Association of Aspirin and Clopidogrel and the Risk of Colon Adenocarcinoma: A Drug-Target Mendelian Randomization Study

Methods

Following STROBE-MR guidelines[1, 2], we conducted a Mendelian randomization study using cis-expression quantitative trait loci (eQTLs) from the eQTLGen Consortium (n = 31,684; European ancestry) as genetic instruments. Two independent cohorts served as discovery (FinnGen R13: 4,895 cases and 372,159 controls) and replication (Colorectal Cancer: 6,581 cases and 463,421 controls) datasets for target identification. Meta-analysis was performed to assess robustness.

Ischemic stroke (34,217 cases and 406,111 controls; European ancestry) was used as a positive control. Results: Significant cis-eQTL single nucleotide polymorphisms were selected as genetic instruments for PTGS1, PTGS2, and P2RY12. While genetic proxies for PTGS1 showed a borderline significant association with ischemic stroke risk only under the simple mode (OR = 1.4500, 95% CI: 1.0973–1.9160, P = 0.0592), and PTGS2 proxies significantly increased stroke risk under the weighted mode (OR = 1.0781, 95% CI: 1.0115–1.1492, P = 0.0355), genetic proxies for P2RY12 demonstrated a significant association with increased ischemic stroke risk (IVW OR = 1.091, 95% CI: 1.029–1.157, P = 0.0035), confirming the validity of the identified genetic instrument.

Our findings indicate that genetically proxied P2RY12 significantly increased colon adenocarcinoma risk in both the discovery (IVW OR = 1.1880, 95% CI: 1.0418–1.3547, P = 0.0101) and replication cohorts (IVW OR = 1.0913, 95% CI: 1.0095–1.1797, P = 0.0280). Translating these genetic associations into drug effects, clopidogrel showed a statistically significant protective effect against colon adenocarcinoma, with ORs of 0.8418 (95% CI: 0.7382–0.9599) in the discovery cohort and 0.9163 (95% CI: 0.8477–0.9906) in the replication cohort.

Meta-analysis confirmed that P2RY12 robustly and significantly increased colon adenocarcinoma risk (OR = 1.12, 95% CI: 1.04–1.21; I² = 15.8%, P = 0.2757). Furthermore, we found no clear genetic evidence supporting an association between aspirin drug targets and colon adenocarcinoma outcomes. Conclusions: Our study provides insufficient evidence for an association between aspirin and colon adenocarcinoma outcomes.

In contrast, clopidogrel-mediated inhibition of P2RY12 significantly reduces the risk of colon adenocarcinoma. Future large-scale prospective cohort studies are warranted to integrate clopidogrel into colorectal cancer therapeutic regimens to improve patient outcomes. Keywords: cancer; drug target; aspirin; clopidogrel; Mendelian randomization