Identification of novel genes influencing eosinophil-specific protein levels in asthma families
Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved..
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 &lt; 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:150 |
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| Enthalten in: |
The Journal of allergy and clinical immunology - 150(2022), 5 vom: 05. Nov., Seite 1168-1177 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Vernet, Raphaël [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.11.2022 Date Revised 08.11.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jaci.2022.05.017 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Identification of novel genes influencing eosinophil-specific protein levels in asthma families |
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| 500 | |a Date Completed 08.11.2022 | ||
| 500 | |a Date Revised 08.11.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 American Academy of Allergy, Asthma &amp; Immunology. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVE: We sought to identify genetic variants influencing ECP and EDN levels in asthma-ascertained families | ||
| 520 | |a 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 | ||
| 520 | |a RESULTS: We identified 5 genome-wide significant loci (P &lt; 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Meta-Analysis | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Eosinophil cationic protein | |
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| 650 | 7 | |a EC 3.1.27.- |2 NLM | |
| 650 | 7 | |a Eosinophil Granule Proteins |2 NLM | |
| 650 | 7 | |a Blood Proteins |2 NLM | |
| 700 | 1 | |a Matran, Régis |e verfasserin |4 aut | |
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| 700 | 1 | |a Madore, Anne-Marie |e verfasserin |4 aut | |
| 700 | 1 | |a Lavoie, Marie-Eve |e verfasserin |4 aut | |
| 700 | 1 | |a Gagnon, Pierre-Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Mohamdi, Hamida |e verfasserin |4 aut | |
| 700 | 1 | |a Margaritte-Jeannin, Patricia |e verfasserin |4 aut | |
| 700 | 1 | |a Siroux, Valérie |e verfasserin |4 aut | |
| 700 | 1 | |a Dizier, Marie-Hélène |e verfasserin |4 aut | |
| 700 | 1 | |a Demenais, Florence |e verfasserin |4 aut | |
| 700 | 1 | |a Laprise, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Nadif, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Bouzigon, Emmanuelle |e verfasserin |4 aut | |
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