Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>

<i>Aspergillus fumigatus</i> 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...

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Main Authors: Yuying Fan, Yue Wang, Gregory A. Korfanty, Meagan Archer, Jianping Xu
Format: Article
Language:English
Published: MDPI AG 2021-06-01
Series:Pathogens
Subjects:
Online Access:https://www.mdpi.com/2076-0817/10/6/701
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spelling doaj-afa05e5120684bada41186232046a5092021-06-30T23:18:52ZengMDPI AGPathogens2076-08172021-06-011070170110.3390/pathogens10060701Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>Yuying Fan0Yue Wang1Gregory A. Korfanty2Meagan Archer3Jianping Xu4Department of Biology, McMaster University, Hamilton, ON L8S 4K1, CanadaDepartment of Biology, McMaster University, Hamilton, ON L8S 4K1, CanadaDepartment of Biology, McMaster University, Hamilton, ON L8S 4K1, CanadaDepartment of Biology, McMaster University, Hamilton, ON L8S 4K1, CanadaDepartment of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada<i>Aspergillus fumigatus</i> 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 <i>A. fumigatus</i> has been reported in an increasing number of countries. While most studies of triazole resistance have focused on mutations in the triazole target gene <i>cyp51A</i>, >70% of triazole-resistant strains in certain populations showed no mutations in <i>cyp51A</i>. To identify potential non-<i>cyp51A</i> mutations associated with triazole resistance in <i>A. fumigatus</i>, 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 <i>A. fumigatus</i>.https://www.mdpi.com/2076-0817/10/6/701Aspergillustriazolesitraconazolevoriconazole<i>Aspergillus fumigatus</i>antifungal resistance
collection DOAJ
language English
format Article
sources DOAJ
author Yuying Fan
Yue Wang
Gregory A. Korfanty
Meagan Archer
Jianping Xu
spellingShingle Yuying Fan
Yue Wang
Gregory A. Korfanty
Meagan Archer
Jianping Xu
Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>
Pathogens
Aspergillus
triazoles
itraconazole
voriconazole
<i>Aspergillus fumigatus</i>
antifungal resistance
author_facet Yuying Fan
Yue Wang
Gregory A. Korfanty
Meagan Archer
Jianping Xu
author_sort Yuying Fan
title Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>
title_short Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>
title_full Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>
title_fullStr Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>
title_full_unstemmed Genome-Wide Association Analysis for Triazole Resistance in <i>Aspergillus fumigatus</i>
title_sort genome-wide association analysis for triazole resistance in <i>aspergillus fumigatus</i>
publisher MDPI AG
series Pathogens
issn 2076-0817
publishDate 2021-06-01
description <i>Aspergillus fumigatus</i> 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 <i>A. fumigatus</i> has been reported in an increasing number of countries. While most studies of triazole resistance have focused on mutations in the triazole target gene <i>cyp51A</i>, >70% of triazole-resistant strains in certain populations showed no mutations in <i>cyp51A</i>. To identify potential non-<i>cyp51A</i> mutations associated with triazole resistance in <i>A. fumigatus</i>, 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 <i>A. fumigatus</i>.
topic Aspergillus
triazoles
itraconazole
voriconazole
<i>Aspergillus fumigatus</i>
antifungal resistance
url https://www.mdpi.com/2076-0817/10/6/701
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