Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus.
Genome-Wide Association Analysis for Triazole Resistance in Aspergillus fumigatus.
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DOI：
10.3390/pathogens10060701
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发表时间：
2021-06-04
期刊：
影响因子：
--
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Fan Y;Wang Y;Korfanty GA;Archer M;Xu J
烟曲霉菌是一种普遍存在的真菌，是免疫缺陷人群中常见的真菌感染曲霉病的主要病原体。三氮唑类药物如伊曲康唑和伏立康唑是治疗曲霉菌病的常用一线药物。然而，越来越多的国家报告了烟曲霉菌对三氮唑的耐药性。虽然大多数关于三氮唑耐药性的研究都集中在三氮唑靶基因cyp51a的突变上，但在某些人群中，70%的三氮唑耐药菌株在cyp51a上没有突变。为了确定与烟曲霉对三氮唑耐药性相关的潜在的非cyp51a突变，我们分析了来自12个国家和地区的195株菌株的全基因组序列和三氮唑敏感性。这些菌株分属三个不同的分支。我们的全基因组关联研究发现，共有6个错义突变与伊曲康唑耐药显著相关，18个错义突变与伏立康唑耐药有关。此外，为了研究伊曲康唑和泛唑的耐药性，Fisher的准确测试发现了另外26个错义变异，这些变异与Gwas获得的前20个SNPs紧密连锁，其中两个始终与三氮唑耐药性有关。大量与三氮唑耐药性相关的新突变将有助于进一步研究其分子机制及其临床意义，并开发一套全面的烟曲霉菌三唑耐药性分子诊断工具箱。
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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影响因子：
6.7
作者：
Chowdhary A;Kathuria S;Xu J;Meis JF
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影响因子：
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