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Abstract：
Genome-wide association studies (GWASs) have repeatedly reported multiple non-coding single-nucleotide polymorphisms (SNPs) at 2p14 associated with rheumatoid arthritis (RA), but their functional roles in the pathological mechanisms of RA remain to be explored. In this study, we integrated a series of bioinformatics and functional experiments and identified three intronic RA SNPs (rs1876518, rs268131, and rs2576923) within active enhancers that can regulate the expression of SPRED2 directly. At the same time, SPRED2 and ACTR2 influence each other as a positive feedback signal amplifier to strengthen the protective role in RA by inhibiting the migration and invasion of rheumatoid fibroblast-like synoviocytes (FLSs). In particular, the transcription factor CEBPB preferentially binds to the rs1876518-T allele to increase the expression of SPRED2 in FLSs. Our findings decipher the molecular mechanisms behind the GWAS signals at 2p14 for RA and emphasize SPRED2 as a potential candidate gene for RA, providing a potential target and direction for precise treatment of RA.
摘要：
全基因组关联研究（GWASs）反复报道了与类风湿关节炎（RA）相关的2p14的多个非编码单核苷酸多态性（SNPs）。但其在RA病理机制中的功能作用仍有待探索。在这项研究中,我们整合了一系列生物信息学和功能实验，并在活性增强子中鉴定了三个内含子RASNP（rs1876518，rs268131和rs2576923），它们可以直接调节SPRED2的表达。同时,SPRED2和ACTR2作为正反馈信号放大器相互影响，通过抑制类风湿性成纤维细胞样滑膜细胞（FLSs）的迁移和侵袭来加强对RA的保护作用。特别是,转录因子CEBPB优先结合rs1876518-T等位基因以增加FLS中SPRED2的表达。我们的发现破译了RA在2p14的GWAS信号背后的分子机制，并强调SPRED2是RA的潜在候选基因，为RA的精准治疗提供了潜在的目标和方向。
