Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; University of Cambridge, Cambridge, UK.
Cell Genom. 2024 Jul 10;4(7):100587. doi: 10.1016/j.xgen.2024.100587. Epub 2024 Jun 18.
Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by a dysregulated response to infection, for which disease heterogeneity is a major obstacle to developing targeted treatments. We have previously identified gene-expression-based patient subgroups (sepsis response signatures [SRS]) informative for outcome and underlying pathophysiology. Here, we aimed to investigate the role of genetic variation in determining the host transcriptomic response and to delineate regulatory networks underlying SRS. Using genotyping and RNA-sequencing data on 638 adult sepsis patients, we report 16,049 independent expression (eQTLs) and 32 co-expression module (modQTLs) quantitative trait loci in this disease context. We identified significant interactions between SRS and genotype for 1,578 SNP-gene pairs and combined transcription factor (TF) binding site information (SNP2TFBS) and predicted regulon activity (DoRothEA) to identify candidate upstream regulators. Overall, these approaches identified putative mechanistic links between host genetic variation, cell subtypes, and the individual transcriptomic response to infection.
脓毒症是一种危及生命的器官功能障碍的临床综合征，由感染引起的失调反应引起，疾病异质性是开发靶向治疗的主要障碍。我们之前已经确定了基于基因表达的患者亚组（脓毒症反应特征[SRS]），这些亚组对预后和潜在病理生理学有信息作用。在这里，我们旨在研究遗传变异在决定宿主转录组反应中的作用，并描绘 SRS 下的调控网络。使用 638 名成年脓毒症患者的基因分型和 RNA-seq 数据，我们报告了 16049 个独立的表达（eQTLs）和 32 个共表达模块（modQTLs）在这种疾病背景下的数量性状基因座。我们确定了 SRS 和基因型之间有 1578 个 SNP-基因对存在显著的相互作用，并结合转录因子（TF）结合位点信息（SNP2TFBS）和预测的调控子活性（DoRothEA）来鉴定候选上游调控因子。总的来说，这些方法确定了宿主遗传变异、细胞亚型和感染后个体转录组反应之间的潜在机制联系。
