Study Identifies Asthma SNPs Linked with Eosinophilia, Atopy, and Obstruction

Zaid El-Husseini, PhD

Credit: The University of Groningen

Investigators identified many asthma single nucleotide polymorphisms (SNPs) associated with blood eosinophil counts and genetically driven molecular pathways of asthma-associated traits. According to the study, these findings could provide new insights into the pathogenesis of asthma and help identify novel drug targets for the treatment of asthma.¹

Data from the analysis revealed 42 SNPs were associated with eosinophil counts, 18 SNPs with airway obstruction, and 21 SNPs with atopy.

Genetically driven pathways regulating eosinophilia were also discovered with the most extensive network of eosinophilia containing 2 genes, interleukin-4 receptor (IL4R) and thymic stromal lymphopoietin (TSLP) targeted by drugs currently available for eosinophilic asthma.

In addition to the available drugs mentioned, the data noted IL-18, CCR4, and calcineurin as novel targets for further research.

Investigating Asthma Genetics and Traits

The pathogenesis of asthma is multifactorial, involving genetic and environmental factors. The genetic component of asthma has been studied extensively, and several genome-wide association studies (GWAS) have identified SNPs associated with asthma susceptibility.²

The team, led by Zaid El-Husseini, PhD, Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, aimed to investigate the association between 128 independent asthma SNPs and asthma-associated traits, as well as assess the downstream functional effects of the significant SNPs and identify novel drug targets.¹

Investigators implemented regression modeling to examine the association between the 128 asthma SNPs and asthma-associated traits. The associated traits consisted of blood eosinophil numbers, atopy, airway obstruction, and airway hyperresponsiveness.

Functional enrichment and pathway analysis were performed using genes linked to the significant SNPs by expression quantitative trait locus (e-QTL) analysis. Data from 3 population-based studies were used in the analysis: Lifelines (N = 32,817), Vlagtwedde-Vlaardingen (N = 1554), and the Dutch Asthma genome-wide association study (N = 917).

Linking Asthma SNPs to Traits

In the findings, 69 asthma SNPs were associated with at least one asthma-associated trait, and 20 SNPs were linked with multiple traits.

Among the total 128 SNPs, those located on the SMAD3 gene were found to be the most diverse range of effects or associations with different asthma-related traits. Specifically, investigators reported these SNPs were associated with high eosinophil counts, atopy, and airway obstruction, which indicates the involvement of the SMAD3 gene in different aspects of asthma pathology.

“We found evidence for pleiotropic genes, but also some disease-specific genes were identified,” investigators wrote. “This study shows that there are distinct sets of asthma SNPs that constitute distinct molecular pathways, according to protein interaction networks analysis. We identified genetically driven pathways regulating eosinophilia in asthma, with two genes (IL4R, TSLP) targeted by drugs currently available for eosinophilic asthma.”

References:

1. El-Husseini, ZW, Vonk, JM, van den Berge, M, Gosens, R, Koppelman, GH. Association of asthma genetic variants with asthma-associated traits reveals molecular pathways of eosinophilic asthma. Clin Transl Allergy. 2023;e12239. https://doi.org/10.1002/clt2.12239
2. El-Husseini ZW, Gosens R, Dekker F, Koppelman GH. The genetics of asthma and the promise of genomics-guided drug target discovery. Lancet Respir Med. 2020;8(10):1045-1056.