PDF(Pubmed)
Abstract：
Type I diabetes is an autoimmune disease mediated by T-cell destruction of β cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include CLEC16A and SOCS1. While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.
摘要：
I型糖尿病是由胰岛β细胞的T细胞破坏介导的自身免疫性疾病。目前,没有已知的治疗方法,治疗包括每天注射胰岛素。全基因组关联研究和双胞胎研究表明，I型糖尿病具有很强的遗传遗传性，并涉及多个基因。由于最强烈相关的变体是非编码的，仍然缺乏对功能的识别，因此,可能是因果变异。鉴于许多这些遗传变异存在于增强子元件中，我们检测了121种与T1D相关的CD4+T细胞增强子变异体.我们发现四个通过大规模平行报告子测定是有功能的。三种增强子变体削弱了活性，而第四加强活动。我们使用3D基因组结构或eQTL数据将它们链接到它们的同源基因，并使用CRISPR编辑验证它们。验证的靶基因包括CLEC16A和SOCS1。虽然这些基因以前与1型糖尿病和其他自身免疫性疾病有关，我们表明控制其表达的增强剂具有功能性变体。这些变种,因此,可能是1型糖尿病的因果变异。
