Abstract

Role of microRNA Regulatory Networks for Leukotriene Modifier Response in Asthma

Amber Dahlin, Instructor of Medicine and Associate Epidemiologist, Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School

Asthma is a major global public health burden, and severe asthma subtypes such as aspirin-exacerbated respiratory disease (AERD), represent a particular treatment challenge. AERD is characterized by excessive leukotriene (LT) production and end organ hyper-reactivity to cysteinyl LTs following aspirin ingestion. As a result, these patients may ideally benefit from leukotriene modifiers (LTMs) such as montelukast that block LT receptors to relieve symptoms. However, substantial inter-individual variability in montelukast response exists, which is partly due to genetic variation in LT regulatory pathways, resulting in unpredictable therapeutic outcomes. The activity of microRNAs also influences disease pathogenesis and treatment, as microRNAs have key roles in regulating gene expression. Interactions between genes and microRNAs are complex, since multiple microRNAs can regulate multiple genes and genes can be regulated by multiple miRNAs. These interactions can be explored computationally by integrating gene and microRNA expression data to construct networks of correlated microRNA-gene pairs (i.e. regulatory networks). Rather than analyzing microRNA-gene pairs separately, this approach enables analysis of multiple genes and microRNAs simultaneously. Using this approach to understand how AERD patients may respond to medication can promote development of personalized therapies, and obtaining insight into biological pathways will ultimately inspire development of more effective treatment regimens.