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 PalotieLaura 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

Cancer and Genomic Sciences

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

38 Citations (Scopus)

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
Early online date	6 Apr 2017
DOIs	https://doi.org/10.1002/ijc.30709
Publication status	Published - 15 Jun 2017

Keywords

Cholesterol
Colorectal Neoplasms
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Hyperlipidemias
Lipoproteins, HDL
Lipoproteins, LDL
Logistic Models
Mendelian Randomization Analysis
Odds Ratio
Polymorphism, Single Nucleotide
Risk Assessment
Risk Factors
Triglycerides
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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10.1002/ijc.30709

http://discovery.ucl.ac.uk/1555010/

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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{17ae600d243140b48c78bb8d8fea7243,

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 = "Cholesterol, Colorectal Neoplasms, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Hyperlipidemias, Lipoproteins, HDL, Lipoproteins, LDL, Logistic Models, Mendelian Randomization Analysis, Odds Ratio, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Triglycerides, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't",

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 Antti-Pekka Sarin 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 Jukka-Pekka Mecklin 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 = "{\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",

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Rodriguez-Broadbent, H, Law, PJ, Sud, A, Palin, K, Tuupanen, S, Gylfe, A, Hänninen, UA, Cajuso, T, Tanskanen, T, Kondelin, J, Kaasinen, E, Sarin, A-P, Ripatti, S, Eriksson, JG, Rissanen, H, Knekt, P, Pukkala, E, Jousilahti, P, Salomaa, V, Palotie, A, Renkonen-Sinisalo, L, Lepistö, A, Böhm, J, Mecklin, J-P, 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 - Cholesterol

KW - Colorectal Neoplasms

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Hyperlipidemias

KW - Lipoproteins, HDL

KW - Lipoproteins, LDL

KW - Logistic Models

KW - Mendelian Randomization Analysis

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Risk Assessment

KW - Risk Factors

KW - Triglycerides

KW - Journal Article

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

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

U2 - 10.1002/ijc.30709

DO - 10.1002/ijc.30709

M3 - Article

C2 - 28340513

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

Abstract

Keywords

UN SDGs

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