The First Clinical College, Guangzhou Medical University, Guangzhou, China.
Nanshan College, Guangzhou Medical University, Guangzhou, China.
Clin Rheumatol. 2024 Sep;43(9):2843-2856. doi: 10.1007/s10067-024-07059-3. Epub 2024 Jul 13.
OBJECTIVES: 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.
目的：系统性红斑狼疮（SLE）是一种异质性自身免疫性疾病，治疗效果不尽人意。我们旨在从遗传角度探索 SLE 的新靶点。
方法：利用 eQTLGen 联盟提供的 31684 份全血样本的顺式表达数量性状基因座（eQTL），以及两个大型 SLE 队列，筛选和验证与 SLE 因果相关的基因。共定位分析用于进一步研究 GWAS 信号指示的风险基因表达变化是否影响 SLE 的发生和发展。使用表型全基因组关联研究（PheWAS）评估用于药物开发的靶点是否存在潜在的副作用。基于多个数据库，我们探索了药物预测和评估现有药物的药物与基因之间的相互作用。
结果：该分析共包含 5427 个可成药基因。在发现阶段的两样本孟德尔随机化（MR）分析中，确定了 20 个与 SLE 因果相关的基因，并在验证阶段验证了 8 个基因。共定位分析最终确定了 5 个基因（BLK、HIST1H3H、HSPA1A、IL12A、NEU1）的 PPH4 > 0.8。PheWAS 进一步表明，作用于 BLK 和 IL12A 的药物不太可能有潜在的副作用，而 HSPA1A 和 NEU1 与其他特征有关。有 4 个基因（BLK、HSPA1A、IL12A、NEU1）已被确定为自身免疫性疾病和其他疾病的药物开发靶点。
结论：本研究确定了五个 SLE 的治疗靶点基因。重新利用和开发针对这些基因的药物有望改善 SLE 的现有治疗状态。
关键点：
Front Cell Infect Microbiol. 2024-4-10
Int Immunopharmacol. 2023-1
Annu Rev Med. 2023-1-27
Eur J Hum Genet. 2022-6
Trends Mol Med. 2021-2
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