Association of a functional polymorphism in the 3′-untranslated region of SPI1 with systemic lupus erythematosus

Abstract

Objective. SPI1, also referred to as PU.1, is an Ets family transcription factor that interacts with IRF2, IRF4, and IRF8. In view of the significance of the type I interferon pathway in systemic lupus erythematosus (SLE), this study was undertaken to investigate a possible association between SPI1 polymorphisms and SLE.Methods. A case-control association study was performed using 6 tag single-nucleotide polymorphisms (SNPs), as well as a SNP located upstream of SPI1 previously found to be associated with acute myelogenous leukemia, in 400 Japanese patients with SLE and 450 healthy controls. Resequencing of all exons and known regulatory regions was performed to identify functional polymorphisms. Association of genotype and SPI1 expression was examined using the GENEVAR database and reporter assays.Results. A significant association was detected in 2 SNPs in intron 2 (rs10769258 and rs4752829) (P ‫؍‬ 0.005 and P ‫؍‬ 0.008, respectively, under the dominant model). The association was stronger in patients with nephropathy. Resequencing identified a potentially functional polymorphism in the 3 -untranslated region (3 -UTR), rs1057233, which was in strong linkage disequilibrium with the SNPs in intron 2. The number of risk alleles at rs1057233 was strongly correlated with SPI1 messenger RNA (mRNA) level in the database analysis (P ‫؍‬ 0.0002), and was confirmed by a reporter assay. Interestingly, rs1057233 alters a target sequence for microRNA hsa-miR-569 (miR-569). Transfection experiments demonstrated that miR-569 inhibits expression of a reporter construct with the 3 -UTR sequence containing the nonrisk allele but not the risk allele.Conclusion. Our findings indicate that a SNP in the 3 -UTR of SPI1 is associated with elevated SPI1 mRNA level and with susceptibility to SLE.

Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice

“…This is the first report to identify the importance of haploinsufficiency of IRF4 for disease resistance in autoimmune disease. This finding is highly critical from a clinical point of view, as it suggests the importance of subtle differences in IRF4 expression due to gene polymorphisms such as SPI1 for disease development or activity in systemic lupus erythematosus [40]. Similar results have been demonstrated in studies of mitogen-inducible gene 6 protein in streptozotocin-induced diabetes and in our previous study of IL-17 in autoimmune thyroiditis in NOD-H2 h4 mice [41,42].…”

Polymorphisms of microRNA-Binding Sites in Integrin Genes Are Associated with Oral Squamous Cell Carcinoma Susceptibility and Progression

“…For example, the base transition of T to C at rs8126, a polymorphism located in the miRNA-binding site of TNFAIP2, was suggested to contribute in the up-regulation of TNFAIP2 in Head and Neck Squamous Cell Carcinoma (HNSCC) . Another study in systemic lupus erythematosus showed that rs1057233 in the 3′UTR of SPI1 was associated with the elevation of SPI1 mRNA level (Hikami et al 2011). Similar results were also found in ovarian cancer (Wynendaele et al 2010) and breast cancer (Zhang et al 2011).…”

Novel Insights into miRNA in Lung and Heart Inflammatory Diseases

“…A SNP rs1057233*T (T/C) in the 3′-UTR of SPI1 alters a target sequence for miR-569 that is associated with elevated SPI1 mRNA level and with susceptibility to SLE [28]. However, another variant rs57095329*G (G/A) in the promoter region of miR-146a primary transcript was associated with SLE in Chinese [29].…”