Functional implications of rs9373441 with FOXP3+Treg and Tr1 for the clinical effectiveness of csDMARDs in rheumatoid arthritis

• Published in: Clinica chimica acta 2023-11, Vol.551, p.117612-117612, Article 117612
• Main Authors: Hsieh, Ting-Yu, Lin, Jun-Fu, Liu, Feng-Cheng, Chen, Hsiang-Cheng, Lui, Shan-Wen, Chang, Yu-Tien
• Format: Article
• Language: English
• Subjects: Antirheumatic Agents - metabolism; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - genetics; csDMARD; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Genome-Wide Association Study; GWAS; Humans; RNA-seq; T-Lymphocytes, Regulatory; Tr1; Treatment Outcome; Treg
• ISSN: 0009-8981; 1873-3492
• DOI: 10.1016/j.cca.2023.117612

[Display omitted] •rs9373441 was associated with the response to csDMARDs in Taiwanese RA patients.•TT allele of rs9373441 was linked to better clinical effectiveness of csDMARDs.•rs9373441 was a cis-acting SNP of UTRN with implication in FOXP3 + Treg and Tr1.•Increased expression of FOXP3 + Treg and Tr1 were observed with TT allele. Rheumatoid arthritis (RA) is characterized by a deficiency in regulatory T cells (Treg), which play a crucial role in immune regulation. While conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are widely used, there remains a challenge as efficacy varies among patients. In this genome-wide association study (GWAS) involving 410 RA patients, rs9373441 emerged as the most significantly linked single-nucleotide polymorphism (SNP) to csDMARDs response. This non-coding variant functions as a cis-acting regulatory element within the UTRN gene, which is associated with cortical erosion and osteoporosis. Particularly, individuals with the TT allele at rs9373441 exhibited a more favorable response, characterized by a significant increase in FOXP3 + Treg and Type 1 regulatory T cells (Tr1) (p = 0.04, 0.02) and a decrease in Effector T helper cells (Effector Th) (p = 0.03). The GATA3-GCM2-PTH and GATA3-FOXO1-FOXP3 pathways were implicated. RNA-sequencing (RNA-seq) analysis revealed increased expression levels of UTRN, PTH2R, FOXO1, and FOXO3 in good and moderate responders (p = 0.01, 0.03, 0.0005, and 0.02). Notably, the change in FOXP3 + Treg and Tr1 was positively correlated with UTRN expression (both p = 0.03). These findings underscore the critical link between rs9373441 and the response to csDMARDs, empowering clinicians to tailor treatments for enhanced outcomes in patients with RA.