Université Paris Cité, Inserm, UMR 1124, Group of Genomic Epidemiology and Multifactorial Diseases, Paris, France.
Université Lille, CHU Lille, Institut Pasteur de Lille, ULR 4483, Lille, France.
J Allergy Clin Immunol. 2022 Nov;150(5):1168-1177. doi: 10.1016/j.jaci.2022.05.017. Epub 2022 Jun 6.
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<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.
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.
嗜酸性粒细胞通过释放细胞毒性分子，如嗜酸性粒细胞阳离子蛋白（ECP）和嗜酸性粒细胞衍生神经毒素（EDN），在哮喘过敏反应中发挥关键作用，这些分子会导致上皮损伤。
我们旨在鉴定影响哮喘患者嗜酸性粒细胞 ECP 和 EDN 水平的遗传变异。
我们对 EGEA 研究中的 1018 名受试者进行了 ECP 和 EDN 水平的单变量和双变量全基因组关联分析，并对 Saguenay-Lac-Saint-Jean 研究中的 153 名受试者进行了随访，并通过荟萃分析合并了这两项研究的结果。然后，我们进行了贝叶斯统计精细映射以及数量性状基因座和功能注释分析，以确定最可能的功能遗传变异和候选基因。
我们确定了 5 个全基因组显著位点（P < 5 × 10−8），包括 7 个与 ECP 和/或 EDN 水平相关的独特信号。我们的精细映射和功能搜索靶向的基因包括 RNASE2 和 RNASE3（14q11），分别编码 EDN 和 ECP，以及 4 个调节 ECP 和 EDN 水平的其他基因。这 4 个基因是 JAK1（1p31），它在免疫反应中起着关键作用，是嗜酸性哮喘的潜在治疗靶点；ARHGAP25（2p13），参与白细胞向炎症部位的募集；NDUFA4（7p21），编码线粒体呼吸链的一个组成部分，参与细胞对应激的反应；以及 CTSL（9q22），参与免疫反应、细胞外重塑和过敏炎症。
对嗜酸性粒细胞产生的特定表型进行分析，可以鉴定出在过敏反应和炎症中起主要作用的基因，并为哮喘提供潜在的治疗靶点。
