Genetic variation at rs11574891 and rs3125003 in NOTCH1 is associated with therapeutic efficacy of Janus kinase inhibitors in Taiwanese patients with rheumatoid arthritis.

OBJECTIVES

Janus kinase inhibitors (JAKi) have been widely adopted in the treatment of rheumatoid arthritis (RA); however, inter-individual variability in therapeutic response remains a significant challenge. Pharmacogenomic data specific to the Taiwanese population are still limited. This study aimed to identify single nucleotide polymorphisms (SNPs) associated with JAKi efficacy in Taiwanese RA patients.

METHODS

Using data from the Taiwan Precision Medicine Initiative, we analyzed RA patients receiving JAKi (n = 34) and non-JAKi treatment (n = 376) through a genome-wide association study. In a subset of patients, pretreatment peripheral blood samples were collected from 15 JAKi-treated and 54 non-JAKi individuals for immunophenotyping and polygenic risk score (PRS) modeling.

RESULTS

GWAS identified 26 SNPs significantly associated with JAKi treatment response. Four SNPs-rs11574891, rs3125003, rs61807669, and Affx-4817039-showed significant associations with B cell subsets previously shown to predict JAKi response. Among them, rs11574891 (OR = 3.67) and rs3125003 (OR = 3.14), both located within NOTCH1 gene, were independently validated using clumping-and-thresholding and PRSice-2 models. Furthermore, rs75547179 in the CSMD2 gene was consistently identified across four independent PRS models.

CONCLUSIONS

To our knowledge, this is the first pharmacogenomic study in a Taiwanese RA cohort to identify these SNPs and propose rs11574891 and rs3125003 in NOTCH1 as potential predictive biomarkers for JAKi efficacy. Further validation in larger, independent cohorts is warranted to facilitate the implementation of precision medicine in RA treatment.