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Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus

Aspergillus fumigatus is a ubiquitous fungus and the main agent of aspergillosis, a common fungal infection in the immunocompromised population. Triazoles such as itraconazole and voriconazole are the common first-line drugs for treating aspergillosis. However, triazole resistance in A. fumigatus ha...

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Autores principales: Fan, Yuying, Wang, Yue, Korfanty, Gregory A., Archer, Meagan, Xu, Jianping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227032/
https://www.ncbi.nlm.nih.gov/pubmed/34199862
http://dx.doi.org/10.3390/pathogens10060701
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author Fan, Yuying
Wang, Yue
Korfanty, Gregory A.
Archer, Meagan
Xu, Jianping
author_facet Fan, Yuying
Wang, Yue
Korfanty, Gregory A.
Archer, Meagan
Xu, Jianping
author_sort Fan, Yuying
collection PubMed
description Aspergillus fumigatus is a ubiquitous fungus and the main agent of aspergillosis, a common fungal infection in the immunocompromised population. Triazoles such as itraconazole and voriconazole are the common first-line drugs for treating aspergillosis. However, triazole resistance in A. fumigatus has been reported in an increasing number of countries. While most studies of triazole resistance have focused on mutations in the triazole target gene cyp51A, >70% of triazole-resistant strains in certain populations showed no mutations in cyp51A. To identify potential non-cyp51A mutations associated with triazole resistance in A. fumigatus, we analyzed the whole genome sequences and triazole susceptibilities of 195 strains from 12 countries. These strains belonged to three distinct clades. Our genome-wide association study (GWAS) identified a total of six missense mutations significantly associated with itraconazole resistance and 18 missense mutations with voriconazole resistance. In addition, to investigate itraconazole and pan-azole resistance, Fisher’s exact tests revealed 26 additional missense variants tightly linked to the top 20 SNPs obtained by GWAS, of which two were consistently associated with triazole resistance. The large number of novel mutations related to triazole resistance should help further investigations into their molecular mechanisms, their clinical importance, and the development of a comprehensive molecular diagnosis toolbox for triazole resistance in A. fumigatus.
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spelling pubmed-82270322021-06-26 Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus Fan, Yuying Wang, Yue Korfanty, Gregory A. Archer, Meagan Xu, Jianping Pathogens Article Aspergillus fumigatus is a ubiquitous fungus and the main agent of aspergillosis, a common fungal infection in the immunocompromised population. Triazoles such as itraconazole and voriconazole are the common first-line drugs for treating aspergillosis. However, triazole resistance in A. fumigatus has been reported in an increasing number of countries. While most studies of triazole resistance have focused on mutations in the triazole target gene cyp51A, >70% of triazole-resistant strains in certain populations showed no mutations in cyp51A. To identify potential non-cyp51A mutations associated with triazole resistance in A. fumigatus, we analyzed the whole genome sequences and triazole susceptibilities of 195 strains from 12 countries. These strains belonged to three distinct clades. Our genome-wide association study (GWAS) identified a total of six missense mutations significantly associated with itraconazole resistance and 18 missense mutations with voriconazole resistance. In addition, to investigate itraconazole and pan-azole resistance, Fisher’s exact tests revealed 26 additional missense variants tightly linked to the top 20 SNPs obtained by GWAS, of which two were consistently associated with triazole resistance. The large number of novel mutations related to triazole resistance should help further investigations into their molecular mechanisms, their clinical importance, and the development of a comprehensive molecular diagnosis toolbox for triazole resistance in A. fumigatus. MDPI 2021-06-04 /pmc/articles/PMC8227032/ /pubmed/34199862 http://dx.doi.org/10.3390/pathogens10060701 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fan, Yuying
Wang, Yue
Korfanty, Gregory A.
Archer, Meagan
Xu, Jianping
Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
title Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
title_full Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
title_fullStr Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
title_full_unstemmed Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
title_short Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
title_sort genome-wide association analysis for triazole resistance in aspergillus fumigatus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8227032/
https://www.ncbi.nlm.nih.gov/pubmed/34199862
http://dx.doi.org/10.3390/pathogens10060701
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