Potential drug targets for asthma identified in the plasma and brain through Mendelian randomization analysis

Abstract

Background: Asthma is a heterogeneous disease, and the involvement of neurogenic inflammation is crucial in its development. The standardized treatments focus on alleviating symptoms. Despite the availability of medications for asthma, they have proven to be inadequate in controlling relapses and halting the progression of the disease. Therefore, there is a need for novel drug targets to prevent asthma.

Methods: We utilized Mendelian randomization to investigate potential drug targets for asthma. We analyzed summary statistics from the UK Biobank and then replicated our findings in GWAS data by Demenais et al. and the FinnGen cohort. We obtained genetic instruments for 734 plasma and 73 brain proteins from recently reported GWAS. Next, we utilized reverse causal relationship analysis, Bayesian co-localization, and phenotype scanning as part of our sensitivity analysis. Furthermore, we performed a comparison and protein-protein interaction analysis to identify causal proteins. We also analyzed the possible consequences of our discoveries by the given existing asthma drugs and their targets.

Results: Using Mendelian randomization analysis, we identified five protein-asthma pairs that were significant at the Bonferroni level (P < 6.35 × 10^-5). Specifically, in plasma, we found that an increase of one standard deviation in IL1R1 and ECM1 was associated with an increased risk of asthma, while an increase in ADAM19 was found to be protective. The corresponding odds ratios were 1.03 (95% CI, 1.02-1.04), 1.00 (95% CI, 1.00-1.01), and 0.99 (95% CI, 0.98-0.99), respectively. In the brain, per 10-fold increase in ECM1 (OR, 1.05; 95% CI, 1.03-1.08) and PDLIM4 (OR, 1.05; 95% CI, 1.04-1.07) increased the risk of asthma. Bayesian co-localization found that ECM1 in the plasma (coloc.abf-PPH4 = 0.965) and in the brain (coloc.abf-PPH4 = 0.931) shared the same mutation with asthma. The target proteins of current asthma medications were found to interact with IL1R1. IL1R1 and PDLIM4 were validated in two replication cohorts.

Conclusion: Our integrative analysis revealed that asthma risk is causally affected by the levels of IL1R1, ECM1, and PDLIM4. The results suggest that these three proteins have the potential to be used as drug targets for asthma, and further investigation through clinical trials is needed.

Keywords: Mendelian randomization; asthma; drug target; neurogenic inflammation; protein quantitative trait loci.