Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug-repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug-repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug-repurposing opportunities that could improve lung function.
Keywords: GWAS; TWAS; causal inference; drug repurposing; genetics; genomics; human; lung function; polygenic scoring.
Chronic respiratory disorders like asthma affect around 600 million people worldwide. Although these illnesses are widespread, they can have several different underlying causes, making them difficult to treat. Drugs that work well on one type of respiratory disorder may be completely ineffective on another. Understanding the biological and environmental factors that cause these illnesses will allow them to be treated more effectively by tailoring therapies to each patient. Reduced lung function is a factor in respiratory disorders and it can have many genetic causes. Studying the genes of patients with reduced lung function can reveal the genes involved, some of which may already be targets of existing drugs for other illnesses. So, could a patient’s genetics be used to repurpose existing drugs to treat their respiratory disorders? Reay et al. combined three methods to link genetics and biological processes to the causes of reduced lung function. The results reveal several factors that could lead to new treatments. In one example, reduced lung function showed a link to genes associated with high blood sugar. As such, treatments used in diabetes might help improve lung function in some patients. Reay et al. also developed a scoring system that could predict the efficacy of a treatment based on a patient’s genetics. The study suggests that COVID-19 infection could be affected by blood sugar levels too. Chronic respiratory disorders are a critical issue worldwide and have proven difficult to treat, but these results suggest a way to identify new therapies and target them to the right patients. The findings also support a connection between lung function and blood sugar levels. This implies that perhaps existing diabetes treatments – including diet and lifestyle changes aimed at reducing or limiting blood sugar – could be repurposed to treat respiratory disorders in some patients. The next step will be to perform clinical trials to test whether these therapies are in fact effective.
© 2021, Reay et al.