Nonsteroidal anti-inflammatory drugs (NSAIDs) are consistently shown in epidemiological and clinical studies to exert chemo-preventive effects on colorectal cancer (CRC). Specifically, aspirin binds irreversibly to COX1/2 enzymes, attenuating pro-inflammatory signaling pathways, but it can also exert protective effects via Wnt-β-catenin signaling, circulating inflammatory cytokines, and platelet mediated mechanisms. In this analysis, we conduct genome-wide interaction scans on a large CRC dataset to expand upon previous work and identify novel G x NSAIDs interactions.

We pooled epidemiological and imputed genetic data from 72,667 individuals (41,876 controls, and 30,806 cases) of European descent from 31 studies. Genotypes were imputed to the Haplotype Reference Consortium panel. Regular use of aspirin and combined aspirin/non-aspirin NSAIDs (henceforth termed ‘nsaidsALL') were harmonized across studies and measured as ever/never at reference time. We employed several statistical methods in our GWIS: traditional logistic regression with an interaction term, case-only analyses, joint tests (2df/3df), two-step methods. We also assessed interactions between CRC polygenic risk scores (PRS) and aspirin/nsaidsALL on additive and multiplicative scales. PRS was modeled categorically (quartiles) and continuously as a per 1 SD increase from the minimum value. All models were adjusted for age, sex, study, and ancestry.

Aspirin (OR=0.789, 95% CI=0.753-0.826) and nsaidsALL (OR=0.760; 95% CI=0.726-0.793) use were inversely associated with CRC risk. Using standard logistic regression, we identified a genome-wide significant interaction between rs72833769 (chromosome 6 intergenic region upstream of PHACTR1) and both aspirin and nsaidsALL (p = 4.0e-09, p = 1.3e-08, respectively). An additional genome-wide interaction locus was identified for nsaidsALL only, on rs35118762 (p = 2.2e-08), located in the Major Histocompatibility Complex region and in close linkage with a previously identified marginal GWAS hit (rs9271695). We identified another region of interest using two-step methods tagged by SNP rs350047 (aspirin pgxe = 1.1e-05, nsaidsALL pgxe = 4.4e-05). This region also coincides with another previously identified marginal GWAS hit (rs12514517), and is notable for being upstream of PTGER4, an important receptor for aspirin mediated inflammatory response signaling. For interactions with PRS, we observed a significant super-additive interaction for both aspirin (RERI=0.102, p=7e-08) and nsaidsALL use (RERI=0.132, p=4.6e-12). Results were similar when modeling PRS categorically. There were no multiplicative scale interactions between PRS and any NSAID use.

GWIS for aspirin and nsaidsALL use identified several loci of interest that warrant follow-up in functional studies.

Citation Format: Andre E. Kim, David A. Drew, Yi Lin, Conghui Qu, John P. Morrison, Stephanie Bien, Victor Moreno, Graham Casey, Ulrike Peters, Andrew T. Chan, W James Gauderman. NSAIDs and colorectal cancer risk: Results from genome-wide interaction scans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 820.