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

Abstract

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, P combined = 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.

LncRNA Expression Profiles in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Emerging Biomarkers and Therapeutic Targets

“…Recently, the genetic significance of lncRNAs in many autoimmune diseases has been investigated, and most of the susceptibility loci for SLE were found to be located in noncoding regions of the genome ( 47 , 48 ). A novel SLE susceptibility locus in a lncRNA gene (SLEAR) was identified at the single-nucleotide polymorphism rs13259960, which can result in decreased SLEAR production in PBMCs from patients with SLE.…”

“…Moreover, it could interact with RNA binding proteins and thus affect the downstream target genes. In addition, the level of SLEAR expression was correlated with the percentage of PBMC death in patients with SLE ( 47 ). The rs145204276 ID/DD genotypes in the promoter region of the LncRNA-GAS5 gene may have a protective effect against SLE by up-regulating LncRNA-GAS5 expression and its targets miR-21 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) ( 48 ).…”

Exploring the Role of Non-Coding RNAs in the Pathophysiology of Systemic Lupus Erythematosus

“…SLEAR interacts with ILF2, hnRNP F and TAF15 to construct a complex that enhances the transcription of the anti-apoptotic genes. The role of this SNP in the regulation of apoptosis has also been verified in clinical samples [ 28 ]. The assessment of transcript signatures in SLA patients identified the lcnRNA linc00513 as significantly upregulated relative to healthy controls [ 32 ].…”

Involvement of lncRNA IL21-AS1 in interleukin-2 and T follicular regulatory cell activation in systemic lupus erythematosus

“…Interestingly, many disease-associated SNPs are located in the promoter, intron, or exon regions of lncRNAs, suggesting that SNPs may influence the expression levels of lncRNAs or alter their secondary structure, thereby affecting their regulatory functions [ 15 ]. Many studies have revealed the correlation between SNPs in lncRNAs and cancer and autoimmune and inflammatory diseases [ 16 – 20 ]. Notably, a study using meta-analysis identified the SNP rs62324212 (C>A), located in IL21 antisense RNA 1 (IL21-AS1), residing just upstream of IL-21 and IL-2 in all ten pediatric autoimmune diseases, including SLE [ 21 ].…”