Thomas Levin, Batra Yashi, Mathur Mitali, Kulavalli Shrivathsa, Sv Chidananda Sanju, Dutt Naveen, Bhardwaj Pankaj, Varma Muralidhar, Saravu Kavitha, Banerjee Mithu, Rao Mahadev
Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education (MAHE), Manipal, India.
Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India.
Ann Med. 2025 Dec;57(1):2478316. doi: 10.1080/07853890.2025.2478316. Epub 2025 Mar 26.
Isoniazid is primarily metabolized by the arylamine -acetyltransferase 2 (NAT2) enzyme. Single nucleotide polymorphisms (SNPs) in the gene could classify an individual into three distinct phenotypes: rapid, intermediate and slow acetylators. 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 SNPs, genotypes and phenotypes among patients with TB and AT-DILI from the Southern and Western regions of India. The 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 MAF characteristics. However significant heterogeneity in 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 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 slow acetylators, among whom a relatively higher proportion experienced AT-DILI.
Further studies exploring the risk of SNPs in different AT-DILI patients with larger sample sizes and a population-specific approach are required to establish a policy for genotyping as a pre-emptive biomarker for AT-DILI monitoring for personalized isoniazid therapy in clinics.
异烟肼主要由芳胺 - N - 乙酰基转移酶2（NAT2）代谢。该基因中的单核苷酸多态性（SNP）可将个体分为三种不同的表型：快速乙酰化者、中间型乙酰化者和慢速乙酰化者。在多个结核病（TB）人群中，SNP和慢速乙酰化者表型被认为是抗结核药物性肝损伤（AT - DILI）发生的危险因素。
我们进行了一项前瞻性观察研究，以对来自印度南部和西部地区的结核病及AT - DILI患者的SNP、基因型和表型进行特征描述和比较。将这些地区患者的药物基因组学特征分别与来自多个地理区域不同的结核病群体以及从文献综述和“我们所有人”研究计划数据库中提取的不同遗传血统参与者的报告进行比较。
印度南部和西部地区以及其他几个地理位置较近地区的结核病患者表现出近乎相似的SNP次要等位基因频率（MAF）特征。然而，在AT - DILI人群以及“我们所有人”研究计划数据库中不同遗传血统的参与者之间，观察到各国国内和国家之间SNP存在显著异质性。印度南部和西部地区结核病患者的SNP rs1041983、rs1801280、rs1799929、rs1799930和rs1208的MAF与“我们所有人”研究计划数据库中具有南亚遗传血统者的MAF接近。印度南部和西部地区的结核病患者中约三分之一为慢速乙酰化者，其中经历AT - DILI的比例相对较高。
需要进一步开展研究，采用更大样本量并针对特定人群的方法，探索不同AT - DILI患者中SNP的风险，以制定一项政策，将基因分型作为临床中异烟肼个体化治疗AT - DILI监测的前瞻性生物标志物。
