一个系统的策略,用于识别因果单核酸多态和他们的目标基因在青少年关节炎风险单元类型的识别
Kaiyu Jiang1, Tao Liu2, Susan Kales3
1Department of Pediatrics, Clinical and Translational Research Center, University at Buffalo Jacobs School of Medicine School Medicine & Biomedical Sciences, 701 Ellicott St, Buffalo, NY, 14203, USA.
BMC medical genomics
|July 12, 2024
概括
这项研究使用功能性基因组学方法确定了青少年异常性关节炎 (JIA) 的潜在疾病驱动单核酸多态 (SNP) . 这些发现有助于确定因果变异及其向基因,推进JIA遗传研究.
科学领域:
- 遗传学 遗传学是一种遗传学.
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
背景情况:
- 全基因组关联研究 (GWAS) 已经确定了JIA风险区域,但因果变异仍然未知.
- 识别风险驱动的单核酸多态 (SNPs) 对于理解JIA病原和临床转化至关重要.
- 需要一种功能性方法来确定因果变异及其对象基因在JIA风险单元类型上的原因变异.
研究的目的:
- 确定因果变异候选人和其向基因在青少年异常性关节炎 (JIA) 风险单元类型上.
- 功能性地评估SNP对JIA风险区域内基因表达的影响.
主要方法:
- 大规模并行记者测试 (MPRA) 用于测试5226个来自JIA风险单元型的非编码SNP,以检测K562细胞中的基因表达改变.
- 在未受刺激的K562细胞和受干扰素马 (IFNg) 刺激的K562细胞中进行MPRA.
- 使用CRISPR干扰 (CRISPRi) 验证增强剂活性并识别受调节的基因.
主要成果:
- 在未受刺激的细胞中发现了553个改变表达的SNP,在IFNg刺激的细胞中发现了490个.
- 通过功能色素标记进行过,每种条件产生42个独特的SNP (共84个).
- 克里斯普里证实,在TRAF1和LNPEP/ERAP2位点中,MPRA选变异的增强剂调节多个基因.
结论:
- MPRA和CRISPRi有效地查询JIA风险单元类型,以确定可能的疾病驱动变异.
- 在3D染色体结构的指导下,CRISPRi可以识别已识别的候选变异的目标基因.
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