Journal article

Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

Aayah Nounu, Rebecca C Richmond, Isobel D Stewart, Praveen Surendran, Nicholas J Wareham, Adam Butterworth, Stephanie J Weinstein, Demetrius Albanes, John A Baron, John L Hopper, Jane C Figueiredo, Polly A Newcomb, Noralane M Lindor, Graham Casey, Elizabeth A Platz, Loic Le Marchand, Cornelia M Ulrich, Christopher I Li, Fraenzel JB van Dujinhoven, Andrea Gsur Show all

NUTRIENTS | MDPI | Published : 2021

Abstract

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three me..

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Awarded by German Federal Ministry of Education and Research


Awarded by Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services


Awarded by Center for Inherited Disease Research (CIDR)


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Awarded by project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project - European Union Seventh Framework Programme (FP7/2007-2013)


Awarded by National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. Department of Health and Human Services


Awarded by National Institutes of Environmental Health Sciences, National Institutes of Health


Awarded by CORSA: "Osterreichische Nationalbank Jubilaumsfondsprojekt"


Awarded by Austrian Research Funding Agency (FFG)


Awarded by FEDER funds-a way to build Europe


Awarded by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government


Awarded by Junta de Castilla y Leon


Awarded by Xarxa de Bancs de Tumors de Catalunya - Pla Director d'Oncologia de Catalunya (XBTC), Plataforma Biobancos


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Awarded by ISCIII RETIC (Spain)


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Awarded by MRC Cambridge Initiative in Metabolic Science


Awarded by Innovative Medicines Initiative Joint Undertaking under EMIF


Awarded by Fondo de Investigacion Sanitaria/FEDER (Accion Transversal de Cancer)


Awarded by Xunta de Galicia


Awarded by Ministerio de Economia y Competitividad


Awarded by Fundacion Cientifica de la Asociacion Espanola contra el Cancer


Awarded by Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya)


Awarded by PERIS (Generalitat de Catalunya)


Awarded by COST Actions


Awarded by The National Institutes of Health


Awarded by Chonnam National University Hwasun Hospital)


Awarded by NIHR Blood and Transplant Research Unit in Donor Health and Genomics


Awarded by UKMedical Research Council


Awarded by British Heart Foundation


Awarded by Damon Runyon Cancer Research Foundation


Awarded by Food Standards Agency and Cancer Research UK Programme Award


Awarded by Australian National Health and Medical Research Council


Awarded by National Institutes of Health, U.S. Department of Health and Human Services


Awarded by Florida Department of Health Bankhead-Coley


Awarded by Tissue Core at the H. Lee Moffitt Cancer Center & Research Institute, a National Cancer Institute-designated Comprehensive Cancer Center


Awarded by Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research


Awarded by National Cancer Institute of Canada


Awarded by National Cancer Institute (NCI) of the National Institutes of Health (NIH)


Awarded by Ontario Research Fund award


Awarded by National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI)


Awarded by National Cancer Institute of the National Institutes of Health


Awarded by The National Cancer Institute


Awarded by National Center for Advancing Translational Sciences at the National Institutes of Health


Awarded by Swedish research council


Awarded by National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services



Funding Acknowledgements

This work was funded by a PhD studentship from the Medical Research Council (AN), a Cancer Research UK Programme Grant (C19/A11975, ACW), an MRC Research Grant (MR/R017247/1, ACW) and by the John James Bristol Foundation. Further funding was provided by The UK Medical Research Council Integrative Epidemiology Unit (MC_UU_12013_2, CLR) and Cancer Research UK (C18281/A19169, CLR). RCR is a de Pass Vice Chancellor Research Fellow at the University of Bristol. PS is supported by a Rutherford Fund Fellowship from the Medical Research Council grant MR/S003746/1. DS was supported by the German Federal Ministry of Education and Research (01KT1510). Consortia funding: Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA164930, U01 CA137088, R01 CA059045, R21 CA191312, R01201407). Genotyping/Sequencing services were provided by the Center for Inherited Disease Research (CIDR) contract number HHSN268201700006I and HHSN268201200008I. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704. Scientific Computing Infrastructure at Fred Hutch funded by ORIP grant S10OD028685. 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 Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). The ATBC Study is supported by the Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health. CLUE II funding was from the National Cancer Institute (U01 CA86308, Early Detection Research Network; P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. Maryland Cancer Registry (MCR) cancer data was provided by the Maryland Cancer Registry, Center for Cancer Prevention and Control, Maryland Department of Health, with funding from the State of Maryland and the Maryland Cigarette Restitution Fund. The collection and availability of cancer registry data is also supported by the Cooperative Agreement NU58DP006333, funded by the Centers for Disease Control and Prevention. Its contents are solely the responsibility of the authors, and do not necessarily represent the official views of the Centers for Disease Control and Prevention or the Department of Health and Human Services. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184 (Li/Ulrich), U01 CA206110 (Ulrich/Li/Siegel/Figueireido/Colditz, 2P30CA01570440 (Gilliland), R01 CA207371 (Ulrich/Li)), the Matthias Lackas Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. The Colon Cancer Family Registry (CCFR, www.coloncfr.org, accessed on 16 November 2021) is supported in part by funding from the National Cancer Institute (NCI), National Institutes of Health (NIH) (award U01 CA167551). The CCFR Set-1 (Illumina 1M/1M-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 600K 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. The SCCFR Illumina HumanCytoSNP array was supported through NCI award R01 CA076366 (to PAN). 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 content of this manuscript does not necessarily reflect the views or policies of the NCI, NIH, or any of the collaborating centers in the Colon Cancer Family Registry (CCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government, any cancer registry, or the CCFR. 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. Colorectal Cancer Transdisciplinary (CORECT) Study: The CORECT Study was supported by the National Cancer Institute, National Institutes of Health (NCI/NIH), U.S. 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). CORSA: "Osterreichische Nationalbank Jubilaumsfondsprojekt" (12511) and Austrian Research Funding Agency (FFG) grant 829675. CPS-II: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II (CPS-II) cohort. This study was conducted with Institutional Review Board approval. 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 Leon (grant LE22A10-2). Sample collection of this work was supported by the Xarxa de Bancs de Tumors de Catalunya sponsored by Pla Director d'Oncologia de Catalunya (XBTC), Plataforma Biobancos PT13/0010/0013 and ICOBIOBANC, sponsored by the Catalan Institute of Oncology. Czech Republic CCS: This work was supported by the Czech Science Foundation (20-03997S) and by the Grant Agency of the Ministry of Health of the Czech Republic (grants NV18/03/00199 and NU21-07-00247).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, 01ER1505B and 01GL1712). The sponsors had no role in the study design and the collection, analysis, and interpretation of data. DALS: National Institutes of Health (R01 CA48998 to M. L. Slattery). EDRN: This work is funded and supported by the NCI, EDRN Grant (U01 CA 84968-06). 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 Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (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 CancroAIRCItaly 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 Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPICNorfolk; C570/A16491 and C8221/A19170 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPICOxford) (United Kingdom). The EPIC-Norfolk study (https://doi.org/10.22025/2019.10.105.00004, accessed on 16 November 2021) has received funding from the Medical Research Council (MR/N003284/1, MC-UU_12015/1 and MC_UU_00006/1) and Cancer Research UK (C864/A14136). The genetics work in the EPIC-Norfolk study was funded by the Medical Research Council (MC_PC_13048). Metabolite measurements in the EPIC-Norfolk study were supported by the MRC Cambridge Initiative in Metabolic Science (MR/L00002/1) and the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement no. 115372.EPICOLON: This work was supported by grants from Fondo de Investigacion Sanitaria/FEDER (PI08/0024, PI08/1276, PS09/02368, PI11/00219, PI11/00681, PI14/00173, PI14/00230, PI17/00509, 17/00878, PI20/00113, PI20/00226, Accion Transversal de Cancer), Xunta de Galicia (PGIDIT07PXIB9101209PR), Ministerio de Economia y Competitividad (SAF07-64873, SAF 2010-19273, SAF2014-54453R), Fundacion Cientifica de la Asociacion Espanola contra el Cancer (GCB13131592CAST), Beca Grupo de Trabajo "Oncologia" AEG (Asociacion Espanola de Gastroenterologia), Fundacion Privada Olga Torres, FP7 CHIBCHA Consortium, Agencia de Gestio 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 Actions BM1206 and CA17118. CIBERehd is funded by the Instituto de Salud Carlos III. ESTHER/VERDI. This work was supported by grants from the Baden-Wurttemberg Ministry of Science, Research and Arts and the German Cancer Aid. 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). Hawaii Adenoma Study: NCI grants R01 CA72520. HCES-CRC: the Hwasun Cancer Epidemiology Study-Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1). Interval: Participants in the INTERVAL randomised controlled trial were recruited with the active collaboration of NHS Blood and Transplant England (www.nhsbt.nhs.uk, accessed on 16 November 2021), which has supported field work and other elements of the trial. DNA extraction and genotyping was co-funded by the National Institute for Health Research (NIHR), the NIHR BioResource (http://bioresource.nihr.ac.uk, accessed on 16 November 2021) and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. Metabolon Metabolomics assays were funded by the NIHR BioResource and the NIHR [Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust] [*]. The academic coordinating centre for INTERVAL was supported by core funding from: NIHR Blood and Transplant Research Unit in Donor Health and Genomics (NIHR BTRU-2014-10024), UKMedical Research Council (MR/L003120/1), British Heart Foundation (SP/09/002; RG/13/13/30194; RG/18/13/33946) and the NIHR (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and Wellcome.Kentucky: This work was supported by the following grant support: Clinical Investigator Award from Damon Runyon Cancer Research Foundation (CI-8); NCI R01CA136726. LCCS: The Leeds Colorectal Cancer Study was funded by the Food Standards Agency and Cancer Research UK Programme Award (C588/A19167). Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database. Multiethnic Cohort (MEC) Study: National Institutes of Health (R37 CA54281, P01 CA033619, R01 CA063464 and U01 CA164973). MECC: This work was supported by the National Institutes of Health, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR). 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). NCCCS I & II: We acknowledge funding support for this project from the National Institutes of Health, R01 CA66635 and P30 DK034987. 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, U.S. 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 Genome Quebec Innovation Centre, Montreal, Canada, for genotyping the Sequenom panel in the NFCCR samples. Funding was provided to Michael O. Woods by the Canadian Cancer Society Research Institute. NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region Vasterbotten; Knut and Alice Wallenberg Foundation; Lion's Cancer Research Foundation at Umea University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Umea University, Umea, Sweden. 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 and 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. OSUMC: OCCPI funding was provided by Pelotonia and HNPCC funding was provided by the NCI (CA16058 and CA67941).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 National Institutes of Health (NIH), Genes, Environment and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. 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, U01 CA074794 (to JDP), and awards U24 CA074794 and R01 CA076366 (to PAN). SEARCH: The University of Cambridge has received salary support in respect of PDPP from the NHS in the East of England through the Clinical Academic Reserve. Cancer Research UK (C490/A16561); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge. 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. 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.). 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, K200672X-20157-01-2 and the Stockholm County Council (ALF project). 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. UK Biobank: This research has been conducted using the UK Biobank Resource under Application Number 8614. VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.