Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Medical Genetics, Shandong University School of Medicine, Shandong, PRC.
Genes Immun. 2012 Oct;13(7):536-42. doi: 10.1038/gene.2012.33. Epub 2012 Sep 13.
Two recent genome-wide association studies of East Asian populations revealed three genetic variants in WDFY4/LRRC18 associated with systemic lupus erythematosus (SLE). To identify the gene contributing to this disease susceptibility, we examined the mRNA expression of WDFY4 and LRRC18 in patients with SLE and healthy controls. WDFY4 was significantly downregulated in SLE patients as compared with controls. We used allelic expression and dual-luciferase assays to identify the functional variant. Transcriptional activity was lower for the rs877819A than -G allele. Electrophoretic mobility shift and supershift assays revealed that the transcription factor Yinyang1 (YY1) binds to rs877819, with lower affinity to the A allele, which explained the reduced transcriptional activity. This effect was further confirmed by YY1 small interfering RNA knockdown, overexpression and chromatin immunoprecipitation experiments. rs877819 in WDFY4 might be the functional site associated with SLE by reduced binding of YY1 and downregulating WDFY4 expression.
两项最近针对东亚人群的全基因组关联研究揭示了 WDFY4/LRRC18 中的三个遗传变异与系统性红斑狼疮（SLE）相关。为了确定导致这种疾病易感性的基因，我们检测了 SLE 患者和健康对照者中 WDFY4 和 LRRC18 的 mRNA 表达。与对照组相比，SLE 患者的 WDFY4 表达明显下调。我们使用等位基因表达和双荧光素酶报告基因 assay 来鉴定功能变体。rs877819A 等位基因的转录活性低于-G 等位基因。电泳迁移率变动和超迁移分析显示转录因子 YinYang1 (YY1) 与 rs877819 结合，与 A 等位基因的亲和力较低，这解释了转录活性的降低。通过 YY1 小干扰 RNA 敲低、过表达和染色质免疫沉淀实验进一步证实了这一效应。WDFY4 中的 rs877819 可能是通过降低 YY1 的结合和下调 WDFY4 的表达与 SLE 相关的功能位点。
