OBJECTIVE Genome-wide association studies have identified many susceptibility loci for systemic lupus erythematosus (SLE). However, most of these loci are located in noncoding regions of the genome. Long noncoding RNAs (lncRNAs) are pervasively expressed and have been reported to be involved in various diseases. This study aimed to explore the genetic significance of lncRNAs in SLE. METHODS A genome-wide survey of SLE risk variants in lncRNA gene loci was performed in Han Chinese subjects (4,556 with SLE and 9,451 healthy controls). The functional relevance of an SLE risk variant in one of the lncRNA genes was explored using biochemical and molecular cell biology analyses. In vitro loss-of-function and gain-of-function strategies were used to clarify the functional and phenotypic relevance of this SLE susceptibility lncRNA. Moreover, correlation of this lncRNA with the degree of apoptosis in the peripheral blood of SLE patients was evaluated. RESULTS A novel SLE susceptibility locus in a lncRNA gene, designated SLEAR (for SLE-associated RNA), was identified at the single-nucleotide polymorphism rs13259960 (odds ratio 1.35, Pcombined = 1.03 × 10-11 ). The A>G variation at rs13259960, located in an intronic enhancer, was found to impair STAT1 recruitment to the enhancer that loops to the SLEAR promoter, resulting in decreased SLEAR production in peripheral blood mononuclear cells from patients with SLE (3 with the G/G genotype, 22 with A/G, and 103 with A/A at rs13259960; P = 0.0241). Moreover, SLEAR interacted with the RNA binding proteins interleukin enhancer binding factor 2, heterogeneous nuclear RNP F, and TATA-binding protein-associated factor 15, to form a complex for transcriptional activation of the downstream antiapoptotic genes. In addition, SLEAR regulated apoptosis of Jurkat cells in vitro, and its expression level was correlated with the degree of cell death in the peripheral blood of patients with SLE (r = 0.824, P = 2.15 × 10-8 ; n = 30). CONCLUSION These findings suggest a mechanism by which the risk variant at rs13259960 modulates SLEAR expression and confers a predisposition to SLE. Taken together, these results may give insights into the etiology of SLE.

中文翻译：

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SLEAR基因多态性rs13259960与系统性红斑狼疮易感性的关系。

目的全基因组关联研究确定了系统性红斑狼疮（SLE）的许多易感基因座。但是，这些基因座中的大多数位于基因组的非编码区。长的非编码RNA（lncRNA）普遍表达，并且据报道与多种疾病有关。本研究旨在探讨lncRNA在SLE中的遗传意义。方法在汉族人群（4,556例SLE患者和9,451名健康对照者）中进行了lncRNA基因位点SLE风险变异的全基因组调查。使用生化和分子细胞生物学分析探索了lncRNA基因之一中SLE风险变异的功能相关性。使用体外功能丧失和功能获得策略来阐明这种SLE易感性lncRNA的功能和表型相关性。此外，评价该lncRNA与SLE患者外周血细胞凋亡程度的相关性。结果在单核苷酸多态性rs13259960（比值为1.35，Pcombined = 1.03×10-11）处发现了lncRNA基因中新的SLE易感基因座，命名为SLEAR（与SLE相关的RNA）。发现位于内含子增强子中的rs13259960处的A> G变异会削弱STAT1募集到循环至SLEAR启动子的增强子，从而导致SLE患者外周血单核细胞的SLEAR产生减少（G / 3 G基因型，具有A / G的22个基因型，位于rs13259960的A / A的基因型103； P = 0.0241）。此外，SLEAR与RNA结合蛋白白介素增强子结合因子2，异质核RNP F和TATA结合蛋白相关因子15相互作用，形成用于下游抗凋亡基因转录激活的复合物。此外，SLEAR调节了Jurkat细胞的体外凋亡，其表达水平与SLE患者外周血细胞死亡程度相关（r = 0.824，P = 2.15×10-8； n = 30）。结论这些发现表明，rs13259960的风险变异体可通过这种机制调节SLEAR表达并赋予SLE易感性。综上所述，这些结果可能有助于深入了解SLE的病因。结论这些发现表明，rs13259960的风险变异体可通过这种机制调节SLEAR表达并赋予SLE易感性。综上所述，这些结果可能有助于深入了解SLE的病因。结论这些发现表明，rs13259960的风险变异体可通过这种机制调节SLEAR表达并赋予SLE易感性。综上所述，这些结果可能有助于深入了解SLE的病因。