Dissecting vancomycin-intermediate resistance in staphylococcus aureus using genome-wide association.
Dissecting vancomycin-intermediate resistance in staphylococcus aureus using genome-wide association.
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DOI：
10.1093/gbe/evu092
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发表时间：
2014-04-30
影响因子：
3.3
通讯作者：
Read TD
中科院分区：
文献类型：
--
作者：
Alam MT;Petit RA 3rd;Crispell EK;Thornton TA;Conneely KN;Jiang Y;Satola SW;Read TD
万古霉素中间体金黄色葡萄球菌（VISA）目前定义为最小抑菌浓度（MIC）为4-8 µg/ml。VISA通过多个遗传位点的变化而进化，在临床和体外选择的VISA菌株中鉴定出至少16个候选基因。我们报告了49株万古霉素敏感的S.金黄色葡萄球菌和26株VISA菌株。通过微量肉汤稀释法、Etest和群体分析曲线下面积（PAP-AUC）测定万古霉素耐药性。在一个或多个菌株中鉴定的55，977个单核苷酸多态性的全基因组关联研究（GWAS）发现rpoB基因密码子481（H481）的非同义突变与万古霉素MIC增加之间存在高度显著性关联（P = 8.78E-08）。此外，我们使用了一个公共S。金黄色葡萄球菌基因组序列，以确定与VISA相关的候选基因中的罕见突变。在这些数据的基础上，我们提出了一个名为ECM+RMCG的VISA表型的初步模型，作为未来工作的基准。该模型基于一组候选基因（walKR，vraSR，graSR和agrA）中存在的罕见突变和/或三个先前实验验证的突变（包括rpoB H481位点）预测VISA，准确度为81%，灵敏度为73%。此外，通过Etest和PAP-AUC测量的耐药性水平随着菌株中存在的突变数量正回归。这项研究证明了1）GWAS识别与细菌抗生素耐药性相关的常见遗传变异的能力，以及2）使用大型基因组数据集识别的候选基因中的罕见突变也可能与耐药表型相关。
Vancomycin-intermediate Staphylococcus aureus (VISA) is currently defined as having minimal inhibitory concentration (MIC) of 4–8 µg/ml. VISA evolves through changes in multiple genetic loci with at least 16 candidate genes identified in clinical and in vitro-selected VISA strains. We report a whole-genome comparative analysis of 49 vancomycin-sensitive S. aureus and 26 VISA strains. Resistance to vancomycin was determined by broth microdilution, Etest, and population analysis profile-area under the curve (PAP-AUC). Genome-wide association studies (GWAS) of 55,977 single-nucleotide polymorphisms identified in one or more strains found one highly significant association (P = 8.78E-08) between a nonsynonymous mutation at codon 481 (H481) of the rpoB gene and increased vancomycin MIC. Additionally, we used a database of public S. aureus genome sequences to identify rare mutations in candidate genes associated with VISA. On the basis of these data, we proposed a preliminary model called ECM+RMCG for the VISA phenotype as a benchmark for future efforts. The model predicted VISA based on the presence of a rare mutation in a set of candidate genes (walKR, vraSR, graSR, and agrA) and/or three previously experimentally verified mutations (including the rpoB H481 locus) with an accuracy of 81% and a sensitivity of 73%. Further, the level of resistance measured by both Etest and PAP-AUC regressed positively with the number of mutations present in a strain. This study demonstrated 1) the power of GWAS for identifying common genetic variants associated with antibiotic resistance in bacteria and 2) that rare mutations in candidate gene, identified using large genomic data sets, can also be associated with resistance phenotypes.
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DOI：
10.1093/bioinformatics/btp347
发表时间：
2009-08-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Assefa S;Keane TM;Otto TD;Newbold C;Berriman M
通讯作者：
Berriman M
影响因子：
4.5
作者：
Fritz SA;Camins BC;Eisenstein KA;Fritz JM;Epplin EK;Burnham CA;Dukes J;Storch GA
通讯作者：
Storch GA
DOI：
10.1128/genomea.01011-13
发表时间：
2013-11-01
期刊：
GENOME ANNOUNCEMENTS
影响因子：
--
作者：
Chen, Feng-Jui;Lauderdale, Tsai-Ling;Huang, I-Wen
通讯作者：
Huang, I-Wen
影响因子：
2.6
作者：
Gardete, S.;Aires-De-Sousa, M.;de Lencastre, H.
通讯作者：
de Lencastre, H.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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