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, Loïc Le Marchand, Cornelia M. Ulrich, Christopher I. Li, Fränzel J.B. van Duijnhoven, Andrea GsurPeter T. Campbell, Víctor Moreno, Pavel Vodicka, Ludmila Vodickova, Efrat Amitay, Elizabeth Alwers, Jenny Chang-Claude, Lori C. Sakoda, Martha L. Slattery, Robert E. Schoen, Marc J. Gunter, Sergi Castellví-Bel, Hyeong Rok Kim, Sun Seog Kweon, Andrew T. Chan, Li Li, Wei Zheng, D.T. Bishop, Daniel D. Buchanan, Graham G. Giles, Stephen B. Gruber, Gad Rennert, Zsofia K. Stadler, Tabitha A. Harrison, Yi Lin, Temitope O. Keku, Michael O. Woods, Clemens Schafmayer, Bethany Van Guelpen, Steven Gallinger, Heather Hampel, Sonja I. Berndt, Paul D.P. Pharoah, Annika Lindblom, Alicja Wolk, Anna H. Wu, Emily White, Ulrike Peters, David A. Drew, Dominique Scherer, Justo Lorenzo Bermejo, Hermann Brenner, Michael Hoffmeister, Ann C. Williams, Caroline L. Relton

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Article number4164
Issue number11
Publication statusPublished - 21 Nov 2021


  • Aspirin
  • Colorectal cancer
  • Mendelian randomization
  • Salicylic acid


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