A nanopore sequencing-based pharmacogenomic panel to personalise tuberculosis drug dosing

The primary aim of this study was to evaluate a targeted panel based on Oxford Nanopore sequencing to understand pharmacogenomic effects on dosing for tuberculosis (TB) drugs. Standardised dosing often results in variability in drug plasma levels, leading to adverse drug reactions, delayed treatment response, or relapse. The researchers sought to create a pharmacogenomic assay that would predict drug metabolism by detecting mutations in key genes involved in TB drug metabolism, including those that impact isoniazid (INH), rifampin (RIF), linezolid (LZD), and bedaquiline (BDQ).

The study utilized the Oxford Nanopore MinION sequencer to perform pharmacogenomic analysis. The nanopore sequencing panel targeted 15 SNPs across five genes (NAT2, CYP2E1, SLCO1B1, AADAC, and CYP3A5), which affect the metabolism of these TB drugs. This assay was investigated on samples from the 1000 Genomes Project and then applied to 100 individuals from South Africa affected with TB.

Key findings revealed that 33% of the patients were slow acetylators of INH, 47% were intermediate, and 20% were rapid acetylators. INH clearance was significantly higher among rapid acetylators compared to slow acetylators, showing a 3.8-fold increase. For RIF, the study found a 17.3% lower clearance in patients with the AADAC rs1803155 mutation. This approach using Nanopore sequencing demonstrated that it could effectively detect genetic variations impacting TB drug metabolism, with potential for providing an affordable and scalable solution for personalising TB treatment dosing in diverse populations.