IF 3.3 Q2 GENETICS & HEREDITY
Evan Tarbell, James N Jarvis
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引用次数: 0

摘要

尽管在改善少关节型和多关节型幼年特发性关节炎(JIA)的治疗效果方面取得了进展,但该领域仍然面临着巨大的挑战。半数以上曾患 JIA 的成年人仍处于疾病活动期,功能受到限制。药物副作用很常见,而且具有侵扰性。因此,该领域仍在继续寻找针对疾病病理生物学特定方面的治疗药物,这些药物的副作用更少,干扰性更低。我们根据开放靶基因学(Open Targets Genetics)确定了 28 个与 JIA 相关的候选靶基因,这些基因在活动性 JIA 患儿的 CD4+ T 细胞中也有不同程度的表达(与健康对照组相比)。在 28 个候选基因中,出现的最强新靶基因是同源染色体互作激酶 (HIPK1),它能抑制 T 细胞的活化,位于 rs6679677 标记的 PTPN22 基因座内。该基因座包括一个与 HIPK1 启动子接触的增强子元件,与对照组相比,HIPK1 在 JIA CD4+ T 细胞中的表达量减少。与HIPK1相关的基因本体论术语在JIA和对照组的差异表达基因中占有很大比例,而HIPK1的已知共调控因子PML也显示出类似的基因表达受抑制的情况。HIPK1 的两个下游转录因子 TP53 和 GATA4 在 JIA 上调基因的启动子附近显示出丰富的结合模式。综上所述,这些数据表明 HIPK1 在 JIA 中具有致病作用,并使其成为治疗调节的主要候选因子。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Using Genetics, Genomics, and Transcriptomics to Identify Therapeutic Targets in Juvenile Idiopathic Arthritis.

Despite progress in improving outcomes for oligoarticular and polyarticular juvenile idiopathic arthritis (JIA), the field still faces considerable challenges. More than half of adults who had JIA continue to have active disease and have developed functional limitations. Medication side-effects are common and intrusive. Thus, the field continues to search for therapeutic agents that target specific aspects of disease pathobiology and will be accompanied by fewer and less intrusive side effects. We identified 28 candidate target genes that were associated with JIA according to Open Targets Genetics and were also differentially expressed in the CD4+ T cells of children with active JIA patients (when compared to healthy controls). Of the 28 candidates, the strongest new target to emerge was homeodomain interacting kinase (HIPK1), which suppresses T cell activation and is within the PTPN22 locus tagged by rs6679677. This locus includes an enhancer element that contacts the HIPK1 promoter, and HIPK1 shows decreased expression in JIA CD4+ T cells when compared to controls. Gene Ontology terms associated with HIPK1 were overrepresented among the differentially expressed genes between JIA and controls and PML, a known co-regulator of HIPK1, showed a similar suppressed gene expression profile. Two downstream transcription factors of HIPK1, TP53 and GATA4, showed enriched binding patterns near the promoters of JIA up-regulated genes. Taken together, these data suggest a pathogenic role for HIPK1 in JIA and make it a prime candidate for therapeutic modulation.

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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
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