Non‐steroidal anti‐inflammatory drugs, polygenic risk score and colorectal cancer risk

Summary Background The regular use of non‐steroidal anti‐inflammatory drugs (NSAIDs) has been associated with reduced colorectal cancer (CRC) risk. Aim To explore whether this association varies according to background polygenic risk for CRC. Methods Data were collected from a large population‐based case‐control study on CRC in Germany. A polygenic risk score (PRS) based on 140 CRC‐related risk loci was used to quantify the genetic risk. The associations of regular use of NSAIDs (≥2times per week for at least 1 year) with CRC risk were estimated in the whole population and in subgroups according to PRS levels using multivariable logistic regression. The impact of NSAIDs on CRC risk was compared to PRS using the ‘genetic risk equivalent’ (GRE), a recently developed metric for effective risk communication. Results In total 5129 CRC cases and 4093 controls were included in this analysis. The regular use of NSAIDs (including aspirin) was associated with reduced CRC risk [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.59, 0.74], as was regular use of aspirin only (OR 0.73, 95% CI 0.65, 0.83), without indication of interaction with the PRS (P = 0.10 and 0.22 respectively). The effect of NSAID use was equivalent to the effect of having a 32 percentiles lower PRS (GRE −32, 95% CI −41, −22). Conclusions The regular use of NSAIDs is associated with greatly reduced CRC risk regardless of individual genetic profile. With an equivalent reduction of relative risk across all polygenic risk groups, absolute risk reduction would be expected to be strongest among those with the highest polygenic risk score. The regular use of NSAIDs is associated with greatly reduced colorectal cancer (CRC) risk regardless of polygenic risk for CRC. The estimated large genetic risk equivalent indicates that a substantial proportion of genetic risk could be compensated for with regular use of NSAIDs.