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Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus
Yuying Fan1, Yue Wang1, Gregory A Korfanty1
1Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
Abstract:
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.
Insights
Triazole resistance in Aspergillus fumigatus is increasing. This study identified novel non-cyp51A gene mutations linked to itraconazole and voriconazole resistance, aiding in diagnosis and treatment strategies.
Area of Science:
- Mycology
- Medical Mycology
- Genetics
Background:
- Aspergillus fumigatus causes aspergillosis, a significant fungal infection in immunocompromised individuals.
- Triazole antifungals (itraconazole, voriconazole) are first-line treatments, but resistance is a growing global concern.
- Many resistant A. fumigatus strains lack mutations in the primary target gene, cyp51A, necessitating investigation into other genetic factors.
Purpose of the Study:
- To identify novel non-cyp51A gene mutations associated with triazole resistance in Aspergillus fumigatus.
- To analyze whole genome sequences and drug susceptibilities of a global collection of A. fumigatus strains.
- To explore genetic variants linked to itraconazole, voriconazole, and pan-azole resistance.
Main Methods:
- Genome-wide association study (GWAS) on 195 A. fumigatus strains from 12 countries.
- Analysis of whole genome sequences and triazole drug susceptibilities.
- Fisher's exact tests to identify variants linked to resistance.
Main Results:
- GWAS identified six missense mutations associated with itraconazole resistance and 18 with voriconazole resistance.
- Twenty-six additional missense variants, tightly linked to top SNPs, were found associated with azole resistance.
- Two novel missense variants showed consistent association with triazole resistance across strains.
Conclusions:
- Novel non-cyp51A mutations are significantly associated with triazole resistance in A. fumigatus.
- These findings are crucial for understanding resistance mechanisms and clinical impact.
- The identified mutations can contribute to developing diagnostic tools for triazole resistance in A. fumigatus.
