NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury

Suvichapanich, Supharat; Fukunaga, Koya; Zahroh, Hilyatuz; Mushiroda, Taisei; Mahasirimongkol, Surakameth; Toyo-Oka, Licht; Chaikledkaew, Usa; Jittikoon, Jiraphun; Yuliwulandari, Rika; Yanai, Hideki; Wattanapokayakit, Sukanya; Tokunaga, Katsushi

doi:10.1097/fpc.0000000000000339

Cited by 37 publications

(35 citation statements)

References 42 publications

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“…In accordance with two previous reports (Leise et al, 2014;Suvichapanich et al, 2018) and the results of the univariate logistic regression in our study, age (threshold value 50 years old), sex, and TB subtypes were considered as covariates in the subsequent multivariate logistic regression analysis. The mutant alleles of rs8085707, rs76986960, and rs949037 were identified as independent risk factors of ATT-DILI (p = 0.004, p = 0.038, and p = 0.040, respectively) ( Table 3).…”

Section: Clinical Characteristics Of Enrolled Patientsmentioning

confidence: 55%

Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

Lyu

Jiao

Zhou

et al. 2020

International Journal of Infectious Diseases

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The aim of this study was to identify the relationship between B-cell CLL/lymphoma 2 (BCL2) polymorphisms and susceptibility to anti-tuberculous therapy-associated drug-induced liver injury (ATT-DILI). Methods: A total of 746 tuberculosis (TB) patients were enrolled in this study. Twenty-one selected single nucleotide polymorphisms in BCL2 were analyzed by custom-by-design 2 Â 48-Plex SNPscan kit. The allele and genotype frequencies between patients with and without ATT-DILI were compared using three different genetic models. Results: A total of 727/746 participants were successfully genotyped, and 112 of them were diagnosed with ATT-DILI. The A allele of rs8085707, G allele of rs76986960, and A allele of rs949037 conferred an increased risk of ATT-DILI, with estimated odd ratios (ORs) of 2.181 (95% confidence interval (CI) 1.345-3.536, p = 0.001), 1.983 (95% CI 1.060-3.709, p = 0.029), and 1.390 (95% CI 1.032-1.873, p = 0.03), respectively. Bonferroni correction indicated that the A allele of rs8085707 was a risk factor for ATT-DILI (Bonferroni correction: p = 0.026). The additive model suggested that patients with the AA genotype of rs8085707 had a significantly higher risk of ATT-DILI compared with those with the GG genotype (Bonferroni correction: p = 0.036). The influence of BCL2 polymorphisms on clinical characteristics (clinical symptoms, disease subtypes, and laboratory indicators) was also identified. Conclusions: This study is novel in suggesting an association between BCL2 polymorphisms and the risk of ATT-DILI.

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Section: Clinical Characteristics Of Enrolled Patientsmentioning

confidence: 55%

Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

Lyu

Jiao

Zhou

et al. 2020

International Journal of Infectious Diseases

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“…The "acetylator trait" describing differences in drugs' acetylation was one of the first identified PGx traits 60 . NAT2 alleles are known to exhibit three phenotypes: rapid, intermediate, and slow acetylators with a variable presentation of these alleles among different populations 61 . Among the few pharmacogenetic studies in the Emirati population, NAT2 was the most studied pharmacogene 62,63 .…”

Section: Discussionmentioning

confidence: 99%

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations

Al-Mahayri

Patrinos

Wattanapokayakit

et al. 2020

Sci Rep

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Genetic variations have an established impact on the pharmacological response. Investigating this variation resulted in a compilation of variants in “pharmacogenes”. The emergence of next-generation sequencing facilitated large-scale pharmacogenomic studies and exhibited the extensive variability of pharmacogenes. Some rare and population-specific variants proved to be actionable, suggesting the significance of population pharmacogenomic research. A profound gap exists in the knowledge of pharmacogenomic variants enriched in some populations, including the United Arab Emirates (UAE). The current study aims to explore the landscape of variations in relevant pharmacogenes among healthy Emiratis. Through the resequencing of 100 pharmacogenes for 100 healthy Emiratis, we identified 1243 variants, of which 63% are rare (minor allele frequency ≤ 0.01), and 30% were unique. Filtering the variants according to Pharmacogenomics Knowledge Base (PharmGKB) annotations identified 27 diplotypes and 26 variants with an evident clinical relevance. Comparison with global data illustrated a significant deviation of allele frequencies in the UAE population. Understudied populations display a distinct allelic architecture and various rare and unique variants. We underscored pharmacogenes with the highest variation frequencies and provided investigators with a list of candidate genes for future studies. Population pharmacogenomic studies are imperative during the pursuit of global pharmacogenomics implementation.

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“…Meta-analyses found that rapid acetylators are at increased risk of treatment failure, relapse, and drug resistance [38]. Several studies have proposed pharmacogenomicsguided INH therapy for TB [29,[38][39][40][41][42][43].…”

Section: Isoniazid (Inh)mentioning

confidence: 99%

“…HYD (Figure 2(e)) and SMZ (Figure 3(e)) N-acetylation rates within the slow acetylator phenotype follow the rank order of NAT2*5B/*5B > NAT2*5B/*6A > NAT2*6A/ NAT2*6A in cryopreserved human hepatocytes. A recent review and meta-analysis [39] included 18 studies with 822 cases of anti-tuberculosis drug-induced liver injury and 4630 controls. A more robust association was noted with liver injury in ultra-slow NAT2 acetylators (OR: 3.60; 95% CI: 2.30-5.63) compared to all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.-20-3.57).…”

Section: Genetic Heterogeneity Within the Slow Acetylator Phenotypementioning

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 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury

Abstract: This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.

Cited by 37 publications

References 42 publications

Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

Variation in 100 relevant pharmacogenes among emiratis with insights from understudied populations

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

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