Association of asthma genetic variants with asthma-associated traits reveals molecular networks of eosinophilic asthma

Abstract

<b>Introduction:</b> Asthma is a complex, polygenic, heterogenous inflammatory disease. Recently, we generated a list of 128 independent single nucleotide polymorphisms (SNPs) associated with asthma in Genome-wide association studies (El-Husseini et al. LRM 2020). However, it is unknown if asthma SNPs are associated with asthma-associated traits (ATs) such as eosinophilia, allergy, and airway obstruction. We aim to identify the association between asthma SNPs and asthma-associated traits, and reveal their molecular networks. <b>Methods:</b> Association analyses between 128 asthma SNPs and ATs (eosinophils, allergy, airway obstruction) were conducted using regression modelling (Lifelines N=32,817 / Vlagtwedde-Vlaardingen N=1,554 / Dutch Asthma GWAS N=917 cohorts). Functional enrichment and pathway analysis were performed with the genes linked to the significant SNPs by expression-QTL mapping. <b>Results:</b> We identified 70 asthma SNPs that were associated with at least one AT, with 20 SNPs having effects on multiple traits. The SNP annotated to SMAD3 was the most pleiotropic SNP being associated with eosinophilia, airway obstruction, and allergy. In total, 42 SNPs were associated with blood eosinophilia, 18 SNPs with airway obstruction, and 21 SNPs to allergy. We identified genetically driven pathways regulating blood eosinophilia in asthma, with several genes already targeted by drugs currently available for eosinophilic asthma including IL4R (Dupilumab), and TSLP (Tezepelumab). Several novel targets were identified. <b>Conclusion:</b> Many asthma SNPs are also associated with blood eosinophilia, and genetically driven molecular networks of eosinophilic asthma were identified.