Genomic factors associated with katG-S315T in Mycobacterium tuberculosis clinical isolates in Vietnam

Abstract

Background: Isoniazid (INH)-resistant tuberculosis (TB) could seriously affect the fight against TB. We investigated genomic factors that may be associated with katG-S315T, a major INH-resistance conferring mutation, in two large cities of Vietnam. Methods:Mycobacterium tuberculosis (Mtb) isolates were collected from patients with smear-positive pulmonary TB living in two different geographical areas of Vietnam; one in the central and the other in the northern area. Whole genome sequencing was performed using an Illumina MiSeq platform. Major drug resistance-conferring mutations were extracted with the TB-Profiler tool. Using a bacterial genome-wide approach based on linear mixed models, we investigated associations between 31-bp k-mers and Mtb isolates harboring katG-S315T in each cohort, and then compared them. Results: Genome sequences were obtained from 181 Mtb isolates in the central and 322 in the northern area. Isolates with katG-S315T accounted for 12.7% and 26.2% respectively. Ten genes harboring k-mers significantly associated with the katG-S315T phenotype were shared by the two cohorts. Genomic variants responsible for these k-mers of all these genes also showed significant associations with the S315T mutation, when a variant-based approach was conducted. A deletion-based analysis also identified several significant genes, including esxD with a 324-bp deletion and PE_PGRS30 with 109-bp deletion in the central-area cohort. Conclusions: We demonstrated that several genomic variations of the pathogen are associated with katG-S315T in common, and these genomic factors may be related to the low fitness cost of INH-resistant strains in Vietnam.