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

PRACTICAL consortium, Neil M. Davies, Tom R. Gaunt, Sarah J. Lewis, Jeff 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 & 31 others 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, Cook, Angela Morgan, Artitaya Lophatananon, Fisher Cyril, Leongamornlert Daniel, Edward J. Saunders, Emma J. Sawyer, Govindasami Koveela, Malgorzata Tymrakiewicz, Michelle Guy, Pamela Saunders

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

LanguageEnglish
Pages1603-1616
Number of pages14
JournalCancer Causes and Control
Volume26
Issue number11
DOIs
Publication statusPublished - 1 Nov 2015

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{550a8c7363254d9287132cbda616832e,
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’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 = "Body mass index, Height, Instrumental variables analysis, Mendelian randomization, Prostate cancer, Single nucleotide polymorphisms",
author = "{PRACTICAL consortium} and Davies, {Neil M.} and Gaunt, {Tom R.} and Lewis, {Sarah J.} and Jeff Holly 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 Khaw, {Kay Tee} 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 Smith, {George Davey} and Martin, {Richard M.} and Cook and Angela Morgan and Artitaya Lophatananon and Fisher Cyril and Leongamornlert Daniel and Saunders, {Edward J.} and Sawyer, {Emma J.} and Govindasami Koveela and Malgorzata Tymrakiewicz and Michelle Guy and Pamela Saunders",
year = "2015",
month = "11",
day = "1",
doi = "10.1007/s10552-015-0654-9",
language = "English",
volume = "26",
pages = "1603--1616",
journal = "Cancer Causes and Control",
issn = "0957-5243",
publisher = "Springer Netherlands",
number = "11",

}

TY - JOUR

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

T2 - Cancer Causes and Control

AU - PRACTICAL consortium

AU - Davies, Neil M.

AU - Gaunt, Tom R.

AU - Lewis, Sarah J.

AU - Holly, Jeff

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 - Smith, George Davey

AU - Martin, Richard M.

AU - Cook,

AU - Morgan, Angela

AU - Lophatananon, Artitaya

AU - Cyril, Fisher

AU - Daniel, Leongamornlert

AU - Saunders, Edward J.

AU - Sawyer, Emma J.

AU - Koveela, Govindasami

AU - Tymrakiewicz, Malgorzata

AU - Guy, Michelle

AU - Saunders, Pamela

PY - 2015/11/1

Y1 - 2015/11/1

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 - Body mass index

KW - Height

KW - Instrumental variables analysis

KW - Mendelian randomization

KW - Prostate cancer

KW - Single nucleotide polymorphisms

UR - http://www.scopus.com/inward/record.url?scp=84943363498&partnerID=8YFLogxK

U2 - 10.1007/s10552-015-0654-9

DO - 10.1007/s10552-015-0654-9

M3 - Article

VL - 26

SP - 1603

EP - 1616

JO - Cancer Causes and Control

JF - Cancer Causes and Control

SN - 0957-5243

IS - 11

ER -