Association of the Polymorphism rs13259960 in SLEAR With Predisposition to Systemic Lupus Erythematosus

Abstract

Objective GWASs 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 reported to be involved in various diseases. This study aimed to explore the genetic significance of lncRNAs in SLE. Methods We performed a genome‐wide survey of SLE risk variants in lncRNA gene loci among Han Chinese (4,556 SLE and 9,451 controls). The functional relevance of a risk variant in a lncRNA gene was explored using biochemical and molecular cell biology analyses. In vitro loss and gain of function strategies were performed to clarify the functional and phenotypic relevance of the susceptibility lncRNA. Moreover, correlation of this lncRNA with apoptosis were evaluated in SLE patients. Results We identified a new susceptibility locus in a lncRNA gene which we named SLEAR (rs13259960, P_combined=1.03×10^‐11, OR=1.35). The A>G variation at rs13259960, located in an intronic enhancer, impairs STAT1 recruitment to the enhancer that loops to the SLEAR promoter, resulting in decreased SLEAR level (3 G/G, 22 A/G, 103 A/A at rs13259960; P=0.0241). Moreover, SLEAR interacts with ILF2, hnRNP F and TAF15 to form a complex for transcriptional activation of the downstream anti‐apoptotic genes. SLEAR regulates apoptosis in vitro and its expression level is correlated with cell death in SLE patients (n=30, r=0.824, P=2.15E‐8). Conclusion These findings suggest a mechanism by which the risk variant at rs13259960 modulates SLEAR expression and predisposes to SLE and may give insights into the SLE etiology.