目的:系统性红斑狼疮(SLE)是一种异质性自身免疫性疾病,治疗状态不佳。我们旨在从遗传学的角度探索SLE的新靶标。
方法:使用eQTLGen联盟提供的31,684份全血的顺式表达定量性状基因座(eQTL)以及两个大型SLE队列用于筛选和验证与SLE相关的基因。采用共定位分析来进一步研究风险基因表达是否发生变化,如GWAS信号所示,影响SLE的发生发展。使用表型全关联研究(PheWAS)评估了药物开发的靶标的潜在副作用。基于多个数据库,我们探索了药物和基因之间的相互作用,用于药物预测和当前药物的评估.
结果:分析共包括5427个可药用基因。发现阶段的双样本孟德尔随机化(MR)鉴定了20个与SLE有因果关系的基因,并在复制阶段验证了8个基因。共定位分析最终确定了五个基因(BLK,HIST1H3H,HSPA1A,IL12A,NEU1),PPH4>0.8。Phewas进一步指出,作用于BLK和IL12A的药物不太可能具有潜在的副作用,而HSPA1A和NEU1与其他性状相关。四个基因(BLK,HSPA1A,IL12A,NEU1)已成为自身免疫性疾病和其他疾病药物开发的目标。
结论:。这项研究确定了五个基因作为SLE的治疗靶标。重新开发和开发靶向这些基因的药物有望改善SLE的现有治疗状态。关键点•我们确定了治疗SLE的五个优先基因靶标,BLK和IL12A表明副作用较少。在针对这些候选基因的现有药物中,Ustekinumab,Ebdarokimab,Briakinumab(靶向IL12基因)和CD24FC(靶向HSPA1A)可能有可能被用于SLE的治疗。
OBJECTIVE: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with an unsatisfactory state of treatment. We aim to explore novel targets for SLE from a genetic standpoint.
METHODS: Cis-expression quantitative trait loci (eQTLs) for whole blood from 31,684 samples provided by the eQTLGen Consortium as well as two large SLE cohorts were utilized for screening and validating genes causally associated with SLE. Colocalization analysis was employed to further investigate whether changes in the expression of risk genes, as indicated by GWAS signals, influence the occurrence and development of SLE. Targets identified for drug development were evaluated for potential side effects using a phenome-wide association study (PheWAS). Based on the multiple databases, we explored the interactions between drugs and genes for drug prediction and the assessment of current medications.
RESULTS: The analysis comprised 5427 druggable genes in total. The two-sample Mendelian randomization (MR) in the discovery phase identified 20 genes causally associated with SLE and validated 8 genes in the replication phase. Colocalization analysis ultimately identified five genes (BLK, HIST1H3H, HSPA1A, IL12A, NEU1) with PPH4 > 0.8. PheWAS further indicated that drugs acting on BLK and IL12A are less likely to have potential side effects, while HSPA1A and NEU1 were associated with other traits. Four genes (BLK, HSPA1A, IL12A, NEU1) have been targeted for drug development in autoimmune diseases and other conditions.
CONCLUSIONS: .This study identified five genes as therapeutic targets for SLE. Repurposing and developing drugs targeting these genes is anticipated to improve the existing treatment state for SLE. Key Points • We identified five gene targets of priority for the treatment of SLE, with BLK and IL12A indicating fewer side effects. • Among the existing drugs that target these candidate genes, Ustekinumab, Ebdarokimab, and Briakinumab (targeting the IL12 gene) and CD24FC (targeting HSPA1A) may potentially be repurposed for the treatment of SLE.