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

• Published in: Journal of allergy and clinical immunology Vol. 150; no. 5; pp. 1168 - 1177
• Main Authors: Vernet, Raphaël, Matran, Régis, Zerimech, Farid, Madore, Anne-Marie, Lavoie, Marie-Eve, Gagnon, Pierre-Alexandre, Mohamdi, Hamida, Margaritte-Jeannin, Patricia, Siroux, Valérie, Dizier, Marie-Hélène, Demenais, Florence, Laprise, Catherine, Nadif, Rachel, Bouzigon, Emmanuelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2022; Elsevier
• Subjects: allergy; asthma; Eosinophil cationic protein; eosinophil-derived neurotoxin; genetics; GWAS; Human health and pathology; Life Sciences; Pulmonology and respiratory tract; Santé publique et épidémiologie; eosinophil-derived neurotoxin; GWAS; BF; allergy; asthma; eQTL; EDN; genetics; ECP; PC; SNP; HI-C; SLSJ; LD; Eosinophil cationic protein; EGEA; eosinophil cationic protein
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2022.05.017

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. We sought to identify genetic variants influencing ECP and EDN levels in asthma-ascertained families. 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. We identified 5 genome-wide significant loci (P < 5 × 10−8) 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. 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.