Multi-omic networks associated with COPD progression in TOPMed Cohorts

项目摘要 慢性阻塞性肺疾病（COPD）是美国第四大死亡原因。虽然 COPD主要发生在吸烟者中，目前尚不清楚为什么只有少数吸烟者（约20-40%） 出现慢性气流受限或远端气隙破坏（肺气肿）。的差异 对烟草烟雾的易感性可以通过遗传或环境的差异来解释， 导致激活或抑制的途径是重要的发病机制和进展， 慢性阻塞性肺病高通量组学（全基因组测序，DNA甲基化， RNA-Seq，蛋白质组学和代谢组学）应用于NHLBI队列，现在可以进行全面的 评估易感患者的分子特征。该提案将使用稀疏多个 典型相关网络分析（SmCCNet）整合这些现有的组学数据， NHLBI队列：COPDGene、杰克逊心脏研究和SPIROMICS。三个独立的队列 将允许复制特定的分子网络，这些分子网络可用于靶向新的治疗或更多的治疗。 对个体的精确预后信息（即，精准医学）。前两批人 有大量的非裔美国人受试者，他们在组学研究中的代表性不足。我们将 进行群体特异性分析，这将使我们能够确定哪些分子特征， 可能是非洲裔美国人特有的。

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the US. Although COPD occurs predominantly in smokers, it is unknown why only a minority of smokers (~20-40%) develop chronic airflow limitation or destruction of distal airspaces (emphysema). The difference susceptibility to tobacco smoke could be explained by differences in genetics or environment, which lead to activation or repression of pathways that are important in the pathogenesis and progression of COPD. Recent advances in high throughput omics (whole genome sequencing, DNA methylation, RNA-Seq, proteomics and metabolomics) applied to NHLBI cohorts now permits a comprehensive assessment of the molecular profiles of susceptible patients. This proposal will use sparse multiple canonical correlation network analysis (SmCCNet) to integrate these existing -omics data from three NHLBI cohorts: COPDGene, Jackson Heart Study, and SPIROMICS. The three independent cohorts will allow replication of specific molecular networks which can be used to target new therapies or more precise prognostic information to individuals (i.e., precision medicine). The first two of these cohorts have large numbers of African American subjects, who are underrepresented in omics studies. We will perform population specific analyses, which will allow us to determine which molecular signatures and pathways might be specific to African Americans.