A Nanopore sequencing-based pharmacogenomic panel to personalize tuberculosis drug dosing.

Autor:	Verma R; Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, California, USA.; Institute of Bioinformatics, International Tech Park, Bangalore, India.; Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India., da Silva KE; Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, California, USA., Rockwood N; Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Dept. Medicine, University of Cape Town, Observatory 7925, South Africa.; Department of Infectious Diseases, Imperial College, London, W12 0NN, United Kingdom.; Department of Medical Microbiology and Immunology, Faculty of Medicine, University of Colombo, Sri Lanka., Wasmann RE; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Yende N; Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa., Song T; Department of Pathology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa., Kim E; Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, California, USA., Denti P; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Wilkinson RJ; Center for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine and Dept. Medicine, University of Cape Town, Observatory 7925, South Africa.; Department of Infectious Diseases, Imperial College, London, W12 0NN, United Kingdom.; Francis Crick Institute, London NW1 1AT, United Kingdom., Andrews JR; Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, California, USA.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Sep 10. Date of Electronic Publication: 2023 Sep 10.
DOI:	10.1101/2023.09.08.23295248
Abstrakt:	Rationale: Standardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking. Objectives: To develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing. Measurements and Main Results: We developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of isoniazid (INH), rifampin (RIF), linezolid and bedaquiline. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF. Results: The PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was >100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was significantly impacted by acetylator status (p<0.0001) with median (IQR) clearances of 11.2 L/h (9.3-13.4), 27.2 L/h (22.0-31.7), and 45.1 L/h (34.1-51.1) in slow, intermediate, and rapid acetylators. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G>A substitutions (p=0.0015). Conclusion: Targeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention. Competing Interests: Conflicts of Interest The authors declare no conflict of interest.
Databáze:	MEDLINE
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