Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study
Bull, Caroline J; Bell, Joshua A; Murphy, Neil; Sanderson, Eleanor; Davey Smith, George; Timpson, Nicholas J; Banbury, Barbara L; Albanes, Demetrius; Berndt, Sonja I; Bézieau, Stéphane; Bishop, D Timothy; Brenner, Hermann; Buchanan, Daniel D; Burnett-Hartman, Andrea; Casey, Graham; Castellví-Bel, Sergi; Chan, Andrew T; Chang-Claude, Jenny; Cross, Amanda J; de la Chapelle, Albert; Figueiredo, Jane C; Gallinger, Steven J; Gapstur, Susan M; Giles, Graham G; Gruber, Stephen B; Gsur, Andrea; Hampe, Jochen; Hampel, Heather; Harrison, Tabitha A; Hoffmeister, Michael; Hsu, Li; Huang, Wen-Yi; Huyghe, Jeroen R; Jenkins, Mark A; Joshu, Corinne E; Keku, Temitope O; Kühn, Tilman; Kweon, Sun-Seog; Le Marchand, Loic; Li, Christopher I; Li, Li; Lindblom, Annika; Martín, Vicente; May, Anne M; Milne, Roger L; Moreno, Victor; Newcomb, Polly A; Offit, Kenneth; Ogino, Shuji; Phipps, Amanda I; Platz, Elizabeth A; Potter, John D; Qu, Conghui; Quirós, J Ramón; Rennert, Gad; Riboli, Elio; Sakoda, Lori C; Schafmayer, Clemens; Schoen, Robert E; Slattery, Martha L; Tangen, Catherine M; Tsilidis, Kostas K; Ulrich, Cornelia M; van Duijnhoven, Fränzel J B; van Guelpen, Bethany; Visvanathan, Kala; Vodicka, Pavel; Vodickova, Ludmila; Wang, Hansong; White, Emily; Wolk, Alicja; Woods, Michael O; Wu, Anna H; Campbell, Peter T; Zheng, Wei; Peters, Ulrike; Vincent, Emma E; Gunter, Marc J
(2020) BMC Medicine, volume 18, issue 1
(Article)
Abstract
BACKGROUND: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. METHODS: We examined sex- and site-specific associations of adiposity with CRC risk
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and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. RESULTS: In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. CONCLUSIONS: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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Keywords: Body mass index, CCFR, CORECT, Colorectal cancer, Epidemiology, GECCO, Mendelian randomization, Metabolism, NMR, Waist-to-hip ratio, General Medicine
ISSN: 1741-7015
Publisher: BioMed Central
Note: Funding Information: MSKCC: The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center (grant number P30 CA076292). Funding Information: HCES-CRC: The Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Funding Information: NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821), the National Institutes of Health, US Department of Health and Human Services (U01 CA74783), and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. Funding Information: NSHDS: Swedish Cancer Society; Cancer Research Foundation in Northern Sweden; Swedish Research Council; J C Kempe Memorial Fund; Faculty of Medicine, Umeå University, Umeå, Sweden; and Cutting-Edge Research Grant from the County Council of Västerbotten, Sweden. Funding Information: SCCFR: The Seattle Colon Cancer Family Registry was supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under awards U01 CA167551. Additional support for the SFCCR, Postmenopausal Hormones and Colon Cancer (PMH) study and the SCCFR Illumina HumanCytoSNP array were through NCI/NIH awards U01/U24 CA074794 and R01 CA076366 (to PAN). Funding Information: OFCCR: The Ontario Familial Colorectal Cancer Registry was supported in part by the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under award U01 CA167551 and award U01/U24 CA074783 (to SG). Additional funding for the OFCCR and ARCTIC testing and genetic analysis was through a Canadian Cancer Society CaRE (Cancer Risk Evaluation) program grant and Ontario Research Fund award GL201-043 (to BWZ), through the Canadian Institutes of Health Research award 112746 (to TJH), and through generous support from the Ontario Ministry of Research and Innovation. Funding Information: COLON: The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and the Dutch Cancer Society (UM 2012–5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). The Nqplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant no. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public-private partnership on precompetitive research in food and nutrition; and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Funding Information: The Multiethnic Cohort Study is supported by the National Cancer Institute grant (CA164973). Funding Information: SMS: This work was supported by the National Cancer Institute (grant P01 CA074184 to J.D.P. and P.A.N.; grants R01 CA097325, R03 CA153323, and K05 CA152715 to P.A.N.) and the National Center for Advancing Translational Sciences at the National Institutes of Health (grant KL2 TR000421 to A.N.B.-H.) Funding Information: Swedish Mammography Cohort and Cohort of Swedish Men: This work is supported by the Swedish Research Council /Infrastructure grant, the Swedish Cancer Foundation, and the Karolinska Institute’s Distinguished Professor Award to Alicja Wolk. Funding Information: EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). Funding Information: Harvard cohorts (HPFS, NHS, PHS): HPFS is supported by the National Institutes of Health (P01 CA055075, UM1 CA167552, U01 CA167552, R01 CA137178, R01 CA151993, R35 CA197735, K07 CA190673, and P50 CA127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA087969, UM1 CA186107, R01 CA151993, R35 CA197735, K07CA190673, and P50 CA127003), and PHS by the National Institutes of Health (R01 CA042182). Funding Information: The Colon Cancer Family Registry (CCFR, www.coloncfr.org ) was supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551), and through U01/U24 cooperative agreements from NCI with the following CCFR centers: Australasian (CA074778 and CA097735), Ontario (OFCCR) (CA074783), Seattle (SFCCR) (CA074794 (and R01 CA076366 to PAN)), USC Consortium (CA074799), Mayo Clinic (CA074800), and Hawaii (CA074806). Support for case ascertainment was provided in part from the Surveillance, Epidemiology, and End Results (SEER) Program and the following US state cancer registries: AZ, CO, MN, NC, and NH; and by the Victoria Cancer Registry (Australia) and Ontario Cancer Registry (Canada). Additional funding for the OFCCR/ARCTIC was through award GL201-043 from the Ontario Research Fund (to BWZ), award 112746 from the Canadian Institutes of Health Research (to TJH), through a Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society (to SG), and through generous support from the Ontario Ministry of Research and Innovation. The SCCFR Illumina HumanCytoSNP array was supported through NCI award R01 CA076366 (to PAN). The CCFR Set-1 (Illumina 1 M/1 M-Duo) and Set-2 (Illumina Omni1-Quad) scans were supported by NIH awards U01 CA122839 and R01 CA143247 (to GC). The CCFR Set-3 (Affymetrix Axiom CORECT Set array) was supported by NIH award U19 CA148107 and R01 CA81488 (to SBG). The CCFR Set-4 (Illumina OncoArray 600 K SNP array) was supported by NIH award U19 CA148107 (to SBG) and by the Center for Inherited Disease Research (CIDR), which is funded by the NIH to the Johns Hopkins University, contract number HHSN268201200008I. Colon Cancer Family Registry (CCFR): The content of this manuscript does not necessarily reflect the views or policies of the NIH or any of the collaborating centers in the CCFR, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government, any cancer registry, or the CCFR. Funding Information: MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Funding Information: PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Funding was provided by the National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. Funding Information: ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184 (Li/Ulrich), U01 CA206110 (Ulrich/Li/Siegel/Figueireido/Colditz, 2P30CA015704-40 (Gilliland), R01 CA207371 (Ulrich/Li)), the Matthias Lackas Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Funding Information: EPICOLON: This work was supported by grants from Fondo de Investigación Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, P111/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, Acción Transversal de Cáncer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundación Científica de la Asociación Española contra el Cáncer (GCB13131592CAST), Beca Grupo de Trabajo “Oncología” AEG (Asociación Española de Gastroenterología), Fundación Privada Olga Torres, FP7 CHIBCHA Consortium, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya, 2014SGR135, 2014SGR255, 2017SGR21, 2017SGR653), Catalan Tumour Bank Network (Pla Director d’Oncologia, Generalitat de Catalunya), PERIS (SLT002/16/00398, Generalitat de Catalunya), CERCA Programme (Generalitat de Catalunya), and COST Action BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. Funding Information: Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350, P01 CA196569, R01 CA201407), and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). Funding Information: MECC: This work was supported by the National Institutes of Health, US Department of Health and Human Services (R01 CA81488 to SBG and GR). Funding Information: DACHS: This work was supported by the German Research Council (BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1, HO 5117/2-1, HE 5998/2-1, KL 2354/3-1, RO 2270/8-1, and BR 1704/17-1); the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany; and the German Federal Ministry of Education and Research (01KH0404, 01ER0814, 01ER0815, 01ER1505A, and 01ER1505B). Funding Information: The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish research council: K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2, and the Stockholm County Council (ALF project). Funding Information: This publication is the work of the authors who are guarantors for its contents. CJB is supported by Diabetes UK (17/0005587), the Wellcome Trust (202802/Z/16/Z), and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). JAB is supported by the Cancer Research UK (C18281/A19169) and the Elizabeth Blackwell Institute for Health Research, University of Bristol and the Wellcome Trust Institutional Strategic Support Fund (204813/Z/16/Z). NJT is a Wellcome Trust Investigator (202802/Z/16/Z); is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z); is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-20011) and the MRC Integrative Epidemiology Unit (MC_UU_12013/3); and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). EEV is supported by Diabetes UK (17/0005587) and the World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme (IIG_2019_2009). GDS works in a unit funded by the UK Medical Research Council (MC_UU_00011/1) and the University of Bristol. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: Women’s Health Initiative: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Funding Information: EPIC: The coordination of EPIC is financially supported by the European Commission (DGSANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRCItaly and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI13/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (UK). Funding Information: NCCCS I & II: We acknowledge the funding support for this project from the National Institutes of Health, R01 CA66635 and P30 DK034987. Funding Information: SELECT: Research reported in this publication was supported in part by the National Cancer Institute of the National Institutes of Health under Award Numbers U10 CA37429 (CD Blanke) and UM1 CA182883 (CM Tangen/IM Thompson). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726. Funding Information: Czech Republic CCS: This work was supported by the Grant Agency of the Czech Republic (grants CZ GA CR: GAP304/10/1286 and 1585) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants AZV 15-27580A, AZV 17-30920A, and NV18/03/00199). Funding Information: ASTERISK: A Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), and the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). Funding Information: ESTHER/VERDI. This work was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. Funding Information: LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Funding Information: The ATBC Study is supported by the Intramural Research Program of the US National Cancer Institute, National Institutes of Health, and by US Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services. Funding Information: CORSA: “Österreichische Nationalbank Jubiläumsfondsprojekt” (12511) and Austrian Research Funding Agency (FFG) grant 829675. Funding Information: ASTERISK: We are very grateful to Dr. Bruno Buecher without whom this project would not have existed. We also thank all those who agreed to participate in this study, including the patients and the healthy control persons, as well as all the physicians, technicians, and students. COLON and NQplus: The authors would like to thank the COLON and NQplus investigators at Wageningen University & Research and the involved clinicians in the participating hospitals. CCFR: The Colon CFR graciously thanks the generous contributions of their 42,505 study participants, dedication of study staff, and the financial support from the US National Cancer Institute, without which this important registry would not exist. CORSA: We kindly thank all those who contributed to the screening project Burgenland against CRC. Furthermore, we are grateful to Doris Mejri and Monika Hunjadi for the laboratory assistance. CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. Funding Information: CRCGEN: Colorectal Cancer Genetics & Genomics, Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds—a way to build Europe—(grants PI14-613 and PI09-1286), Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (grant 2017SGR723), and Junta de Castilla y León (grant LE22A10-2). The sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d’Oncología de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013, and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Funding Information: CLUE II: This research was funded by the American Institute for Cancer Research and the Maryland Cigarette Restitution Fund at Johns Hopkins, the NCI (U01 CA86308, P30 CA006973 to W.G. Nelson), and the National Institute on Aging (U01 AG18033). Publisher Copyright: © 2020, The Author(s).
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