&lt;I&gt;NAT2&lt;/I&gt; slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients

Wattanapokayakit, Sukanya; Mushiroda, Taisei; Yanai, Hideki; Wichukchinda, Nuanjun; Chuchottawon, Charoen; Nedsuwan, Supalert; Rojanawiwat, A; Denjanta, S.; Kantima, Tassawan; Wongyai, Jiraporn; Suwankesawong, Wimon; Rungapiromnan, Watcharee; Kidkeukarun, Runglak; Bamrungram, Warawut; Chaiwong, Achara; Suvichapanich, Supharat; Mahasirimongkol, Surakameth; Tokunaga, Katsushi

doi:10.5588/ijtld.15.0310

Cited by 47 publications

(47 citation statements)

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“…Research results for the relationship between NAT2 and ATLI are also different amongst countries. Only the NAT2 gene 590 (rs1799930) genotype was found to be associated with the occurrence of ATLI in the study of TB patients in Tunisia, Indonesia and Thailand . Gupta VH et al found that the 481 (rs1799929) locus of the NAT2 gene in Indian tuberculosis patients was related.…”

Section: Discussionmentioning

confidence: 98%

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

et al. 2019

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What is known and objective: Anti-tuberculosis drug-induced liver injury (ATLI) is one of the most significant adverse reactions for this line of therapy. N-acetyltransferase 2 (NAT2) is an important metabolic enzyme involved in drug metabolism and detoxification. Genetic polymorphism and DNA methylation have been proven to be key factors that affect the expression of NAT2. Therefore, the objective of the study was to investigate the relationship between NAT2 gene polymorphism and DNA methylation in the promoter region with ATLI risk in Mongolian tuberculosis patients. Methods:Our study is a case-control design. Chi-square test, Mann-Whitney U nonparametric test and Pearson test were all used to analyse existing relationships. The association between NAT2 gene acetylation phenotype and the total methylation of the NAT2 promoter region was analysed by means of binary logistic regression analysis. The general situation of the patients was evaluated by questionnaire, and the NAT2 genotyping of the three major polymorphism loci of gene coding was carried out by a gene sequencing technique. The methylation status of the NAT2 gene promoter region was detected by bisulphite sequencing and mass spectrometry.Result and discussion: Our study found that the detection rate of ATLI in Mongolian tuberculosis patients was 27.6%. There were no significant differences in demographic characteristics and living habits amongst the two groups, while significant differences were observed in the polymorphism of the NAT2 genes 481 (rs1799929) and 590 (rs1799930) and the acetylation phenotype. Moreover, the composition and distribution of the NAT2*4/4 and NAT2*4/5 genotypes were found in the two groups. The risk of ATLI in the slow acetylation type was 3.56 times higher than that of the fast acetylation type. Compared with the control group, the CpG5, CpG10, CpG11.12 and total methylation of the NAT2 promoter region in the ATLI group showed a hypermethylated pattern (P < .05). However, on performing binary logistic regression, neither the slow acetylation, intermediate acetylation nor rapid acetylation were found to be associated with ATLI (P > .05). It was found that the total methylation of NAT2 gene promoter region was an independent influencing factor of ATLI in Mongolian tuberculosis How to cite this article: Zhang D, Hao J, Hou R, Yu Y, Hu B, Wei L. The role of NAT2 polymorphism and methylation in anti-tuberculosis drug-induced liver injury in Mongolian tuberculosis patients. J Clin Pharm Ther. 2020;45:561-569.

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Section: Discussionmentioning

confidence: 98%

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

et al. 2019

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“…In a meta-analysis involving 38 studies with 2225 patients and 4906 controls [48], SA alleles of the NAT2 gene were significantly associated with a higher risk of AT-DILI. Additional clinical studies support the association between SA phenotypes and an increased risk of AT-DILI in Thai [49], Indonesian [50], and Singapore populations [51]. Another study conducted in Moroccan patients observed no NAT2 RA ( Nat2*4 ) alleles in the patients that developed AT-DILI [52].…”

Section: Specific Molecular Mechanisms Of Isoniazid/rifampicin-inducementioning

confidence: 89%

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Bao

Rasmussen

et al. 2018

Curr Pharmacol Rep

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Purpose of this Review In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. Recent Findings The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). Summary The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

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“…Genetic markers for drug toxicity, such as certain n‐acetyltransferase 2 (NAT2) polymorphisms causing higher susceptibility for isoniazid induced liver toxicity, may also be identified for second‐line antituberculosis drugs (e.g. linezolid) by larger‐scale genetic analysis . Positron emission tomography–computed tomography (PET‐CT) scans can help to identify patients at risk for relapse although the interpretation of metabolically active infiltrations is still difficult .…”

Section: Individualized Therapy Versus Standardized Treatment Regimenmentioning

confidence: 99%

“…linezolid) by larger-scale genetic analysis. 111 Positron emission tomography-computed tomography (PET-CT) scans can help to identify patients at risk for relapse although the interpretation of metabolically active infiltrations is still difficult. 112 Although the level of evidence was reported as being low, certain patients with localized infiltrations may benefit from surgical interventions after culture conversion.…”

Section: Individualized Therapy Versus Standardized Treatment Regimenmentioning

confidence: 99%

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

et al. 2018

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The emergence of antimicrobial resistance against Mycobacterium tuberculosis, the leading cause of mortality due to a single microbial pathogen worldwide, represents a growing threat to public health and economic growth. The global burden of multidrug-resistant tuberculosis (MDR-TB) has recently increased by an annual rate of more than 20%. According to the World Health Organization approximately only half of all patients treated for MDR-TB achieved a successful outcome. For many years, patients with drug-resistant tuberculosis (TB) have received standardized treatment regimens, thereby accelerating the development of MDR-TB through drug-specific resistance amplification. Comprehensive drug susceptibility testing (phenotypic and/or genotypic) is necessary to inform physicians about the best drugs to treat individual patients with tailor-made treatment regimens. Phenotypic drug resistance can now often, but with variable sensitivity, be predicted by molecular drug susceptibility testing based on whole genome sequencing, which in the future could become an affordable method for the guidance of treatment decisions, especially in high-burden/resource-limited settings. More recently, MDR-TB treatment outcomes have dramatically improved with the use of bedaquiline-based regimens. Ongoing clinical trials with novel and repurposed drugs will potentially further improve cure-rates, and may substantially decrease the duration of MDR-TB treatment necessary to achieve relapse-free cure.

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<I>NAT2</I> slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients

Abstract: Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.

Cited by 47 publications

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The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury

Drug‐resistant tuberculosis: An update on disease burden, diagnosis and treatment

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