Common genomic mechanisms of disease across asthma and COPD

University Of California, San Francisco, San Francisco CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a major health concern worldwide. As a disease characterized by airflow limitation and an abnormal inflammatory response, it shares many significant features with asthma, both clinically and pathologically. However, less progress has been made into understanding the fundamental mechanisms of disease in COPD than in asthma. Given the disease overlap, investigating whether transcriptomic signatures of asthma are also expressed in patients with COPD is appealing as this may provide insight into these underlying mechanisms and may assist in predicting response to therapies. In previous work, our lab identified a three-gene signature of IL-13 associated inflammation that is induced in a pathologically and clinically distinct sub-phenotype of asthma (TH2 High phenotype), and predicts response to existing therapeutics. We have also identified a family of miRNAs, the miR-34/449 family, that is repressed in asthma, a finding that is replicated with IL-13 exposure in vitro. IL-13 is induced in at least some patiens with COPD, and is important to the development of mucous metaplasia in vitro and in vivo, a process that is also a key pathologic finding in COPD. We propose to investigate whether these transcriptomic signatures of IL-13 are also seen in COPD. We will evaluate whether the three-gene signature associated with the TH-2 High phenotype is over-expressed in COPD, and whether it can identify clinically relevant subpopulations within COPD. To accomplish this we will use airway epithelial mRNA microarray data available from a cohort of 238 patients with and without COPD, applying an unsupervised clustering approach. Using a cohort of never, current, and further smokers we will, furthermore, determine if this signature is present in the setting of COPD- associated airway injury alone. We will also study miRNA alterations in COPD, focusing specifically on the miR-34/449 family, in a subset of subjects from the SPIROMICS study who will undergo research bronchoscopy. We will profile bronchial epithelial miRNA expression in a cohort of 50 subjects (consisting of healthy controls, healthy former smokers, healthy current smokers, former smokers with COPD, and current smokers with COPD) and identify differentially expressed miRNAs with smoking and COPD. We will then develop mRNA and miRNA signatures of mucous metaplasia using COPD-specific mediators of this process. We will use these signatures to probe the mRNA and miRNA expression data to investigate how they contribute to COPD. Ideally, this work could lead to improved targeted therapies in COPD.