School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, Australia.
Hunter Medical Research Institute, Newcastle, Australia.
Elife. 2021 Mar 15;10:e63115. doi: 10.7554/eLife.63115.
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.
肺功能测量具有遗传性，因此，我们试图利用遗传学提出可能改善呼吸结果的药物再利用候选物。研究发现，肺功能测量与七种可用药理学特征具有遗传相关性，并且空腹血糖升高与肺功能下降之间存在因果关系的进一步证据。此外，我们专门针对具有已知药物靶点的途径开发了肺功能多基因评分，并在独立队列中研究了它们与肺表型和基因表达的关系，以确定可能从特定药物再利用机会中受益的个体。然后对肺功能进行了全转录组关联研究（TWAS），确定了几种具有预测肺功能增强作用机制的药物-基因相互作用。通过多基因评分和 TWAS 方法发现了调节血糖的药物。总之，我们为许多可能改善肺功能的新的药物再利用机会提供了遗传依据。
