Genetic Susceptibility to NSAID-Related Gastrointestinal Adverse Events in Korean Patients: An Exploratory Genome-Wide Association Study.

Background/Objectives: Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used but can cause clinically significant gastrointestinal adverse events (GI-AEs). However, genetic susceptibility to NSAID-related GI toxicity remains insufficiently characterized in East Asian populations. This exploratory study aimed to identify genetic loci associated with grade ≥ 2 NSAID-related GI-AEs in Korean patients treated with commonly used NSAIDs. Methods: We conducted an exploratory genome-wide association study in a multicenter Korean cohort of NSAID-treated patients recruited from four Korean hospitals. A total of 339 patients were included, comprising 28 cases with grade ≥ 2 GI-AEs and 311 controls without documented GI-AEs. Genotyping was performed using the Korea Biobank Array, followed by imputation and quality control. Genome-wide association analysis was conducted under an additive logistic regression model adjusted for age, sex, and the first two principal components, with additional sensitivity analyses accounting for the specific NSAID type, cumulative DDD, and concomitant medications. Polygenic risk score analysis was performed using summary statistics from an arthritis-treated subset of the KoGES Ansan/Ansung cohort, and the selected variant were further evaluated using multivariable Firth penalized logistic regression. The discriminatory performance of clinical, laboratory, and genetic models was assessed using bootstrap internal validation. Results: The exploratory GWAS identified 20 suggestive variants associated with NSAID-related GI-AEs at p < 1 × 10-5, although no variant reached genome-wide significance. The KoGES-derived polygenic risk score was significantly associated with GI-AE status in the NSAID cohort, and 10 suggestive variants overlapped with SNPs included in the best-fit PRS model. rs1925245 maintained a consistent association in multivariable Firth penalized logistic regression. Conclusions: These findings suggest that NSAID-related GI-AEs in Korean patients may reflect a multifactorial susceptibility pattern involving both clinical context and polygenic risk. Although exploratory, this study provides candidate genetic signals for future replication and supports the need for larger ancestry-matched pharmacogenomic studies of NSAID-related GI toxicity.