High frequency of NAT2 slow acetylator alleles in the Malay population of Indonesia: an awareness to the anti-tuberculosis drug induced liver injury and cancer

Background: Arylamine N-acetyltransferase 2 (NAT2) polymorphism was previously reported to have association with the risk of drug toxicities and the development of various diseases. Previous research on the Indonesian population, especially Javanese and Sundanese, showed that there were 33% NAT2 slow acetylator phenotype. The aim of this study was to map the NAT2 variation in the Malay ethnic to gain a deeper insight into NAT2 haplotypic composition in this ethnic.Methods: 50 healthy samples from the Indonesian Malay ethnic were obtained. They were interviewed about their ethnic backgrounds for the last three generations. DNA was extracted from peripheral blood and NAT2 genotyping was done using the PCR direct Sequencing. Data were compiled according to the genotype and allele frequencies estimated from the observed numbers of each specific allele. Haplotype reconstruction was performed using PHASE v2.1.1 software.Results: We found 7 haplotypes consisting of 6 SNPs and 14 NAT2 genotype variations in Indonesian Malay population. The most frequent allele was NAT2*6A (38%) which was classified as a slow acetylator allele. According to bimodal distribution, the predicted phenotype of the Malay population was composed of 62% rapid acetylator and 38% slow acetylator. According to trimodal distribution, the predicted phenotypes for rapid, intermediate and slow acetylators were 10%, 52% and 38% respectively.Conclusion: Our result indicates the presence of the allelic distribution and revealed the most frequent acetylator status and phenotype for the Indonesian Malay population. The result of this study will be helpful for future epidemiological or clinical studies and for understanding the genetic basis of acetylation polymorphism in Indonesia.

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Polimorfisme Gen N-Asetiltransferase 2 (NAT2) dan Implementasi Farmakogenomik dalam pengobatan Tuberkulosis

10.31227/osf.io/b32gx ◽

2017 ◽

Author(s):

Rika Yuliwulandari ◽

Kinarsih Prayuni

Keyword(s):

Liver Injury ◽

Odds Ratio ◽

Therapeutic Option ◽

Cost Effective ◽

Acetylator Phenotype ◽

Drug Induced ◽

Major Health Problem ◽

Slow Acetylator ◽

Imple Mentation ◽

The Individual

AbstrakTuberkulosis (TB) masih menjadi masalah kesehatan utama di Indonesia. Enzim N-asetil- transferase 2 (NAT2) telah diketahui memainkan peranan penting dalam proses metabolism obat anti tuberkulosis, terutama Isoniazid. Polimorfisme NAT2 dilaporkan memiliki asosiasi dengan resiko toksisitas obat dan perkembangan berbagai penyakit. Anti-TuberculosisDrug- induced liver injury (AT-DILI) merupakan efek samping yang biasanya terjadi pada pen- gobatan tuberkulosis. Beberapa penelitian menunjukkan bahwa pasien dengan fenotipe aset- ilator NAT2 lambat sangat rentan terhadap perkembangan AT-DILI. Penelitian kami sebe- lumnya menunjukkan bahwa frekuensi asetilator NAT2 lambat di Indonesia cukup tinggi, pada etnis Jawa-sunda sebesar 33% dan pada etnis Melayu 38%. Oleh karena itu, kesadaran masyarakat terhadap kerentanan AT-DILI harus di tingkatkan. Penelitian kami terbaru menunjukkan bahwa NAT2*6A, yang merupakan alel asetilator lambat, memiliki asosiasi yang signifikan terhadap AT-DILI (p=7.7×10−4, odds ratio (OR)=4.75 (1.8–12.55)). Selain itu, pasien dengan fenotipe asetilator lambat menunjukkan risiko AT-DILI lebih tinggi dibandingkan pasien dengan fenotipe cepat atau intermediet (p = 1,7 × 10-4, OR = 3,45 (1,79-6,67)). Farmakogenomik merupakan suatu studi variasi ekspresi gen individu terkait kerentanan terhadap penyakit dan respon terhadap obat baik pada individu itu sendiri mau- pun pada populasi. Penelitian dan penerapan farmakogenomik dapat membantu menentukan pengobatan yang terbaik untuk pasien dan memiliki peluang keberhasilan yang lebih tinggi. Oleh karena itu, kita perlu mendorong pengembangan penelitian farmakogenomik, mengusulkan kolaborasi baik secara nasional maupun internasional dan membuat masyarakat Indonesia menyadari betapa pentingnya penerapan farmakogenomik dalam kehidupan mereka.Kata kunci: NAT2, Asetilator lambat, AT-DILI, Farmakogenomik AbstractTuberculosis (TB) is still remains as a major health problem in Indonesia. The enzyme N- Acetyltransferase 2 (NAT2) has been known to play an important role in metabolizing anti- tuberculosis drugs, especially isoniazid. Polymorphisms of NAT2 are reportedly associated with the risk of drug toxicities and development of various diseases. Anti-Tuberculosis Drug-induced liver injury (AT-DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that a patient with slow acetylator phenotype has a high susceptibility to AT-DILI. Our research on the Indonesian population, in Javanese and Sundanese dan Malay ethnics showed 33% and 38% NAT2 slow acetylator phenotype, respectively. Therefore, Indonesia populations have to be aware with the development of AT-DILI. Our recent study showed thatNAT2*6A as a slow acetylator allele was signifi- cantly associated with AT-DILI (P=7.7×10−4, odds ratio (OR)=4.75 (1.8–12.55)). Addi- tionally, patients with slow acetylator phenotype showed higher risk of AT-DILI than pa- tients with the rapid acetylator or intermediate acetylator phenotypes (P=1.7×10−4,OR=3.45 (1.79–6.67)). Pharmacogenomics is a study of the variation of in- dividual gene expression related to susceptibility to disease and response to drugs both in the individual itself and population. Pharmacogenomics research and implementation can help to select the best therapeutic option for patients suffering from certain diseases that are both cost effective and having higher chance of success. Therefore, we need to foster phar- macogenomics research development, propose collaboration both nationally and interna- tionally and make the Indonesia society realize how important pharmacogenomics imple- mentation is in their life.Keywords: NAT2, Slow acetylator, AT-DILI, Pharmacogenomics

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Hair Analysis for Determination of Isoniazid Concentrations and Acetylator Phenotype during Antituberculous Treatment

Tuberculosis Research and Treatment ◽

10.1155/2012/327027 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6

Author(s):

Michael Eisenhut ◽

Detlef Thieme ◽

Dagmar Schmid ◽

Sybille Fieseler ◽

Hans Sachs

Keyword(s):

Hair Analysis ◽

Plasma Concentrations ◽

Acetylator Phenotype ◽

Slow Acetylator ◽

Antituberculous Treatment ◽

Nat2 Genotype ◽

Design And Methods ◽

Rapid Acetylator

Background. Analysis of isoniazid (INH) uptake has been based on measurement of plasma concentrations providing a short-term and potentially biased view.Objectives. To establish hair analysis as a tool to measure long-term uptake of INH and to assess whether acetylator phenotype in hair reflects N-acetyltransferase-2 (NAT2) genotype.Design and Methods. INH and acetyl-INH concentrations in hair were determined in patients on INH treatment forM. tuberculosisinfection using high pressure liquid chromatography/mass spectrometry. Acetyl-INH/INH ratios were correlated with NAT-2 genotype.Results. Hair concentrations of INH, determined in 40 patients, were not dependent on ethnic group or body mass index and were significantly higher in male compared to female patients (median (range) 2.37 ng/mg (0.76–4.9) versus 1.11 ng/mg (0.02–7.20) (P=0.02). Acetyl-INH/INH ratios were a median of 15.2% (14.5 to 31.7) in homozygous rapid acetylator NAT-2 genotype and 37.3% (1.73 to 51.2) in the heterozygous rapid acetylator NAT-2 genotype and both significantly higher than in the slow acetylator NAT-2 genotype with 5.8% (0.53 to 14.4) (P<0.05).Conclusions. Results of hair analysis for INH showed lower concentrations in females. Acetyl-INH/INH ratios were significantly lower in patients with slow acetylator versus rapid acetylator genotypes.

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Sequoia: an interactive visual analytics platform for interpretation and feature extraction from nanopore sequencing datasets

BMC Genomics ◽

10.1186/s12864-021-07791-z ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Ratanond Koonchanok ◽

Swapna Vidhur Daulatabad ◽

Quoseena Mir ◽

Khairi Reda ◽

Sarath Chandra Janga

Keyword(s):

Single Molecule ◽

Visual Analytics ◽

Visual Analysis ◽

Direct Sequencing ◽

Visual Exploration ◽

Nanopore Sequencing ◽

Sequencing Data ◽

Rna Sequences ◽

Sequencing Technologies ◽

Signal Features

Abstract Background Direct-sequencing technologies, such as Oxford Nanopore’s, are delivering long RNA reads with great efficacy and convenience. These technologies afford an ability to detect post-transcriptional modifications at a single-molecule resolution, promising new insights into the functional roles of RNA. However, realizing this potential requires new tools to analyze and explore this type of data. Result Here, we present Sequoia, a visual analytics tool that allows users to interactively explore nanopore sequences. Sequoia combines a Python-based backend with a multi-view visualization interface, enabling users to import raw nanopore sequencing data in a Fast5 format, cluster sequences based on electric-current similarities, and drill-down onto signals to identify properties of interest. We demonstrate the application of Sequoia by generating and analyzing ~ 500k reads from direct RNA sequencing data of human HeLa cell line. We focus on comparing signal features from m6A and m5C RNA modifications as the first step towards building automated classifiers. We show how, through iterative visual exploration and tuning of dimensionality reduction parameters, we can separate modified RNA sequences from their unmodified counterparts. We also document new, qualitative signal signatures that characterize these modifications from otherwise normal RNA bases, which we were able to discover from the visualization. Conclusions Sequoia’s interactive features complement existing computational approaches in nanopore-based RNA workflows. The insights gleaned through visual analysis should help users in developing rationales, hypotheses, and insights into the dynamic nature of RNA. Sequoia is available at https://github.com/dnonatar/Sequoia.

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Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions

Clinical Pharmacology & Therapeutics ◽

10.1038/clpt.1991.3 ◽

1991 ◽

Vol 49 (1) ◽

pp. 13-17 ◽

Cited By ~ 140

Author(s):

Michael J Rieder ◽

N H Shear ◽

A Kanee ◽

B K Tang ◽

Stephen P Spielberg

Keyword(s):

Acetylator Phenotype ◽

Hypersensitivity Reactions ◽

Slow Acetylator

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Chromosomal localization of human genes for arylamine N-acetyltransferase

Biochemical Journal ◽

10.1042/bj2970441 ◽

1994 ◽

Vol 297 (3) ◽

pp. 441-445 ◽

Cited By ~ 64

Author(s):

D Hickman ◽

A Risch ◽

V Buckle ◽

N K Spurr ◽

S J Jeremiah ◽

...

Keyword(s):

Bladder Cancer ◽

In Situ Hybridization ◽

Yeast Artificial Chromosome ◽

Chromosomal Localization ◽

Artificial Chromosome ◽

Acetylator Phenotype ◽

Chromosome 8 ◽

Slow Acetylator ◽

Human Genes

Arylamine N-acetyltransferase is encoded at two loci, AAC-1 and AAC-2, on human chromosome 8. The products of the two loci are able to catalyse N-acetylation of arylamine carcinogens, such as benzidine and other xenobiotics. AAC-2 is polymorphic and individuals carrying the slow-acetylator phenotype are more susceptible to benzidine-induced bladder cancer. We have identified yeast artificial chromosome clones encoding AAC-1 and AAC-2 and have used the cloned DNAs as fluorescent probes for in situ hybridization. The hybridization patterns allow assignment of AAC-1 and AAC-2 to chromosome 8p21.3-23.1, a region in which deletions have been associated with bladder cancer [Knowles, Shaw and Proctor (1993) Oncogene 8, 1357-1364].

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356 IDENTIFICATION OF HBV DUAL INFECTION USING DIRECT SEQUENCING DATA

Journal of Hepatology ◽

10.1016/s0168-8278(11)60358-9 ◽

2011 ◽

Vol 54 ◽

pp. S143

Author(s):

B. Beggel ◽

M. Neumann-Fraune ◽

G. Lawyer ◽

R. Kaiser ◽

J. Verheyen ◽

...

Keyword(s):

Direct Sequencing ◽

Dual Infection ◽

Sequencing Data

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Carbamazepine-Isoniazid Interaction

PEDIATRICS ◽

10.1542/peds.71.1.139 ◽

1983 ◽

Vol 71 (1) ◽

pp. 139-139

Author(s):

J. M. WRIGHT

Keyword(s):

Case Report ◽

Steady State ◽

Significant Interaction ◽

Similar Case ◽

Drug Regimen ◽

Acetylator Phenotype ◽

Serum Concentrations ◽

Slow Acetylator ◽

Steady State Serum ◽

Clinically Significant

To the Editor.— The case report of carbamazepine intoxication secondary to isoniazid administration recently described in this journal1 is a clinically significant interaction. I have previously presented2 a similar case in which a patient receiving carbamazepine, valproate, and nitrazepam developed severe carbamazepine intoxication when isoniazid was added to the drug regimen. The patient was determined to have inherited the slow acetylator phenotype. On careful rechallenge, 300 mg of isoniazid increased carbamazepine steady-state serum concentrations by 85% and decreased carbamazepine clearance by 45%.

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Relevance of NAT2 genotype to anti‐tuberculosis drug‐induced hepatotoxicity in a Chinese Han population

The Journal of Gene Medicine ◽

10.1002/jgm.3096 ◽

2019 ◽

Vol 21 (6) ◽

Author(s):

Lihuan Lu ◽

Bilin Tao ◽

Haixu Wei ◽

Hongbo Chen ◽

Xiaomin He ◽

...

Keyword(s):

Chinese Han Population ◽

Chinese Han ◽

Drug Induced ◽

Han Population ◽

Nat2 Genotype

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Genotype-Guided Hydralazine Therapy

American Journal of Nephrology ◽

10.1159/000510433 ◽

2020 ◽

Vol 51 (10) ◽

pp. 764-776 ◽

Cited By ~ 1

Author(s):

Kimberly S. Collins ◽

Anthony L.J. Raviele ◽

Amanda L. Elchynski ◽

Alexander M. Woodcock ◽

Yang Zhao ◽

...

Keyword(s):

Resistant Hypertension ◽

Antihypertensive Efficacy ◽

Slow Acetylators ◽

Slow Acetylator ◽

Nat2 Genotype ◽

Significant Relationships ◽

Acetylator Status ◽

Hydralazine Hydrochloride ◽

Personalized Approach ◽

Consistent Direction

Background: Despite its approval in 1953, hydralazine hydrochloride continues to be used in the management of resistant hypertension, a condition frequently managed by nephrologists and other clinicians. Hydralazine hydrochloride undergoes metabolism by the N-acetyltransferase 2 (NAT2) enzyme. NAT2 is highly polymorphic as approximately 50% of the general population are slow acetylators. In this review, we first evaluate the link between NAT2 genotype and phenotype. We then assess the evidence available for genotype-guided therapy of hydralazine, specifically addressing associations of NAT2 acetylator status with hydralazine pharmacokinetics, antihypertensive efficacy, and toxicity. Summary: There is a critical need to use hydralazine in some patients with resistant hypertension. Available evidence supports a significant link between genotype and NAT2 enzyme activity as 29 studies were identified with an overall concordance between genotype and phenotype of 92%. The literature also supports an association between acetylator status and hydralazine concentration, as fourteen of fifteen identified studies revealed significant relationships with a consistent direction of effect. Although fewer studies are available to directly link acetylator status with hydralazine antihypertensive efficacy, the evidence from this smaller set of studies is significant in 7 of 9 studies identified. Finally, 5 studies were identified which support the association of acetylator status with hydralazine-induced lupus. Clinicians should maintain vigilance when prescribing maximum doses of hydralazine. Key Messages: NAT2 slow acetylator status predicts increased hydralazine levels, which may lead to increased efficacy and adverse effects. Caution should be exercised in slow acetylators with total daily hydralazine doses of 200 mg or more. Fast acetylators are at risk for inefficacy at lower doses of hydralazine. With appropriate guidance on the usage of NAT2 genotype, clinicians can adopt a personalized approach to hydralazine dosing and prescription, enabling more efficient and safe treatment of resistant hypertension.

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