Rodriguez-Broadbent, H., Law, P. J., Sud, A., Palin, K., Tuupanen, S., Gylfe, A., Hanninen, 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., Palotie, A., Renkonen-Sinisalo, L., Lepisto, A., Bohm, J., Mecklin, J. P., Al-Tassan, N. A., Palles, C., Martin, L., Barclay, E., Farrington, S. M., Timofeeva, M. N., Meyer, B. F., Wakil, S. M., Campbell, H., Smith, C. G., Idziaszczyk, S., Maughan, T. S., Kaplan, R., Kerr, R., Kerr, D., Passarelli, M. N., Figueiredo, J. C., Buchanan, D. D., Win, A. K., Hopper, J. L., Jenkins, M. A., Lindor, N. M., Newcomb, P. A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Aaltonen, L. A., Cheadle, J. P., Tomlinson, I. P., Dunlop, M. G., Houlston, R. S. (2017) Mendelian randomisation implicates hyperlipidaemia as a risk factor for colorectal cancer. INTERNATIONAL JOURNAL OF CANCER, 140 (12). pp. 2701-2708. ISSN 0020-7136

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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 x 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. What's new? While observational studies have suggested an association between blood cholesterol levels and colorectal cancer (CRC), they do not establish causality and may be influenced by confounding factors. Here the authors used Mendelian randomization, the relationship between genetic risk scores for lipid traits and CRC, to provide new evidence for a causal link between both. Their results point to hyperlipidaemia as an important target for CRC prevention in the population.

Item Type:	Article
Authors (ICR Faculty only):	Houlston, Richard
All Authors:	Rodriguez-Broadbent, H., Law, P. J., Sud, A., Palin, K., Tuupanen, S., Gylfe, A., Hanninen, 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., Palotie, A., Renkonen-Sinisalo, L., Lepisto, A., Bohm, J., Mecklin, J. P., Al-Tassan, N. A., Palles, C., Martin, L., Barclay, E., Farrington, S. M., Timofeeva, M. N., Meyer, B. F., Wakil, S. M., Campbell, H., Smith, C. G., Idziaszczyk, S., Maughan, T. S., Kaplan, R., Kerr, R., Kerr, D., Passarelli, M. N., Figueiredo, J. C., Buchanan, D. D., Win, A. K., Hopper, J. L., Jenkins, M. A., Lindor, N. M., Newcomb, P. A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Aaltonen, L. A., Cheadle, J. P., Tomlinson, I. P., Dunlop, M. G., Houlston, R. S.
Additional Information:	ISI Document Delivery No.: ET3DY Times Cited: 0 Cited Reference Count: 34 Rodriguez-Broadbent, Henry Law, Philip J. Sud, Amit Palin, Kimmo Tuupanen, Sari Gylfe, Alexandra Hanninen, Ulrika A. Cajuso, Tatiana Tanskanen, Tomas Kondelin, Johanna Kaasinen, Eevi Sarin, Antti-Pekka Ripatti, Samuli Eriksson, Johan G. Rissanen, Harri Knekt, Paul Pukkala, Eero Jousilahti, Pekka Salomaa, Veikko Palotie, Aarno Renkonen-Sinisalo, Laura Lepisto, Anna Bohm, Jan Mecklin, Jukka-Pekka Al-Tassan, Nada A. Palles, Claire Martin, Lynn Barclay, Ella Farrington, Susan M. Timofeeva, Maria N. Meyer, Brian F. Wakil, Salma M. Campbell, Harry Smith, Christopher G. Idziaszczyk, Shelley Maughan, Timothy S. Kaplan, Richard Kerr, Rachel Kerr, David Passarelli, Michael N. Figueiredo, Jane C. Buchanan, Daniel D. Win, Aung K. Hopper, John L. Jenkins, Mark A. Lindor, Noralane M. Newcomb, Polly A. Gallinger, Steven Conti, David Schumacher, Fred Casey, Graham Aaltonen, Lauri A. Cheadle, Jeremy P. Tomlinson, Ian P. Dunlop, Malcolm G. Houlston, Richard S. Wellcome Trust [202639/Z/16/Z, 090532/Z/09/Z]; Cancer Research UK (Bobby Moore Fund for Cancer Research UK) [C1298/A8362]; National Cancer Research Network; Cancer Research UK [C348/A12076]; Oxford Comprehensive Biomedical Research Centre; CHIBCHA grant [EU FP7]; European Union [258236]; FP7 collaborative project SYSCOL; COST Action in UK [BM1206]; Cancer Research UK; Medical Research Council; National Institute of Health Research Cancer Research Network; Tenovus; Kidani Trust; Cancer Research Wales; National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit; KFSHRC; Academy of Finland (Finnish Center of Excellence Program) [250345]; Jane and Aatos Erkko Foundation; Finnish Cancer Society; European Research Council (ERC) [268648]; Sigrid Juselius Foundation; SYSCOL; Nordic Information for Action eScience Center (NIASC); Nordic Center of Excellence - by NordForsk [62721]; State Research Funding of Kuopio University Hospital [B1401]; Academy of Finland [271642, 263164, 100499, 205585, 265240, 263278]; Ministry of Education and Culture, Finland; Finnish Academy [139635]; Wellcome Trust Sanger Institute; ENGAGE-European Network for Genetic and Genomic Epidemiology [FP7-HEALTH-F4-2007, 201413]; National Institute of Alcohol Abuse and Alcoholism [AA-12502, AA-00145, K02AA018755]; National Cancer Institute [UM1 CA167551]; National Institutes of Health; Australasian Colorectal Cancer Family Registry [U01 CA074778, U01/U24 CA097735]; USC Consortium Colorectal Cancer Family Registry [U01/U24 CA074799]; Mayo Clinic Cooperative Familial Registry for Colon Cancer Studies [U01/U24 CA074800]; Ontario Familial Colorectal Cancer Registry [U01/U24 CA074783]; Seattle Colorectal Cancer Family Registry [U01/U24 CA074794]; University of Hawaii Colorectal Cancer Family Registry [U01/U24 CA074806]; National Cancer Institute; National Institutes of Health [U01 CA122839, R01 CA143237]; Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center [N01-CN-67009, N01-PC-35142, HHSN2612013000121]; Hawaii Department of Health [N01-PC-67001, N01-PC-35137, HHSN26120100037C]; California Department of Public Health [HHSN261201000035C] Grant sponsor: Wellcome Trust; Grant number: 202639/Z/16/Z; Grant sponsor: Cancer Research UK (Bobby Moore Fund for Cancer Research UK); Grant number: C1298/A8362; Grant sponsors: National Cancer Research Network and Cancer Research UK; Grant number: C348/A12076; Grant sponsors: Oxford Comprehensive Biomedical Research Centre and CHIBCHA grant; Grant number: EU FP7; Grant sponsor: Wellcome Trust; Grant number: 090532/Z/09/Z; Grant sponsor: European Union; Grant number: FP7/207-2013 and 258236; Grant sponsor: FP7 collaborative project SYSCOL and COST Action in UK; Grant number: BM1206; Grant sponsors: Cancer Research UK, Medical Research Council, National Institute of Health Research Cancer Research Network, Tenovus, the Kidani Trust, Cancer Research Wales and the National Institute for Social Care and Health Research Cancer Genetics Biomedical Research Unit (2011-2014), KFSHRC, Academy of Finland (Finnish Center of Excellence Program 2012-2017); Grant number: 250345; Grant sponsors: Jane and Aatos Erkko Foundation, the Finnish Cancer Society, the European Research Council (ERC); Grant number: 268648; Grant sponsors: Sigrid Juselius Foundation, SYSCOL, the Nordic Information for Action eScience Center (NIASC), the Nordic Center of Excellence financed by NordForsk; Grant number: 62721; Grant sponsor: State Research Funding of Kuopio University Hospital; Grant number: B1401; Grant sponsor: Academy of Finland; Grant numbers: 271642 and 263164; Grant sponsors: Ministry of Education and Culture, Finland, Finnish Academy; Grant number: 139635; Grant sponsors: Wellcome Trust Sanger Institute and ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007; Grant number: 201413; Grant sponsor: National Institute of Alcohol Abuse and Alcoholism; Grant numbers: AA-12502 and AA-00145 and K02AA018755; Grant sponsor: Academy of Finland; Grant numbers: 100499, 205585, 265240 and 263278; Grant sponsor: National Cancer Institute; Grant number: UM1 CA167551; Grant sponsors: National Institutes of Health and Australasian Colorectal Cancer Family Registry; Grant numbers: U01 CA074778, U01/U24 CA097735; Grant sponsor: USC Consortium Colorectal Cancer Family Registry; Grant number: U01/U24 CA074799; Grant sponsor: Mayo Clinic Cooperative Familial Registry for Colon Cancer Studies; Grant number: U01/U24 CA074800; Grant sponsor: Ontario Familial Colorectal Cancer Registry; Grant number: U01/U24 CA074783; Grant sponsor: Seattle Colorectal Cancer Family Registry; Grant number: U01/U24 CA074794; Grant sponsor: University of Hawaii Colorectal Cancer Family Registry; Grant number: U01/U24 CA074806; Grant sponsors: National Cancer Institute, National Institutes of Health; Grant numbers: U01 CA122839 and R01 CA143237; Grant sponsor: Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center; Grant numbers: N01-CN-67009, N01-PC-35142, HHSN2612013000121; Grant sponsor: Hawaii Department of Health; Grant numbers: N01-PC-67001, N01-PC-35137, HHSN26120100037C; Grant sponsor: California Department of Public Health; Grant number: HHSN261201000035C 0 WILEY HOBOKEN INT J CANCER
Uncontrolled Keywords:	Mendelian randomisation hyperlipidaemia cholesterol colorectal cancer risk GENOME-WIDE METAANALYSIS BLOOD-LIPIDS DISEASE IDENTIFICATION REGRESSION TRAITS LOCI
Research teams:	ICR divisions > Genetics and Epidemiology > Molecular & Population Genetics ICR divisions > Molecular Pathology > Molecular & Population Genetics ICR divisions > Molecular Pathology > Myeloma Group
Depositing User:	Barry Jenkins
Date Deposited:	23 May 2017 14:42
Last Modified:	23 May 2017 14:42
URI:	http://publications.icr.ac.uk/id/eprint/15948

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