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Article Dans Une Revue Journal of Allergy and Clinical Immunology Année : 2022

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

Identification de nouveaux gènes influençant les niveaux de protéines spécifiques des éosinophiles dans des familles d'asthmatiques.

Résumé

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: 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 1,018 subjects from EGEA study with follow-up in 153 subjects from SLSJ study and combined the results of these two 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 five genome-wide significant loci (P<5x10-8) including seven 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 four other genes which regulate ECP/EDN levels. These four genes were the following: JAK1 (1p31) a transcription factor with a key role in the immune response and a potential therapeutic target for eosinophilic asthma, ARHGAP25 (2p13) involved in leukocyte recruitment to inflammatory sites, NDUFA4 (7p21) encoding a component of the mitochondrial respiratory chain and involved in cellular response to stress and CTSL (9q22) involved in immune response, extra-cellular remodeling and allergic inflammation. Conclusion: This study demonstrates that the analysis of specific phenotypes produced by eosinophils allows identifying genes with a major role in allergic response and inflammation and offering potential therapeutic targets for asthma.

Dates et versions

hal-04281822 , version 1 (13-11-2023)

Licence

Paternité - Pas d'utilisation commerciale - Pas de modification

Identifiants

Citer

Raphaël Vernet, Régis Matran, Farid Zerimech, Anne-Marie Madore, Marie-Eve Lavoie, et al.. Identification of novel genes influencing eosinophil-specific protein levels in asthma families. Journal of Allergy and Clinical Immunology, 2022, 150 (5), pp.1168-1177. ⟨10.1016/j.jaci.2022.05.017⟩. ⟨hal-04281822⟩
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