Identification of novel genes influencing eosinophil-specific protein levels in asthma families

J Allergy Clin Immunol. 2022 Nov;150(5):1168-1177. doi: 10.1016/j.jaci.2022.05.017. Epub 2022 Jun 6.

Abstract

Background: Eosinophils play a key role in the asthma allergic response by releasing cytotoxic molecules such as eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) that generate epithelium damages.

Objective: We sought to identify genetic variants influencing ECP and EDN levels in asthma-ascertained families.

Methods: We performed univariate and bivariate genome-wide association analyses of ECP and EDN levels in 1018 subjects from the EGEA study with follow-up in 153 subjects from the Saguenay-Lac-Saint-Jean study and combined the results of these 2 studies through meta-analysis. We then conducted Bayesian statistical fine mapping together with quantitative trait locus and functional annotation analyses to identify the most likely functional genetic variants and candidate genes.

Results: We identified 5 genome-wide significant loci (P < 5 × 10<sup>-8</sup>) including 7 distinct signals associated with ECP and/or EDN levels. The genes targeted by our fine mapping and functional search include RNASE2 and RNASE3 (14q11), which encode EDN and ECP, respectively, and 4 other genes that regulate ECP and EDN levels. These 4 genes were JAK1 (1p31), a transcription factor that plays a key role in the immune response and acts as a potential therapeutic target for eosinophilic asthma; ARHGAP25 (2p13), which is involved in leukocyte recruitment to inflammatory sites; NDUFA4 (7p21), which encodes a component of the mitochondrial respiratory chain and is involved in cellular response to stress; and CTSL (9q22), which is involved in immune response, extracellular remodeling, and allergic inflammation.

Conclusion: Analysis of specific phenotypes produced by eosinophils allows the identification of genes that play a major role in allergic response and inflammation, and offers potential therapeutic targets for asthma.

Keywords: Eosinophil cationic protein; GWAS; allergy; asthma; eosinophil-derived neurotoxin; genetics.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asthma*
  • Bayes Theorem
  • Blood Proteins / metabolism
  • Eosinophil Cationic Protein / genetics
  • Eosinophil Cationic Protein / metabolism
  • Eosinophil Granule Proteins / genetics
  • Eosinophil Granule Proteins / metabolism
  • Eosinophil-Derived Neurotoxin / genetics
  • Eosinophil-Derived Neurotoxin / metabolism
  • Eosinophils
  • Genome-Wide Association Study
  • Humans
  • Hypersensitivity* / metabolism
  • Inflammation / metabolism

Substances

  • Eosinophil-Derived Neurotoxin
  • Eosinophil Cationic Protein
  • Eosinophil Granule Proteins
  • Blood Proteins