PDF(Pubmed)
Abstract：
To date, no immunomodulatory drug has demonstrated its efficacy in primary SS (pSS). We sought to analyse potential commonalities between pSS transcriptomic signatures and signatures of various drugs or specific knock-in or knock-down genes.
Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database.
We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated.
This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.
Gene expression from peripheral blood samples of patients with pSS was compared with that of healthy controls in two cohorts and three public databases. In each of the five datasets, we analysed the 150 most up- and downregulated genes between pSS patients and controls with regard to the differentially expressed genes resulting from the biological action on nine cell lines of 2837 drugs, 2160 knock-in and 3799 knock-down genes in the Connectivity Map database.
We analysed 1008 peripheral blood transcriptomes from five independent studies (868 patients with pSS and 140 healthy controls). Eleven drugs could represent potential candidate drugs, with histone deacetylases and PI3K inhibitors among the most significantly associated. Twelve knock-in genes were associated with a pSS-like profile and 23 knock-down genes were associated with a pSS-revert profile. Most of those genes (28/35, 80%) were interferon-regulated.
This first drug repositioning transcriptomic approach in SS confirms the interest of targeting interferons and identifies histone deacetylases and PI3K inhibitors as potential therapeutic targets.
摘要：
目标：迄今为止，尚无免疫调节药物在原发性干燥综合征(pSS)中显示其疗效。我们试图分析pSS转录组特征与各种药物或特定敲入或敲低基因的特征之间的潜在共性。
方法：在2个队列和3个公共数据库中比较了pSS患者外周血样本与健康对照的基因表达。在5个数据集中，我们分析了pSS患者和对照组之间150个最上调和下调的基因，这些基因是由2837种药物对9种细胞系的生物学作用引起的差异表达基因，ConnectivityMap数据库中的2160个敲入和3799个敲低基因。
结果：我们分析了来自5项独立研究（868名pSS患者和140名健康对照）的1008个外周血转录组。11种药物可以代表潜在的候选药物，与组蛋白脱乙酰酶和PI3K抑制剂最显著相关。12个敲入基因与pSS样图谱相关,23个敲低基因与pSS-revert图谱相关。这些基因中的大多数(28/35,80%)是干扰素调节的。
结论：这第一个药物重新定位Sjögren综合征的转录组学方法证实了靶向干扰素的兴趣，并将组蛋白脱乙酰酶和PI3K抑制剂确定为潜在的治疗靶标。
方法：在2个队列和3个公共数据库中比较了pSS患者外周血样本与健康对照的基因表达。在5个数据集中，我们分析了pSS患者和对照组之间150个最上调和下调的基因，这些基因是由2837种药物对9种细胞系的生物学作用引起的差异表达基因，ConnectivityMap数据库中的2160个敲入和3799个敲低基因。
结果：我们分析了来自5项独立研究（868名pSS患者和140名健康对照）的1008个外周血转录组。11种药物可以代表潜在的候选药物，与组蛋白脱乙酰酶和PI3K抑制剂最显著相关。12个敲入基因与pSS样图谱相关,23个敲低基因与pSS-revert图谱相关。这些基因中的大多数(28/35,80%)是干扰素调节的。
结论：这第一个药物重新定位Sjögren综合征的转录组学方法证实了靶向干扰素的兴趣，并将组蛋白脱乙酰酶和PI3K抑制剂确定为潜在的治疗靶标。
