<i>NAT2</i> variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis

Richardson, Marty; Kirkham, Jamie J; Dwan, Kerry; Sloan, Derek J.; Davies, Geraint R.; Jorgensen, Andrea

doi:10.5588/ijtld.18.0324

Cited by 35 publications

(31 citation statements)

References 73 publications

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“…By considering the difference of NAT2 acetyl phenotype and by combining it with the PBPK/PD model, doctors can adjust the dose of isoniazid to improve its therapeutic effect. Therefore, the detection of new Asian phenotypes by screening NAT2 gene polymorphism in different races is meaningful for clinical prediction and prevention of adverse reactions …”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…We assume, based on data from meta-analyses, that individuals with rapid metabolizer phenotypes are more likely to fail treatments than slow and intermediate metabolizer phenotypes (risk ratio, 2.02) [ 27 ]. Conversely, we model INH hepatotoxicity to be more common among slow and intermediate metabolizer phenotypes than rapid metabolizer phenotypes (odds ratio, 3.68 and 1.12, respectively) [ 9 ].…”

Section: Methodsmentioning

confidence: 99%

“…NAT2 genotype predicts clinically relevant endpoints as well. Multiple studies have revealed that slow acetylators are at increased risk of drug-induced liver injury from INH [ 9 ]. A meta-analysis found that rapid acetylators are at increased risk of treatment failure, relapse, and acquisition of resistance [ 7 ].…”

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confidence: 99%

Cost-effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis

Rens

Goldhaber-Fiebert

et al. 2020

Clinical Infectious Diseases

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Background There is marked interindividual variability in metabolism and resulting toxicity and effectiveness of drugs used for tuberculosis treatment. For isoniazid, mutations in the N-acetyltransferase 2 (NAT2) gene explain >88% of pharmacokinetic variability. However, weight-based dosing remains the norm globally. The potential clinical impact and cost-effectiveness of pharmacogenomic-guided therapy (PGT) are unknown. Methods We constructed a decision tree model to project lifetime costs and benefits of isoniazid PGT for drug-susceptible tuberculosis in Brazil, South Africa, and India. PGT was modeled to reduce isoniazid toxicity among slow NAT2 acetylators and reduce treatment failure among rapid acetylators. The genotyping test was assumed to cost the same as the GeneXpert test. The main outcomes were costs (2018 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Results In Brazil, PGT gained 19 discounted life-years (23 QALYs) and cost $11 064 per 1000 patients, a value of $476 per QALY gained. In South Africa, PGT gained 15 life-years (19 QALYs) and cost $33 182 per 1000 patients, a value of $1780 per QALY gained. In India, PGT gained 20 life-years (24 QALYs) and cost $13 195 per 1000 patients, a value of $546 per QALY gained. One-way sensitivity analyses showed the cost-effectiveness to be robust to all input parameters. Probabilistic sensitivity analyses were below per capita gross domestic product in all 3 countries in 99% of simulations. Conclusions Isoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India.

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“…A study conducted in Brazil found that the incidence of INH-induced hepatotoxicity differed among rapid (2.9%), intermediate (9.8%), and slow (22%) NAT2 acetylators [29]. Meta-analysis studies report slow acetylators were significantly more likely to experience hepatotoxicity from INH treatment for tuberculosis than rapid acetylators [30,31].…”

Section: Isoniazid (Inh)mentioning

confidence: 99%

Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review

Hein

Millner²

2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: The N-acetylation polymorphism has been the subject of comprehensive reviews describing the role of arylamine N-acetyltransferase 2 (NAT2) in the metabolism of numerous aromatic amine and hydrazine drugs. Areas covered: We describe and review data that more clearly defines the effects of NAT2 haplotypes and genotypes on the expression of acetylator phenotype towards selected drugs within human hepatocytes in vitro, within human hepatocyte cultures in situ, and clinical measures such as bioavailability, plasma metabolic ratios of parent to N-acetyl metabolite, elimination rate constants and plasma half-life, and/or clearance determinations in human subjects. We review several drugs (isoniazid, hydralazine, sulfamethazine, amifampridine, procainamide, sulfasalazine, amonafide and metamizole) for which NAT2 phenotype-guided therapy may be important. The value of pharmacogenomics-guided isoniazid therapy for the prevention and treatment of tuberculosis is presented as a paradigm for NAT2 phenotype-dependent dosing strategies. Expert opinion: Studies in human subjects and cryopreserved human hepatocytes show evidence for rapid, intermediate and slow acetylator phenotypes, with further data suggesting genetic heterogeneity within the slow acetylator phenotype. Incorporation of more robust NAT2 genotype/phenotypes relationships, including genetic heterogeneity within the slow acetylator phenotype, should lead to further advancements in both health outcomes and cost benefit for prevention and treatment of tuberculosis.

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NAT2 variants and toxicity related to anti-tuberculosis agents: a systematic review and meta-analysis

Cited by 35 publications

References 73 publications

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

Cost-effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis

Arylamine N-acetyltransferase acetylation polymorphisms: paradigm for pharmacogenomic-guided therapy- a focused review

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