Oral Presentation GENEMAPPERS 2024

Using genetically regulated expression to investigate drug repurposing opportunities in chronic respiratory disorders (#23)

Tess Geraghty 1 2 , Danielle Adams 1 2 , William Reay 3 , Murray Cairns 1 2
  1. Centre for Complex Disease and Precision Medicine, School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia
  2. Precision Medicine Research Program, Hunter Medical Research Institute, Newcastle, NSW, Australia
  3. Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

Chronic respiratory disorders are a major contributor to the burden of non-communicable diseases worldwide1. There are numerous data from clinical studies revealing that metabolic dysregulation and the associated inflammatory response contribute to the pathogenesis of respiratory disorders. Notably, disorders including asthma, chronic obstructive pulmonary disorder (COPD), and sleep apnoea have been linked to metabolic conditions including obesity and type II diabetes in a bi-directional manner2,3,4. While these systems have been identified as tractable therapeutic targets, these relationships are largely supported through observational studies, and thus, further work is needed to confirm that metabolic and inflammatory mechanisms are causally linked to respiratory outcomes. This project aimed to use genomic methods to identify pre-existing therapeutics that may serve as promising agents for drug repurposing in chronic respiratory disorders. Pharmagenic enrichment was employed to aggregate genetic variants in biological pathways with known druggable targets5 that are associated with asthma, COPD, and sleep apnoea in genome wide association study data from the FinnGen Project6. This revealed two FDA-approved therapeutics as promising drug repurposing candidates for asthma, and a transcriptome-wide association study (TWAS)7 was performed to orthogonally validate the drug directions of effect. Interestingly, the potential therapeutic benefits of one of these compounds was further corroborated through TWAS of the target gene expression, which was shown to be significantly associated with asthma in oesophagus mucosa and stomach GTEx tissues. Together, these results provide further evidence for the causal relationship between metabolic and immunological regulation and chronic respiratory disorders. Furthermore, this highlights the opportunity for genetically informed precision medicine with existing and repurposed treatments for chronic respiratory disorders.

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