Blood lipids and prostate cancer: a Mendelian randomization analysis

Caroline J Bull; Carolina Bonilla; Jeff M P Holly; Claire M Perks; Neil Davies; Philip Haycock; Oriana Hoi Yun Yu; J Brent Richards; Rosalind Eeles; Doug Easton; Zsofia Kote-Jarai; Ali Amin Al Olama; Sara Benlloch; Kenneth Muir; Graham G Giles; Robert J MacInnis; 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; Agnieszka Micheal; Hardev Pandha; George Davey Smith; Sarah J Lewis; Richard M Martin; PRACTICAL consortium

doi:10.1002/cam4.695

Blood lipids and prostate cancer: a Mendelian randomization analysis

Caroline J Bull, Carolina Bonilla, Jeff M P Holly, Claire M Perks, Neil Davies, Philip Haycock, Oriana Hoi Yun Yu, J Brent Richards, Rosalind Eeles, Doug Easton, Zsofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G Giles, Robert J MacInnis, Fredrik Wiklund, Henrik Gronberg, Christopher A Haiman, Johanna SchleutkerBørge 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, Agnieszka Micheal, Hardev Pandha, George Davey Smith, Sarah J Lewis, Richard M Martin, PRACTICAL consortium

Department of Clinical Medicine

34 Citations (Scopus)

Abstract

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.

Original language	English
Journal	Cancer Medicine
Volume	5
Issue number	6
Pages (from-to)	1125-1136
Number of pages	12
ISSN	2045-7634
DOIs	https://doi.org/10.1002/cam4.695
Publication status	Published - 1 Jun 2016

Keywords

Case-Control Studies
Genetic Association Studies
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Humans
Lipids
Male
Mendelian Randomization Analysis
Meta-Analysis as Topic
Neoplasm Grading
Neoplasm Staging
Odds Ratio
Polymorphism, Single Nucleotide
Population Surveillance
Prostatic Neoplasms
Quantitative Trait, Heritable
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

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

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Bull, C. J., Bonilla, C., Holly, J. M. P., Perks, C. M., Davies, N., Haycock, P., Yu, O. H. Y., Richards, J. B., Eeles, R., Easton, D., Kote-Jarai, Z., Amin Al Olama, A., Benlloch, S., Muir, K., Giles, G. G., MacInnis, R. J., Wiklund, F., Gronberg, H., Haiman, C. A., ... PRACTICAL consortium (2016). Blood lipids and prostate cancer: a Mendelian randomization analysis. Cancer Medicine, 5(6), 1125-1136. https://doi.org/10.1002/cam4.695

Bull, CJ, Bonilla, C, Holly, JMP, Perks, CM, Davies, N, Haycock, P, Yu, OHY, Richards, JB, Eeles, R, Easton, D, Kote-Jarai, Z, Amin Al Olama, A, Benlloch, S, Muir, K, Giles, GG, MacInnis, RJ, 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, Micheal, A, Pandha, H, Smith, GD, Lewis, SJ, Martin, RM & PRACTICAL consortium 2016, 'Blood lipids and prostate cancer: a Mendelian randomization analysis', Cancer Medicine, vol. 5, no. 6, pp. 1125-1136. https://doi.org/10.1002/cam4.695

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title = "Blood lipids and prostate cancer: a Mendelian randomization analysis",

abstract = "Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.",

keywords = "Case-Control Studies, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Lipids, Male, Mendelian Randomization Analysis, Meta-Analysis as Topic, Neoplasm Grading, Neoplasm Staging, Odds Ratio, Polymorphism, Single Nucleotide, Population Surveillance, Prostatic Neoplasms, Quantitative Trait, Heritable, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

author = "Bull, {Caroline J} and Carolina Bonilla and Holly, {Jeff M P} and Perks, {Claire M} and Neil Davies and Philip Haycock and Yu, {Oriana Hoi Yun} and Richards, {J Brent} and Rosalind Eeles and Doug Easton and Zsofia Kote-Jarai and {Amin Al Olama}, Ali and Sara Benlloch and Kenneth Muir and Giles, {Graham G} and MacInnis, {Robert J} 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 Agnieszka Micheal and Hardev Pandha and Smith, {George Davey} and Lewis, {Sarah J} and Martin, {Richard M} and {PRACTICAL consortium}",

note = "{\textcopyright} 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.",

year = "2016",

month = jun,

day = "1",

doi = "10.1002/cam4.695",

language = "English",

volume = "5",

pages = "1125--1136",

journal = "Cancer Medicine",

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publisher = "JohnWiley & Sons Ltd",

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TY - JOUR

T1 - Blood lipids and prostate cancer

T2 - a Mendelian randomization analysis

AU - Bull, Caroline J

AU - Bonilla, Carolina

AU - Holly, Jeff M P

AU - Perks, Claire M

AU - Davies, Neil

AU - Haycock, Philip

AU - Yu, Oriana Hoi Yun

AU - Richards, J Brent

AU - Eeles, Rosalind

AU - Easton, Doug

AU - Kote-Jarai, Zsofia

AU - Amin Al Olama, Ali

AU - Benlloch, Sara

AU - Muir, Kenneth

AU - Giles, Graham G

AU - MacInnis, Robert J

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 - Micheal, Agnieszka

AU - Pandha, Hardev

AU - Smith, George Davey

AU - Lewis, Sarah J

AU - Martin, Richard M

AU - PRACTICAL consortium

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.

AB - Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.

KW - Case-Control Studies

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - Lipids

KW - Male

KW - Mendelian Randomization Analysis

KW - Meta-Analysis as Topic

KW - Neoplasm Grading

KW - Neoplasm Staging

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Population Surveillance

KW - Prostatic Neoplasms

KW - Quantitative Trait, Heritable

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/cam4.695

DO - 10.1002/cam4.695

M3 - Journal article

C2 - 26992435

SN - 2045-7634

VL - 5

SP - 1125

EP - 1136

JO - Cancer Medicine

JF - Cancer Medicine

IS - 6

ER -

Blood lipids and prostate cancer: a Mendelian randomization analysis

Abstract

Keywords

UN SDGs

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