Nanopore sequencing panel for saliva-based host pharmacogenomic screening in anti-tubercular therapy.

UGT1A1, ABCB1

UGT1A1 and ABCB1 variants associated with trough concentrations and toxicity of moxifloxacin and linezolid

The authors designed a 16-plex nanopore sequencing panel targeting 23 variants (21 clinically validated, 2 predicted actionable) that affect exposure to linezolid, bedaquiline, clofazimine, moxifloxacin and ethambutol. The panel showed 100% concordance with Illumina whole-genome data on 50 Coriell samples, then was applied to saliva from 202 patients treated in India for drug-resistant tuberculosis, on a MinION, with a median depth of 3,609X. Across 174 genotype–concentration and 152 genotype–toxicity assessments, only three associations reached nominal significance, in subgroups: UGT1A1 rs3755319 with higher moxifloxacin troughs at 800 mg/day, and ABCB1 rs2032582 with lower linezolid Cmin in patients dose-reduced to 300 mg/day, neither holding at standard dosing. Linezolid toxicity was more frequent in ABCB1 rs1128503 heterozygotes (58.3% vs 29.1%), and moxifloxacin toxicity in UGT1A1 rs4148323 heterozygotes (42.9% vs 14.3%). The authors present these signals as a baseline for validation in large pharmacokinetic studies.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The main value lies in the tool: saliva-based pharmacogenetic genotyping from low DNA input, on a portable sequencer, for second-line anti-tuberculosis drugs that guidelines cover poorly. The associations remain fragile: 326 assessments with no correction for multiple testing mentioned in the abstract, subgroups of 14 to 98 patients and effects confined to extreme doses. No dosing change can be drawn at this stage; this is a preprint, to be confirmed in a dedicated pharmacokinetic cohort.

Analysis by Dr Thibaut Benquey