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Article

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

by
Aayah Nounu
1,2,*,
Rebecca C. Richmond
1,
Isobel D. Stewart
3,
Praveen Surendran
4,5,6,7,
Nicholas J. Wareham
3,
Adam Butterworth
4,5,6,8,9,
Stephanie J. Weinstein
10,
Demetrius Albanes
10,
John A. Baron
11,
John L. Hopper
12,13,
Jane C. Figueiredo
14,15,
Polly A. Newcomb
16,17,
Noralane M. Lindor
18,
Graham Casey
19,
Elizabeth A. Platz
20,
Loïc Le Marchand
21,
Cornelia M. Ulrich
22,
Christopher I. Li
16,
Fränzel J. B. van Dujinhoven
23,
Andrea Gsur
24,
Peter T. Campbell
25,
Víctor Moreno
26,27,28,29,
Pavel Vodicka
30,31,32,
Ludmila Vodickova
30,31,32,
Efrat Amitay
33,
Elizabeth Alwers
33,
Jenny Chang-Claude
34,35,
Lori C. Sakoda
16,36,
Martha L. Slattery
37,
Robert E. Schoen
38,
Marc J. Gunter
39,
Sergi Castellví-Bel
40,
Hyeong-Rok Kim
41,
Sun-Seog Kweon
42,43,
Andrew T. Chan
44,45,46,47,48,49,
Li Li
50,
Wei Zheng
51,
D. Timothy Bishop
52,
Daniel D. Buchanan
53,54,55,
Graham G. Giles
12,56,57,
Stephen B. Gruber
58,
Gad Rennert
59,60,61,
Zsofia K. Stadler
62,
Tabitha A. Harrison
23,
Yi Lin
23,
Temitope O. Keku
63,
Michael O. Woods
64,
Clemens Schafmayer
65,
Bethany Van Guelpen
66,67,
Steven Gallinger
68,
Heather Hampel
69,
Sonja I. Berndt
10,
Paul D. P. Pharoah
7,
Annika Lindblom
70,71,
Alicja Wolk
72,73,
Anna H. Wu
74,
Emily White
23,75,
Ulrike Peters
23,75,
David A. Drew
45,47,
Dominique Scherer
76,
Justo Lorenzo Bermejo
76,
Hermann Brenner
34,77,78,
Michael Hoffmeister
34,
Ann C. Williams
2 and
Caroline L. Relton
1
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1
Integrative Cancer Epidemiology Programme (ICEP), Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol BS8 2BN, UK
2
School of Cellular and Molecular Medicine, University of Bristol, Bristol BS8 1TD, UK
3
MRC Epidemiology Unit, School of Clinical Medicine, University of Cambridge, Cambridge CB2 0SL, UK
4
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
5
British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Cambridge, Cambridge CB2 0QQ, UK
6
Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge CB10 1SA, UK
7
Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
8
National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge CB2 1TN, UK
9
National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge University Hospitals, Cambridge CB2 0QQ, UK
10
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
11
Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27516, USA
12
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3053, Australia
13
Department of Epidemiology, Institute of Health and Environment, School of Public Health, Seoul National University, Seoul 08826, Korea
14
Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
15
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 0032, USA
16
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA
17
School of Public Health, University of Washington, Seattle, WA 98195, USA
18
Department of Health Science Research, Mayo Clinic, Scottsdale, AZ 85259, USA
19
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA 22908, USA
20
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA
21
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
22
Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT 84112, USA
23
Division of Human Nutrition and Health, Department of Agrotechnology and Food Sciences, Wageningen University & Research, 6700 HB Wageningen, The Netherlands
24
Institute of Cancer Research, Department of Medicine I, Medical University Vienna, 1090 Vienna, Austria
25
Department of Population Science, American Cancer Society, Atlanta, GA 30303, USA
26
Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, 08908 Barcelona, Spain
27
CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
28
Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, 08007 Barcelona, Spain
29
ONCOBEL Program, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain
30
Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, 142 20 Prague, Czech Republic
31
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Nové Město, 121 08 Prague, Czech Republic
32
Faculty of Medicine and Biomedical Center in Pilsen, Charles University, 323 00 Pilsen, Czech Republic
33
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
34
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
35
Department of Oncology, Haematology and BMT, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), 20251 Hamburg, Germany
36
Division of Research, Kaiser Permanente Northern California, Oakland, CA 94612, USA
37
Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA
38
Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15261, USA
39
Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, 69372 Lyon, France
40
Gastroenterology Department, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, 08036 Barcelona, Spain
41
Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun 58128, Korea
42
Department of Preventive Medicine, Chonnam National University Medical School, Gwangju 61186, Korea
43
Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun 58128, Korea
44
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
45
Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
46
Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
47
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
48
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
49
Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
50
Department of Family Medicine, University of Virginia, Charlottesville, VA 22903, USA
51
Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
52
Leeds Institute of Cancer and Pathology, School of Medicine, University of Leeds, Leeds LS2 9JT, UK
53
Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia
54
Melbourne Medical School, University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC 3010, Australia
55
Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, VIC 3000, Australia
56
Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia
57
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia
58
Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
59
Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa 3448516, Israel
60
Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel
61
Clalit National Cancer Control Center, Haifa 3436212, Israel
62
Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY 10065, USA
63
Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7555, USA
64
Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NL A1B 3V6, Canada
65
Department of General Surgery, University Hospital Rostock, 18057 Rostock, Germany
66
Department of Radiation Sciences, Oncology Unit, Umeå University, 901 87 Umeå, Sweden
67
Wallenberg Centre for Molecular Medicine, Department of Biomedical and Clinical Sciences, Umeå University, 901 87 Umeå, Sweden
68
Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1X5, Canada
69
Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
70
Department of Clinical Genetics, Karolinska University Hospital, 171 64 Solna, Sweden
71
Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 64 Solna, Sweden
72
Institute of Environmental Medicine, Karolinska Institutet, 171 64 Solna, Sweden
73
Department of Surgical Sciences, Uppsala University, 751 85 Uppsala, Sweden
74
Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA
75
Department of Epidemiology, University of Washington School of Public Health, Seattle, WA 98195, USA
76
Institute of Medical Biometry and Informatics, Medical Faculty, University of Heidelberg, Im Neuenheimer Feld 130.3, 69120 Heidelberg, Germany
77
Division of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany
78
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
Nutrients 2021, 13(11), 4164; https://doi.org/10.3390/nu13114164
Submission received: 13 October 2021 / Revised: 10 November 2021 / Accepted: 17 November 2021 / Published: 21 November 2021
(This article belongs to the Section Nutritional Epidemiology)

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 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.
Keywords: salicylic acid; aspirin; colorectal cancer; Mendelian randomization salicylic acid; aspirin; colorectal cancer; Mendelian randomization

Share and Cite

MDPI and ACS Style

Nounu, A.; Richmond, R.C.; Stewart, I.D.; Surendran, P.; Wareham, N.J.; Butterworth, A.; Weinstein, S.J.; Albanes, D.; Baron, J.A.; Hopper, J.L.; et al. Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study. Nutrients 2021, 13, 4164. https://doi.org/10.3390/nu13114164

AMA Style

Nounu A, Richmond RC, Stewart ID, Surendran P, Wareham NJ, Butterworth A, Weinstein SJ, Albanes D, Baron JA, Hopper JL, et al. Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study. Nutrients. 2021; 13(11):4164. https://doi.org/10.3390/nu13114164

Chicago/Turabian Style

Nounu, Aayah, Rebecca C. Richmond, Isobel D. Stewart, Praveen Surendran, Nicholas J. Wareham, Adam Butterworth, Stephanie J. Weinstein, Demetrius Albanes, John A. Baron, John L. Hopper, and et al. 2021. "Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study" Nutrients 13, no. 11: 4164. https://doi.org/10.3390/nu13114164

APA Style

Nounu, A., Richmond, R. C., Stewart, I. D., Surendran, P., Wareham, N. J., Butterworth, A., Weinstein, S. J., Albanes, D., Baron, J. A., Hopper, J. L., Figueiredo, J. C., Newcomb, P. A., Lindor, N. M., Casey, G., Platz, E. A., Marchand, L. L., Ulrich, C. M., Li, C. I., van Dujinhoven, F. J. B., ... Relton, C. L. (2021). Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study. Nutrients, 13(11), 4164. https://doi.org/10.3390/nu13114164

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