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.
Highlights
Colorectal cancer (CRC) is the fourth most common cancer in the UK and worldwide [1,2]
For non-users (n = 5660), we had 80% power to detect an OR of ≤0.73 and ≥1.42 in the reciprocal direction (Table 1), we found no association between Salicylic acid (SA) levels and colorectal cancer (CRC) in aspirin users (OR: 0.66, 95% CI: 0.11–4.12) and non-users (OR: 1.12, 95% CI: 0.42–2.97) (Figure 3C)
We found a positive association between SA and CRC risk in the GECCO sample (OR: 1.13, 95% CI: 1.05–1.22) but no association in the DACHS sample (OR: 0.51, 95% CI: 0.16–1.67), DACHS aspirin users (OR: 0.12, 95% CI: 0.01–2.67) and DACHS aspirin non-users (OR: 0.70, 95% CI: 0.30–1.65)
Summary
Colorectal cancer (CRC) is the fourth most common cancer in the UK and worldwide [1,2]. Incidence rates among the over 50s have remained relatively stable, rates in younger age groups have increased in both the UK and US populations [3,4] This highlights a need to find better and complementary prevention strategies to reduce risk of cancer. Whilst SA can be obtained from the diet, the concentrations achieved (male and female median intake from diet 4.4 mg/day and 3.2 mg/day, respectively [6]) are much lower than through aspirin ingestion (aspirin doses ranging between 75 mg to ≥325 mg given daily/alternate days) [15] It is unclear whether concentrations achieved from the diet alone are sufficient to protect against cancer or whether larger doses obtained through pharmacological intervention are required
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