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.