AUTHOR=Chen Meng-Meng , Shi Guo-Hui , Dai Yi , Fang Wen-Xia , Wu Qi 

TITLE=Identifying genetic variants associated with amphotericin B (AMB) resistance in Aspergillus fumigatus via k-mer-based GWAS

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1133593

DOI=10.3389/fgene.2023.1133593

ISSN=1664-8021

ABSTRACT=<p><italic>Aspergillus fumigatus</italic> is one of the most common pathogenic fungi, which results in high morbidity and mortality in immunocompromised patients. Amphotericin B (AMB) is used as the core drug for the treatment of triazole-resistant <italic>A. fumigatus</italic>. Following the usage of amphotericin B drugs, the number of amphotericin B-resistant <italic>A. fumigatus</italic> isolates showed an increasing trend over the years, but the mechanism and mutations associated with amphotericin B sensitivity are not fully understood. In this study, we performed a <italic>k</italic>-mer-based genome-wide association study (GWAS) in 98 <italic>A. fumigatus</italic> isolates from public databases. Associations identified with <italic>k</italic>-mers not only recapitulate those with SNPs but also discover new associations with insertion/deletion (indel). Compared to SNP sites, the indel showed a stronger association with amphotericin B resistance, and a significant correlated indel is present in the exon region of <italic>AFUA_7G05160</italic>, encoding a fumarylacetoacetate hydrolase (FAH) family protein. Enrichment analysis revealed sphingolipid synthesis and transmembrane transport may be related to the resistance of <italic>A. fumigatus</italic> to amphotericin B. The expansion of variant types detected by the <italic>k</italic>-mer method increases opportunities to identify and exploit complex genetic variants that drive amphotericin B resistance, and these candidate variants help accelerate the selection of prospective gene markers for amphotericin B resistance screening in <italic>A. fumigatus</italic>.</p>