal Investigator), Tilling, K. M. (Researcher) & Tilling, K. M. (Principal Investigator)
1/06/13 → 31/03/18
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

@article{7c9d0abae4834dc8a4c8a3bed57c5617,

title = "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",

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{\textquoteright}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. ",

keywords = "Height, Body mass index, Prostate cancer, Mendelian randomization, Single nucleotide polymorphisms, Instrumental variables analysis",

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

year = "2015",

month = nov,

doi = "10.1007/s10552-015-0654-9",

language = "English",

volume = "26",

pages = "1603--1616",

journal = "Cancer Causes and Control",

issn = "0957-5243",

publisher = "Springer International Publishing AG",

}

Davies, NM, Gaunt, TR , Lewis, SJ, Holly, JMP, Donovan, JL, Hamdy, FC, Kemp, JP, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Nordestgaard, BG, Travis, RC, Neal, D, Pashayan, N, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Lathrop, M, Davey Smith, G , Martin, RM & 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, vol. 26, pp. 1603-1616. https://doi.org/10.1007/s10552-015-0654-9

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. / Davies, Neil M; Gaunt, Tom R ; Lewis, Sarah J et al.
In: Cancer Causes and Control, Vol. 26, 11.2015, p. 1603-1616.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - The effects of height and BMI on prostate cancer incidence and mortality

T2 - a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

AU - Davies, Neil M

AU - Gaunt, Tom R

AU - Lewis, Sarah J

AU - Holly, Jeffrey M P

AU - Donovan, Jenny L

AU - Hamdy, Freddie C

AU - Kemp, John P

AU - Eeles, Rosalind

AU - Easton, Doug

AU - Kote-Jarai, Zsofia

AU - Al Olama, Ali Amin

AU - Benlloch, Sara

AU - Muir, Kenneth

AU - Giles, Graham G

AU - Wiklund, Fredrik

AU - Gronberg, Henrik

AU - Haiman, Christopher A

AU - Schleutker, Johanna

AU - Nordestgaard, Børge G

AU - Travis, Ruth C

AU - Neal, David

AU - Pashayan, Nora

AU - Khaw, Kay-Tee

AU - Stanford, Janet L

AU - Blot, William J

AU - Thibodeau, Stephen

AU - Maier, Christiane

AU - Kibel, Adam S

AU - Cybulski, Cezary

AU - Cannon-Albright, Lisa

AU - Brenner, Hermann

AU - Park, Jong

AU - Kaneva, Radka

AU - Batra, Jyotsna

AU - Teixeira, Manuel R

AU - Pandha, Hardev

AU - Lathrop, Mark

AU - Davey Smith, George

AU - Martin, Richard M

AU - the PRACTICAL Consortium

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Height

KW - Body mass index

KW - Prostate cancer

KW - Mendelian randomization

KW - Single nucleotide polymorphisms

KW - Instrumental variables analysis

U2 - 10.1007/s10552-015-0654-9

DO - 10.1007/s10552-015-0654-9

M3 - Article (Academic Journal)

C2 - 26387087

SN - 0957-5243

VL - 26

SP - 1603

EP - 1616

JO - Cancer Causes and Control

JF - Cancer Causes and Control

ER -

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

Abstract

Research Groups and Themes

Keywords

UN SDGs

Access to Document

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Projects

IEU Theme 2

MRC UoB UNITE Unit - Programme 1

IEU Theme 3

Cite this