Gene Variants Modify Impact of Aspirin, NSAID Use on CRC Risk

Genetic polymorphisms may affect the impact of regular aspirin or nonsteroidal anti-inflammatory drug use on colorectal cancer risk

medwireNews: Scientists have identified two genetic variants that alter the protective relationship between regular use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of developing colorectal cancer (CRC).

“Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies”, say Li Hsu, from the Fred Hutchinson Cancer Center in Seattle, Washington, USA, and co-authors in JAMA.

Data from case–control and cohort studies for 8634 patients with CRC and 8553 healthy individuals of European descent living in the USA, Canada, Australia and Germany confirmed that regular use of aspirin or NSAIDs significantly reduced the risk of CRC compared with infrequent use of the drug (odds ratio [OR]=0.69).

Genome-wide analysis revealed that the single nucleotide polymorphism (SNP) rs2965667 on chromosome 12p12.3 near the microsomal glutathione S-transferase 1 (MGST1) gene significantly interacted with aspirin and NSAID use.  

Patients carrying the TT genotype of this SNP who used aspirin or NSAIDs had a significantly lower risk of CRC than those who did not, with an OR of 0.66.

Richard Wender, from the American Cancer Society in Atlanta, Georgia, USA, explained in an editorial that “[t]his genotype was found in 96% of the population, so it is not surprising that the population-wide protective effect of aspirin is roughly similar to the effect in the protective genotype.”

However, among the 4% of individuals carrying the rare AT or AA genotypes for the rs2965667 SNP, regular aspirin or NSAID use significantly increased the risk of CRC, with an OR of 1.89.

“If subsequent trials validate this gene-environment interaction, patients will need to be counseled about this small, but not insubstantial, risk”, commented Richard Wender.

A second SNP was also found to have genome-wide interaction with regular aspirin or NSAID use when studying only the CRC patients – rs16973225 on chromosome 15q25.2, located near the interleukin 16 gene (IL16).

Individuals carrying the most common AA genotype who regularly used aspirin or NSAIDs had a significantly reduced risk of CRC compared with those who did not, the study authors report. By contrast, aspirin or NSAID use had no impact on the CRC risk of the 9% of individuals with the A C or CC genotype.

The editorialist highlighted the difficulties in translating complex information on gene–environmental interactions into clinical decision-making practices.

“The ability to translate genetic profiling into tailored preventive care plans for individuals is still years away, but with the study by [Hsu] et al, the road, arduous as it may be, is more clearly illuminated”, he writes.


Nan H, Hutter CM, Lin Y, et al. Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants. JAMA 2015; 313: 1133–1142. doi:10.1001/jama.2015.1815

Wender RC. Aspirin and NSAID chemoprevention, gene-environment interactions, and risk of colorectal cancer. JAMA 2015; 313: 1111–1112. doi:10.1001/jama.2015.1032

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