Cai Yi-Xin, Chen Xiao-Li, Zheng Dai-Shan, Huang Yue-Zhong, Bai Zhan-Pei, Huang Xiu-Feng
Zhejiang Provincial Clinical Research Center for Pediatric Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
J Transl Autoimmun. 2024 Oct 26;9:100256. doi: 10.1016/j.jtauto.2024.100256. eCollection 2024 Dec.
Juvenile idiopathic arthritis (JIA) is a prevalent chronic rheumatic disease affecting children. Current medications merely alleviate symptoms rather than curing the disease. Hence, the identification and development of novel drug targets and biomarkers for JIA are imperative for enhancing treatment efficacy.
We employed two-sample Mendelian randomization (MR) analysis to investigate the causal effects of plasma proteins on JIA. Additionally, colocalization, bulk RNA-seq, and single-cell RNA-seq analyses were conducted to further investigate and validate the potential of candidate proteins as drug targets.
Through MR analysis, we successfully identified five plasma proteins that are causally linked to JIA. Genetically inferred lower levels of AIF1, TNF, and TNFSF11 were associated with an elevated risk of JIA, while higher levels of AGER and GP1BA proteins were positively correlated with JIA risk. Colocalization analysis further supported our findings on GP1BA (OR = 9.26, 95 % CI: 2.30-37.20) and TNFSF11 (OR = 0.18, 95 % CI: 0.07-0.45). Based on this evidence, we classified these five proteins into two tiers. Finally, we conducted a systematic evaluation of the druggability and current drug development progress for these identified candidate proteins.
This study employed MR analysis to reveal causal relationships between plasma proteins and JIA, identifying five potential candidate proteins as promising drug targets for JIA, particularly focusing on GP1BA and TNFSF11.
青少年特发性关节炎（JIA）是一种影响儿童的常见慢性风湿性疾病。目前的药物仅能缓解症状，而非治愈该疾病。因此，识别和开发JIA的新型药物靶点和生物标志物对于提高治疗效果至关重要。
我们采用两样本孟德尔随机化（MR）分析来研究血浆蛋白对JIA的因果效应。此外，还进行了共定位、批量RNA测序和单细胞RNA测序分析，以进一步研究和验证候选蛋白作为药物靶点的潜力。
通过MR分析，我们成功鉴定出五种与JIA有因果关系的血浆蛋白。基因推断的AIF1、TNF和TNFSF11水平较低与JIA风险升高相关，而AGER和GP1BA蛋白水平较高与JIA风险呈正相关。共定位分析进一步支持了我们关于GP1BA（OR = 9.26，95% CI：2.30 - 37.20）和TNFSF11（OR = 0.18，95% CI：0.07 - 0.45）的研究结果。基于这些证据，我们将这五种蛋白分为两层。最后，我们对这些已鉴定的候选蛋白的成药性和当前药物开发进展进行了系统评估。
本研究采用MR分析揭示了血浆蛋白与JIA之间的因果关系，鉴定出五种潜在的候选蛋白作为JIA有前景的药物靶点，尤其关注GP1BA和TNFSF11。
