Dissecting Inflammatory Complications in Critically Injured Patients by Within-Patient Gene Expression Changes: A Longitudinal Clinical Genomics Study
Dissecting Inflammatory Complications in Critically Injured Patients by Within-Patient Gene Expression Changes: A Longitudinal Clinical Genomics Study
复制标题
DOI：
10.1371/journal.pmed.1001093
复制
发表时间：
2011-09-01
期刊：
影响因子：
15.8
通讯作者：
Storey, John D.
中科院分区：
文献类型：
--
作者：
Desai, Keyur H.;Tan, Chuen Seng;Storey, John D.
背景：创伤是美国1-44岁人群的头号杀手。严重受伤患者的炎症并发症的预后和治疗仍然具有挑战性，临床试验失败的历史和生物学知之甚少。因此，需要新的方法来提高我们的能力，诊断和治疗这种临床condition.Methods和调查结果：我们进行了一项大规模的研究，对168钝力创伤患者超过28天，测量，400临床变量和纵向分析白细胞基因表达与类似的800微阵列。首先利用马歇尔MOF（多器官衰竭）临床评分轨迹将患者分为五类，这些类别的结局越来越差。然后，我们开发了一个分析框架，对早期患者内的表达变化进行建模，以产生对创伤的基因组反应的强大表征。四分之一的基因组显示出与长期损伤后并发症相关的早期表达变化，这些变化被功能相关基因的至少五个动态共表达模块捕获。特别是，发现MHC-II类基因的早期下调和p38 MAPK信号通路的上调与长期损伤后并发症密切相关，从而在损伤后40-80小时窗口期间从表达变化中区分患者结果。这里提供的基因组表征大大扩展了创伤分子反应的表征和理解范围。这些结果可能有助于我们进一步了解疾病的过程，并确定潜在的治疗干预目标。此外，我们所介绍的定量方法可能适用于未来快速进展的临床条件的基因组学研究。
Background: Trauma is the number one killer of individuals 1-44 y of age in the United States. The prognosis and treatment of inflammatory complications in critically injured patients continue to be challenging, with a history of failed clinical trials and poorly understood biology. New approaches are therefore needed to improve our ability to diagnose and treat this clinical condition.Methods and Findings: We conducted a large-scale study on 168 blunt-force trauma patients over 28 d, measuring,400 clinical variables and longitudinally profiling leukocyte gene expression with similar to 800 microarrays. Marshall MOF (multiple organ failure) clinical score trajectories were first utilized to organize the patients into five categories of increasingly poor outcomes. We then developed an analysis framework modeling early within-patient expression changes to produce a robust characterization of the genomic response to trauma. A quarter of the genome shows early expression changes associated with longer-term post-injury complications, captured by at least five dynamic co-expression modules of functionally related genes. In particular, early down-regulation of MHC-class II genes and up-regulation of p38 MAPK signaling pathway were found to strongly associate with longer-term post-injury complications, providing discrimination among patient outcomes from expression changes during the 40-80 h window post-injury.Conclusions: The genomic characterization provided here substantially expands the scope by which the molecular response to trauma may be characterized and understood. These results may be instrumental in furthering our understanding of the disease process and identifying potential targets for therapeutic intervention. Additionally, the quantitative approach we have introduced is potentially applicable to future genomics studies of rapidly progressing clinical conditions.