Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Henry Rodriguez-Broadbent; Philip J. Law; Amit Sud; Kimmo Palin; Sari Tuupanen; Alexandra Gylfe; Ulrika A. Hänninen; Tatiana Cajuso; Tomas Tanskanen; Johanna Kondelin; Eevi Kaasinen; Antti Pekka Sarin; Samuli Ripatti; Johan G. Eriksson; Harri Rissanen; Paul Knekt; Eero Pukkala; Pekka Jousilahti; Veikko Salomaa; Aarno Palotie; Laura Renkonen-Sinisalo; Anna Lepistö; Jan Böhm; Jukka Pekka Mecklin; Nada A. Al-Tassan; Claire Palles; Lynn Martin; Ella Barclay; Susan M. Farrington; Maria N. Timofeeva; Brian F. Meyer; Salma M. Wakil; Harry Campbell; Christopher G. Smith; Shelley Idziaszczyk; Timothy S. Maughan; Richard Kaplan; Rachel Kerr; David Kerr; Michael N. Passarelli; Jane C. Figueiredo; Daniel D. Buchanan; Aung K. Win; John L. Hopper; Mark A. Jenkins; Noralane M. Lindor; Polly A. Newcomb; Steven Gallinger; David Conti; Fred Schumacher; Graham Casey; Lauri A. Aaltonen; Jeremy P. Cheadle; Ian P. Tomlinson; Malcolm G. Dunlop; Richard S. Houlston

doi:10.1002/ijc.30709

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

Henry Rodriguez-Broadbent
, Philip J. Law
, Amit Sud
, Kimmo Palin
, Sari Tuupanen
, Alexandra Gylfe
, Ulrika A. Hänninen
, Tatiana Cajuso
, Tomas Tanskanen
, Johanna Kondelin
, Eevi Kaasinen
, Antti Pekka Sarin
, Samuli Ripatti
, Johan G. Eriksson
, Harri Rissanen
, Paul Knekt
, Eero Pukkala
, Pekka Jousilahti
, Veikko Salomaa
, Aarno Palotie

Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka Pekka Mecklin, Nada A. Al-Tassan, Claire Palles, Lynn Martin, Ella Barclay, Susan M. Farrington, Maria N. Timofeeva, Brian F. Meyer, Salma M. Wakil, Harry Campbell, Christopher G. Smith, Shelley Idziaszczyk, Timothy S. Maughan, Richard Kaplan, Rachel Kerr, David Kerr, Michael N. Passarelli, Jane C. Figueiredo, Daniel D. Buchanan, Aung K. Win, John L. Hopper, Mark A. Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steven Gallinger, David Conti, Fred Schumacher, Graham Casey, Lauri A. Aaltonen, Jeremy P. Cheadle, Ian P. Tomlinson, Malcolm G. Dunlop, Richard S. Houlston

The Institute of Cancer Research
University of Helsinki
Wellcome Trust
National Institute for Health and Welfare
Folkhalsan
Helsinki University Central Hospital
Finnish Cancer Registry
Tampere University
Massachusetts General Hospital
Broad Institute
Central Finland Central Hospital
University of Eastern Finland
King Faisal Specialist Hospital and Research Centre
University of Oxford
University of Edinburgh
Cardiff University
Medical Research Council
Cedars-Sinai Medical Center
University of Southern California
University of Melbourne
Mayo Clinic Scottsdale-Phoenix, Arizona
Fred Hutchinson Cancer Research Center
University of Toronto
University of Virginia

Research output: Contribution to journal › Article › peer-review

80 Scopus citations

Abstract

While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10⁻⁴). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

Original language	English
Pages (from-to)	2701-2708
Number of pages	8
Journal	International Journal of Cancer
Volume	140
Issue number	12
DOIs	https://doi.org/10.1002/ijc.30709
State	Published - Jun 15 2017

Keywords

Mendelian randomisation
cholesterol
colorectal cancer
hyperlipidaemia
risk

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10.1002/ijc.30709

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Rodriguez-Broadbent, H., Law, P. J., Sud, A., Palin, K., Tuupanen, S., Gylfe, A., Hänninen, U. A., Cajuso, T., Tanskanen, T., Kondelin, J., Kaasinen, E., Sarin, A. P., Ripatti, S., Eriksson, J. G., Rissanen, H., Knekt, P., Pukkala, E., Jousilahti, P., Salomaa, V., ... Houlston, R. S. (2017). Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. International Journal of Cancer, 140(12), 2701-2708. https://doi.org/10.1002/ijc.30709

@article{3ea6cf1965cc490d95849bdebd8f30ed,

title = "Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer",

abstract = "While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95\% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95\% CI: 0.92–1.18, p = 0.49), 0.94 (95\% CI: 0.84–1.05, p = 0.27), and 0.98 (95\% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95\% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.",

keywords = "Mendelian randomisation, cholesterol, colorectal cancer, hyperlipidaemia, risk",

author = "Henry Rodriguez-Broadbent and Law, \{Philip J.\} and Amit Sud and Kimmo Palin and Sari Tuupanen and Alexandra Gylfe and H{\"a}nninen, \{Ulrika A.\} and Tatiana Cajuso and Tomas Tanskanen and Johanna Kondelin and Eevi Kaasinen and Sarin, \{Antti Pekka\} and Samuli Ripatti and Eriksson, \{Johan G.\} and Harri Rissanen and Paul Knekt and Eero Pukkala and Pekka Jousilahti and Veikko Salomaa and Aarno Palotie and Laura Renkonen-Sinisalo and Anna Lepist{\"o} and Jan B{\"o}hm and Mecklin, \{Jukka Pekka\} and Al-Tassan, \{Nada A.\} and Claire Palles and Lynn Martin and Ella Barclay and Farrington, \{Susan M.\} and Timofeeva, \{Maria N.\} and Meyer, \{Brian F.\} and Wakil, \{Salma M.\} and Harry Campbell and Smith, \{Christopher G.\} and Shelley Idziaszczyk and Maughan, \{Timothy S.\} and Richard Kaplan and Rachel Kerr and David Kerr and Passarelli, \{Michael N.\} and Figueiredo, \{Jane C.\} and Buchanan, \{Daniel D.\} and Win, \{Aung K.\} and Hopper, \{John L.\} and Jenkins, \{Mark A.\} and Lindor, \{Noralane M.\} and Newcomb, \{Polly A.\} and Steven Gallinger and David Conti and Fred Schumacher and Graham Casey and Aaltonen, \{Lauri A.\} and Cheadle, \{Jeremy P.\} and Tomlinson, \{Ian P.\} and Dunlop, \{Malcolm G.\} and Houlston, \{Richard S.\}",

note = "Publisher Copyright: {\textcopyright} 2017 UICC",

year = "2017",

month = jun,

day = "15",

doi = "10.1002/ijc.30709",

language = "English",

volume = "140",

pages = "2701--2708",

journal = "International Journal of Cancer",

issn = "0020-7136",

number = "12",

}

Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hänninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, AP, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepistö, A, Böhm, J, Mecklin, JP, Al-Tassan, NA, Palles, C, Martin, L, Barclay, E, Farrington, SM, Timofeeva, MN, Meyer, BF, Wakil, SM, Campbell, H, Smith, CG, Idziaszczyk, S, Maughan, TS, Kaplan, R, Kerr, R, Kerr, D, Passarelli, MN, Figueiredo, JC, Buchanan, DD, Win, AK, Hopper, JL, Jenkins, MA, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Aaltonen, LA, Cheadle, JP, Tomlinson, IP, Dunlop, MG & Houlston, RS 2017, 'Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer', International Journal of Cancer, vol. 140, no. 12, pp. 2701-2708. https://doi.org/10.1002/ijc.30709

TY - JOUR

T1 - Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

AU - Rodriguez-Broadbent, Henry

AU - Law, Philip J.

AU - Sud, Amit

AU - Palin, Kimmo

AU - Tuupanen, Sari

AU - Gylfe, Alexandra

AU - Hänninen, Ulrika A.

AU - Cajuso, Tatiana

AU - Tanskanen, Tomas

AU - Kondelin, Johanna

AU - Kaasinen, Eevi

AU - Sarin, Antti Pekka

AU - Ripatti, Samuli

AU - Eriksson, Johan G.

AU - Rissanen, Harri

AU - Knekt, Paul

AU - Pukkala, Eero

AU - Jousilahti, Pekka

AU - Salomaa, Veikko

AU - Palotie, Aarno

AU - Renkonen-Sinisalo, Laura

AU - Lepistö, Anna

AU - Böhm, Jan

AU - Mecklin, Jukka Pekka

AU - Al-Tassan, Nada A.

AU - Palles, Claire

AU - Martin, Lynn

AU - Barclay, Ella

AU - Farrington, Susan M.

AU - Timofeeva, Maria N.

AU - Meyer, Brian F.

AU - Wakil, Salma M.

AU - Campbell, Harry

AU - Smith, Christopher G.

AU - Idziaszczyk, Shelley

AU - Maughan, Timothy S.

AU - Kaplan, Richard

AU - Kerr, Rachel

AU - Kerr, David

AU - Passarelli, Michael N.

AU - Figueiredo, Jane C.

AU - Buchanan, Daniel D.

AU - Win, Aung K.

AU - Hopper, John L.

AU - Jenkins, Mark A.

AU - Lindor, Noralane M.

AU - Newcomb, Polly A.

AU - Gallinger, Steven

AU - Conti, David

AU - Schumacher, Fred

AU - Casey, Graham

AU - Aaltonen, Lauri A.

AU - Cheadle, Jeremy P.

AU - Tomlinson, Ian P.

AU - Dunlop, Malcolm G.

AU - Houlston, Richard S.

PY - 2017/6/15

Y1 - 2017/6/15

N2 - While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

AB - While elevated blood cholesterol has been associated with an increased risk of colorectal cancer (CRC) in observational studies, causality is uncertain. Here we apply a Mendelian randomisation (MR) analysis to examine the potential causal relationship between lipid traits and CRC risk. We used single nucleotide polymorphisms (SNPs) associated with blood levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as instrumental variables (IV). We calculated MR estimates for each risk factor with CRC using SNP-CRC associations from 9,254 cases and 18,386 controls. Genetically predicted higher TC was associated with an elevated risk of CRC (odds ratios (OR) per unit SD increase = 1.46, 95% confidence interval [CI]: 1.20–1.79, p = 1.68 × 10−4). The pooled ORs for LDL, HDL, and TG were 1.05 (95% CI: 0.92–1.18, p = 0.49), 0.94 (95% CI: 0.84–1.05, p = 0.27), and 0.98 (95% CI: 0.85–1.12, p = 0.75) respectively. A genetic risk score for 3-hydoxy-3-methylglutaryl-coenzyme A reductase (HMGCR) to mimic the effects of statin therapy was associated with a reduced CRC risk (OR = 0.69, 95% CI: 0.49–0.99, p = 0.046). This study supports a causal relationship between higher levels of TC with CRC risk, and a further rationale for implementing public health strategies to reduce the prevalence of hyperlipidaemia.

KW - Mendelian randomisation

KW - cholesterol

KW - colorectal cancer

KW - hyperlipidaemia

KW - risk

UR - https://www.scopus.com/pages/publications/85017448757

U2 - 10.1002/ijc.30709

DO - 10.1002/ijc.30709

M3 - Article

C2 - 28340513

AN - SCOPUS:85017448757

SN - 0020-7136

VL - 140

SP - 2701

EP - 2708

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 12

ER -

Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer

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