دورية أكاديمية
pncA Large Deletion is the Characteristic of Pyrazinamide-Resistant Mycobacterium tuberculosis belonging to the East Asian Lineage.
| العنوان: | pncA Large Deletion is the Characteristic of Pyrazinamide-Resistant Mycobacterium tuberculosis belonging to the East Asian Lineage. |
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| المؤلفون: | Kim NY; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea., Kim DY; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea., Chu J; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea., Jung SH; Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.; Department of Biochemistry, Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.; Integrated Research Center for Genomic Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Korea. hyun@catholic.ac.kr. |
| المصدر: | Infection & chemotherapy [Infect Chemother] 2023 Jun; Vol. 55 (2), pp. 247-256. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Korean Society of Infectious Diseases, Korean Society for Chemotherapy Country of Publication: Korea (South) NLM ID: 101531537 Publication Model: Print Cited Medium: Print ISSN: 2093-2340 (Print) Linking ISSN: 15988112 NLM ISO Abbreviation: Infect Chemother Subsets: PubMed not MEDLINE |
| أسماء مطبوعة: | Original Publication: Seoul : Korean Society of Infectious Diseases, Korean Society for Chemotherapy |
| مستخلص: | Background: Pyrazinamide (PZA) is often used as an add-on agent in the treatment of multidrug-resistant tuberculosis, regardless of phenotypic drug susceptibility testing (pDST) results. However, evaluating the effectiveness of PZA is challenging because of its low pH activity, which can result in unreliable pDST results. This study aimed to investigate the genomic characteristics associated with PZA resistance that can be used to develop genotypic DST. Materials and Methods: A publicly available whole genome sequencing (WGS) dataset of 10,725 Mycobacterium tuberculosis complex genomes (3,326 phenotypically PZA-resistant and 7,399 phenotypically PZA-susceptible isolates) were analyzed. Results: In total, 2,934 pncA non-silent mutations were identified in 2,880 isolates (26.9%). Detected mutations were found throughout the entire coding region of pncA in a scattered pattern, of which the most frequent mutation was p.Q10P (n = 278), followed by p.H57D (n = 167) and c.-11A>G (n = 122). The sensitivity and specificity of the group 1 or 2 mutations reported by the World Health Organization (WHO) mutational catalogue were 73.0% and 98.9%, respectively. We further identified 18 novel pncA mutations that were significantly associated with phenotypically PZA-resistant. In addition to these mutations, we identified 102 large deletions in the pncA gene, and all but two isolates were phenotypically resistant to PZA isolates. Notably, pncA deletions were mutually exclusive to pncA mutations, and more than half of the isolates with pncA large deletions belonged to the East Asian lineage (67.6%). The sensitivity, specificity, positive predictive value, and negative predictive value of the pooled variants (group 1 or 2 mutations, novel resistance-associated mutations, and large deletions of the pncA gene) were 79.0%, 98.9%, 97.0%, and 91.3%, respectively. The area under the curve (AUC) value for the pooled variants was significantly higher than the AUC value for the group 1 or 2 mutations ( P <0.001), indicating that the pooled variants have a better discriminative ability for predicting PZA resistance. Conclusion: Using WGS, we found that the pncA mutations are scattered without specific mutational hotspots, and large deletions associated with PZA resistance are more common in the East Asian lineage of M. tuberculosis isolates. Our data also demonstrated the reliability of group 1 or 2 mutations presented in the WHO mutation catalogue and the need for further investigation on group 3 mutations, contributing to the evaluation of the current knowledge base on mutations associated with the PZA-resistant M. tuberculosis complex. Competing Interests: No conflict of interest. (Copyright © 2023 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS.) |
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| معلومات مُعتمدة: | HI22C0226 Republic of Korea Korea Health Industry Development Institute |
| فهرسة مساهمة: | Keywords: Deletion; Mycobacterium tuberculosis complex; Pyrazinamide; Whole genome sequencing; pncA |
| تواريخ الأحداث: | Date Created: 20230705 Latest Revision: 20230718 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC10323538 |
| DOI: | 10.3947/ic.2023.0037 |
| PMID: | 37407242 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2093-2340 |
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| DOI: | 10.3947/ic.2023.0037 |