Loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae: a genome-wide association study.
Loci for prediction of penicillin and tetracycline susceptibility in Neisseria gonorrhoeae: a genome-wide association study.
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DOI：
10.1016/s2666-5247(22)00034-9
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发表时间：
2022-05
期刊：
影响因子：
38.2
通讯作者：
Grad, Yonatan H.
中科院分区：
文献类型：
--
作者：
Mortimer, Tatum D.;Zhang, Jessica J.;Ma, Kevin C.;Grad, Yonatan H.
由于抗菌素耐药性不断增加，淋病奈瑟菌对公共卫生构成了紧迫的威胁；然而，许多流动人群仍然容易受到历史治疗方案的影响。报告敏感性的即时诊断可以允许重新引入这些治疗方案，但此类诊断的开发仅限于环丙沙星，可以从单个基因座预测其敏感性。我们的目的是定义与青霉素和四环素敏感性相关的遗传变异。我们收集了临床淋病奈瑟菌分离株的公开全球全基因组测序数据 (n=12 045)，以及青霉素 (n=6935) 和四环素 (n=5727) 的表型耐药性数据。通过有条件的全基因组关联研究，我们定义了与青霉素和四环素敏感性相关的遗传变异。我们排除了无法归类为易感或耐药的菌株。为了验证我们的结果，我们组装了来自美国疾病控制与预防中心 (CDC) 淋球菌分离株监测项目的 1479 个基因组，该项目的尿道标本是在美国各地的哨点监测点采集的。我们使用临床和实验室标准研究所在全局和验证数据集中的易感性和非耐药性断点评估了易感性相关等位基因的敏感性和特异性。在我们的条件青霉素全基因组关联研究中，由非嵌合 penA 等位基因定义的遗传变异的存在，在密码子 345 处没有插入，与青霉素敏感性相关，并且显着变异的负效应大小 (β) 最高 (p=5·0×10–14，β –2·5)。结合缺乏 blaTEM，该变体以高特异性 (99·8%) 和中等敏感性 (36·7%) 预测青霉素敏感性。对于四环素，rpsJ 密码子 57 处编码缬氨酸的野生型等位基因在调节 tetM 的存在后与四环素敏感性相关 (p=5·6×10–16，β –1·6)。 rpsJ 密码子 57 等位基因和 tetM 缺失的组合预测四环素敏感性，具有高特异性 (97·2%) 和敏感性 (88·7%)。只需两个基因位点即可高度特异性地预测淋病奈瑟菌对青霉素和四环素的敏感性。针对这些位点的分子护理点诊断有可能增加淋病的可用治疗方法。美国国家过敏和传染病研究所、国家科学基金会和史密斯家庭基金会。
Neisseria gonorrhoeae poses an urgent public health threat because of increasing antimicrobial resistance; however, much of the circulating population remains susceptible to historical treatment regimens. Point-of-care diagnostics that report susceptibility could allow for reintroduction of these regimens, but development of such diagnostics has been restricted to ciprofloxacin, for which susceptibility can be predicted from a single locus. We aimed to define genetic variants associated with susceptibility to penicillin and tetracycline. We collected publicly available global whole-genome sequencing data (n=12 045) from clinical N gonorrhoeae isolates, with phenotypic resistance data for penicillin (n=6935), and tetracycline (n=5727). Using conditional genome-wide association studies, we defined genetic variants associated with susceptibility to penicillin and tetracycline. We excluded isolates that could not be classified as either susceptible or resistant. To validate our results, we assembled 1479 genomes from the US Centers for Disease Control and Prevention (CDC)’s Gonococcal Isolate Surveillance Project, for which urethral specimens are collected at sentinel surveillance sites across the USA. We evaluated the sensitivity and specificity of susceptibility-associated alleles using Clinical & Laboratory Standards Institute breakpoints for susceptibility and non-resistance in both the global and validation datasets. In our conditional penicillin genome-wide association study, the presence of a genetic variant defined by a non-mosaic penA allele without an insertion at codon 345 was associated with penicillin susceptibility and had the highest negative effect size (β) of significant variants (p=5·0×10–14, β –2·5). In combination with the absence of blaTEM, this variant predicted penicillin susceptibility with high specificity (99·8%) and modest sensitivity (36·7%). For tetracycline, the wildtype allele at rpsJ codon 57, encoding valine, was associated with tetracycline susceptibility (p=5·6×10–16, β –1·6) after conditioning on the presence of tetM. The combination of rpsJ codon 57 allele and tetM absence predicted tetracycline susceptibility with high specificity (97·2%) and sensitivity (88·7%). As few as two genetic loci can predict susceptibility to penicillin and tetracycline in N gonorrhoeae with high specificity. Molecular point-of-care diagnostics targeting these loci have the potential to increase available treatments for gonorrhoea. National Institute of Allergy and Infectious Diseases, the National Science Foundation, and the Smith Family Foundation.