Exploring potential therapeutic targets for asthma: a proteome-wide Mendelian randomization analysis

Area of Science:

• Genetics and Molecular Biology
• Immunology
• Pharmacology

Background:

• Asthma is a major global health concern with significant morbidity and mortality.
• Current treatments are insufficient for many severe asthma cases, necessitating novel therapeutic strategies.
• Identifying circulating plasma proteins associated with asthma risk is crucial for developing new treatments.

Purpose of the Study:

• To investigate the association between circulating plasma proteins and asthma risk using Mendelian randomization.
• To identify potential drug targets for asthma by analyzing protein associations and druggability.
• To explore plasma protein links to asthma subtypes for targeted therapies.

Main Methods:

• Employed summary-data-based Mendelian randomization (MR) and two-sample MR on UK Biobank data.
• Utilized discovery (FinnGen) and replication (GERA) cohorts with Bayesian colocalization for validation.
• Conducted protein-protein interaction, druggability, and candidate drug prediction analyses.

Main Results:

• Identified 75 plasma proteins associated with asthma in the discovery cohort, including IL1RAP, IL1RL1, IL6, CXCL5, and CXCL8.
• Validated 6 proteins (IL4R, LTB, CASP8, MAX, PCDH12, SCLY) through co-localization and replication.
• MAX protein demonstrated significant druggability potential; IL4R, CASP8, and SCLY were identified as potential drug targets.

Conclusions:

• Established a link between plasma proteins and asthma, enhancing understanding of its molecular pathogenesis.
• Discovered novel potential therapeutic targets for asthma, including MAX, IL4R, CASP8, and SCLY.
• Findings provide new insights for asthma drug target research and development.