Pharmacogenomic heterogeneity of <i>N-acetyltransferase 2</i>: a comprehensive analysis of real world data in Indian tuberculosis patients and from literature and database review

Isoniazid is primarily metabolized by the arylamine <i>N</i>-acetyltransferase 2 (NAT2) enzyme. Single nucleotide polymorphisms (SNPs) in the <i>NAT2</i> gene could classify an individual into three distinct phenotypes: rapid, intermediate and slow acetylators. <i>NAT2</i> SNPs and the slow acetylator phenotype have been implicated as risk factors for the development of antitubercular drug-induced liver injury (AT-DILI) in several tuberculosis (TB) populations. We conducted a prospective observational study to characterize and compare the <i>NAT2</i> SNPs, genotypes and phenotypes among patients with TB and AT-DILI from the Southern and Western regions of India. The <i>NAT2</i> pharmacogenomic profile of patients from these regions was compared with the reports from several geographically diverse TB populations and participants of different genetic ancestries extracted from literature reviews and the ‘All of Us’ Research Program database, respectively. The TB patients of Southern and Western regions of India and several other geographically closer regions exhibited near similar <i>NAT2</i> MAF characteristics. However significant heterogeneity in <i>NAT2</i> SNPs was observed within and between countries among AT-DILI populations and the participants of different genetic ancestry from the ‘All of Us’ Research Program database. The MAF of the <i>NAT2</i> SNPs rs1041983, rs1801280, rs1799929, rs1799930 and rs1208 of the TB patients from Southern and Western Indian Sites were in near range to that of the South Asian genetic ancestry of ‘All of Us’ Research Program database. About one-third of the total TB patients from the Southern and Western regions of India were <i>NAT2</i> slow acetylators, among whom a relatively higher proportion experienced AT-DILI. Further studies exploring the risk of <i>NAT2</i> SNPs in different AT-DILI patients with larger sample sizes and a population-specific approach are required to establish a policy for <i>NAT2</i> genotyping as a pre-emptive biomarker for AT-DILI monitoring for personalized isoniazid therapy in clinics.