School of Medicine, National Defense Medical Center, ROC, Taipei, Taiwan.
School of Public Health, National Defense Medical Center, ROC, Taipei, Taiwan.
Clin Chim Acta. 2023 Nov 1;551:117612. doi: 10.1016/j.cca.2023.117612. Epub 2023 Oct 20.
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.
类风湿关节炎（RA）的特征是调节性 T 细胞（Treg）缺乏，而 Treg 在免疫调节中起着至关重要的作用。虽然广泛使用传统的合成疾病修饰抗风湿药物（csDMARDs），但由于患者之间的疗效存在差异，仍然存在挑战。在这项涉及 410 名 RA 患者的全基因组关联研究（GWAS）中，rs9373441 是与 csDMARDs 反应最显著相关的单核苷酸多态性（SNP）。这种非编码变体作为 UTRN 基因内的顺式作用调节元件发挥作用，与皮质侵蚀和骨质疏松症有关。特别是，rs9373441 处的 TT 等位基因个体表现出更有利的反应，其特征是 FOXP3+Treg 和 Type 1 调节性 T 细胞（Tr1）显著增加（p=0.04，0.02），效应 T 辅助细胞（Effector Th）减少（p=0.03）。GATA3-GCM2-PTH 和 GATA3-FOXO1-FOXP3 途径被牵连。RNA 测序（RNA-seq）分析显示，在良好和中度反应者中，UTR N、PTH2R、FOXO1 和 FOXO3 的表达水平增加（p=0.01，0.03，0.0005 和 0.02）。值得注意的是，FOXP3+Treg 和 Tr1 的变化与 UTRN 表达呈正相关（均 p=0.03）。这些发现强调了 rs9373441 与 csDMARDs 反应之间的关键联系，使临床医生能够为 RA 患者量身定制治疗方案，以提高治疗效果。
