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

Aayah G Nounu*, Rebecca Richmond, Ann C Williams, Caroline L Relton

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. As-pirin (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 methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes’ coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR:1.03, 95% CI: 0.84–1.27 and OR: 1.08, 95% CI:0.86–1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
Original languageEnglish
Article number4164
Issue number11
Publication statusPublished - 21 Nov 2021

Bibliographical note

Funding Information:
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).

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. 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 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. NSHDS: Swedish Research Council; Swedish Cancer Society; Cutting-Edge Research Grant and other grants from Region Västerbotten; Knut and Alice Wallenberg Foundation; Lion’s Cancer Research Foundation at Umeå University; the Cancer Research Foundation in Northern Sweden; and the Faculty of Medicine, Umeå University, Umeå, 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, K2006-72X-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.

Funding Information:
Data Availability Statement: Summary data is available upon request by contacting the respective studies Acknowledgments: ASTERISK: We are very grateful to 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 controls, as well as all the physicians, technicians and students. CCFR: The Colon CFR graciously thanks the generous contributions of their study participants, dedication of study staff, and the financial support from the U.S. National Cancer Institute, without which this important registry would not exist. The authors would like to thank the study participants and staff of the Seattle Colon Cancer Family Registry and the Hormones and Colon Cancer study (CORE Studies). CLUE II: We thank the participants of Clue II and appreciate the continued efforts of the staff at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the Clue II Cohort Study. 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. 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 laboratory assistance. CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. Czech Republic CCS: We are thankful to all clinicians in major hospitals in the Czech Republic, without whom the study would not be practicable. We are also sincerely grateful to all patients participating in this study. DACHS: We thank all participants and cooperating clinicians, and Ute Handte-Daub, Utz Benscheid, Muhabbet Celik and Ursula Eilber for excellent technical assistance. EDRN: We acknowledge all the following contributors to the development of the resource: University of Pittsburgh School of Medicine, Department of Gastroenterology, Hepatology and Nutrition: Lynda Dzubinski; University of Pittsburgh School of Medicine, Department of Pathology: Michelle Bisceglia; and University of Pittsburgh School of Medicine, Department of Biomedical Informatics. EPIC: 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. The EPIC-Norfolk study: we are grateful to all the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. EPICOLON: We are sincerely grateful to all patients participating in this study who were recruited as part of the EPICOLON project. We acknowledge the Spanish National DNA Bank, Biobank of Hospital Clínic–IDIBAPS and Biobanco Vasco for the availability of the samples. The work was carried out (in part) at the Esther Koplowitz Centre, Barcelona. Harvard cohorts (HPFS, NHS, PHS): The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. We would like to thank the participants and staff of the HPFS, NHS and PHS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. Interval: A complete list of the investigators and contributors to the INTERVAL trial is provided in reference [33]. The academic coordinating centre would like to thank blood donor centre staff and blood donors for participating in the INTERVAL trial. Kentucky: We would like to acknowledge the staff at the Kentucky Cancer Registry. LCCS: We acknowledge the contributions of Jennifer Bar-rett, Robin Waxman, Gillian Smith and Emma Northwood in conducting this study. NCCCS I & II: We would like to thank the study participants, and the NC Colorectal Cancer Study staff. NSHDS investigators thank the Biobank Research Unit at Umeå University, the Västerbotten Intervention Programme, the Northern Sweden MONICA study and Region Västerbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650). PLCO: The authors thank the PLCO Cancer Screening Trial screening centre investigators and the staff from Information Management Services Inc and Westat Inc. Most importantly, we thank the study participants for their contributions that made this study possible. SCCFR: The authors would like to thank the study participants and staff of the Hormones and Colon Cancer and Seattle Cancer Family Registry studies (CORE Studies). SEARCH: We thank the SEARCH team. SELECT: We thank the research and clinical staff at the sites that participated on SELECT study, without whom the trial would not have been successful. We are also grateful to the 35,533 dedicated men who participated in SELECT. UK Biobank: We would like to thank the participants and researchers of the UK Biobank for their participation and acquisition of data. WHI: The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A full listing of WHI investigators can be found at:

Funding Information:
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.

Publisher Copyright:
© 2021 by the authors. Li-censee MDPI, Basel, Switzerland.

Structured keywords

  • ICEP


  • salicylic acid
  • aspirin
  • colorectal cancer
  • Mendelian randomization


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