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Purpose: N-acetyltransferase-2 enzyme in the liver, encoded by NAT2 gene, plays a central role in metabolizing tuberculosis (TB) drug isoniazid (INH). Low compliance of patients toward six-month TB therapy and internal host factors, ie comorbid diseases, immune status, and genetic profiles, are factors leading to treatment failure and recurrence of pulmonary TB infection. This study aimed to explore the NAT2 acetylator status among newly diagnosed and recurrent pulmonary TB patients in eastern part of Indonesia. Patients and Methods: Archived DNA of TB patients (n=124) and healthy controls (n=124) were sequenced, and NAT2 acetylator status was determined, then categorized as fast, intermediate, or slow acetylators. Pulmonary TB patients who had no previous TB treatment history were designated as newly diagnosed pulmonary TB, whereas patients with a history of TB treatment were designated as recurrent pulmonary TB. The demographic, clinical, and microbiological data between pulmonary TB groups were compared, and acetylator status was described among groups. Results: Male was more significantly prevalent in the recurrent pulmonary TB group (p=0.025), and anemia was more prevalent in new pulmonary TB (p=0.003). The acetylator status in pulmonary TB patients compared to healthy controls were rapid (33.9% vs 48.1%), intermediate (57.8% vs 33.0%), and slow acetylators (8.3% vs 18.9%), respectively. Interestingly, the rapid and intermediate acetylator were significantly more prevalent in pulmonary TB patients than in healthy controls (p=0.023, OR=2.58 (1.12– 5.97). Furthermore, no differences were found in acetylator status between new and recurrent pulmonary (p=0.776). Conclusion: Rapid and intermediate acetylators status predominated the pulmonary TB patients in Kupang, eastern part of Indonesia, postulating different genetic makeup in this area. As the pulmonary TB patients in Kupang exhibit more rapid acetylator phenotype, the acetylator status might be relevant to be checked before TB therapy for adjusting treatment dose to prevent drug resistances. [ABSTRACT FROM AUTHOR]

Background: N‐acetyltransferase 2 (NAT2) is a key enzyme involved in the phase II metabolism of aromatic amines and heterocyclic aromatic amines present in a wide range of xenobiotics. The aim of this study was to investigate the NAT2 polymorphism in the Buginese ethnic group of Indonesia to determine the frequency of NAT2 alleles in this population. Results: We found six haplotypes consisting of six single‐nucleotide polymorphisms and 12 NAT2 genotype variations. NAT2*6A haplotype (42%) showed the highest frequency, followed by NAT2*4 (33%), NAT2*7B (15%), NAT2*5B (5%), NAT2*12A (3%), and NAT2*13 (2%). In terms of phenotypes, the Buginese population comprised 18% rapid acetylators, 40% intermediate acetylators, and 42% slow acetylators. Conclusion: We confirmed the high‐frequency slow acetylator phenotype in the Buginese population. The NAT2*6A/*6A genotype was the most frequent slow acetylator genotype, followed by NAT2*6A/*7B. The pattern of NAT2 alleles of Buginese is similar to Southeast Asian populations but not Northeast Asian populations. However, the slow acetylator frequencies in the Buginese population were higher than those in Northeast Asian populations and lower than those in Caucasians and some American populations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Polymorphisms of arylamine N-acetyltransferase 2 ( NAT2) are reportedly associated with the risk of drug toxicities and development of various diseases. The present study examined NAT2 polymorphisms in both promoter and coding regions in the Indonesian population using PCR direct sequencing. The promoter and coding regions of NAT2 displayed 23 polymorphisms/variations, including eight new ones. Seven haplotypes in the promoter region and six haplotypes in the coding region were inferred. The haplotypes in promoter and coding regions showed limited combinations, and 13 combined haplotypes were inferred. The most frequent haplotypes were U1 (38.9%), U2 (33.5%) in the promoter region and NAT2*4 (37.3%), NAT2*6A (36.8%) in the coding region. When converted to predicted phenotypes, the studied population comprised 65.4% rapid acetylators and 35.6% slow acetylators according to bimodal distribution. According to trimodal distribution, frequencies of predicted phenotypes were 13.6, 50.8 and 35.6% for rapid, intermediate and slow acetylators, respectively. Frequencies of NAT2 alleles for the Indonesian population resembled those of other Southeast Asian populations. We also propose a new NAT2 nomenclature composed of haplotypes in the promoter region and conventional NAT2 haplotypes in the coding region, symbolized by NAT2*4.U1, NAT2*4.U2, NAT2*4.U3, NAT2*4.U5, NAT2*4.U6, NAT2*4.U7, NAT2*6A.U1, NAT2*7B.U2, NAT2*7B.U3, NAT2*5B.U1, NAT2*5B.U4, NAT2*12A.U4 and NAT2*13.U1. [ABSTRACT FROM AUTHOR]

Background: Owing to the high resistance rate of tuberculosis (TB) to isoniazid, which is metabolized by N -acetyltransferase 2 (NAT2), we investigated the associations between NAT2 variants and multidrug-resistant (MDR)-TB. Materials & methods: The acetylator status based on NAT2 haplotypes of 128 patients with MDR-TB in Indonesia were compared with our published data from patients with anti-TB drug-induced liver injury (AT-DILI), TB and the general population. Results: NAT2*4 was more frequent in the MDR-TB group than in the AT-DILI group, TB controls and general controls. NAT2*4/*4 was significantly more frequent in patients with MDR-TB than in those with AT-DILI. NAT2*5B/7B, *6A/6A  and *7B/*7B were detected at lower frequencies in patients with AT-DILI. Rapid acetylators were significantly more frequent in patients with MDR-TB than in those with AT-DILI. Conclusion: These results provide an initial data for optimizing TB treatment in the Indonesian population, and suggest that NAT2 genotyping may help to select appropriate treatment by predicting TB-treatment effect.

Aim: We investigated the contribution of NAT2 variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100 patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7 × 10 -7 ; odds ratio [95% CI] = 3.64 [2.21-6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3 × 10 -6 ; odds ratio [95% CI] = 3.37 [2.00-5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.

Background: Gene polymorphisms have been associated with drug-induced liver injury (DILI). This study aimed to elucidate the association between polymorphisms of NAT2, CYP2E1, GSTT1, GSTM1, and HLA genes with isoniazid plasma concentration and DILI., Methods: This study was a prospective cohort study recruiting adult newly diagnosed tuberculosis (TB) patients who met the inclusion criteria from the Public Health Centers in Yogyakarta and Lampung. Defined single-nucleotide polymorphisms were rs1799929, rs1799930, rs1799931, rs1801280, and rs1041983 of NAT2; rs2031920, rs8192775, and rs2515641 of CYP2E1; rs1041981, rs1063355, and rs6906021 of HLA. GSTT1 and GSTM1 were defined as GSTT1, GSTM1, and GSTT1 deletion and GSTM1 deletion. The DNA was taken from the patient saliva. Data of anti-TB drug plasma concentration on the weeks 4-8 of treatment were retrieved from the patients' medical report. Statistical analysis was performed using Chi-square test, Student's t-test, and multinomial logistic regression., Results: Over the 207 patients, up to 1.9% of them experienced DILI. The percentage of slow acetylators of NAT2 was 69.5%. Patients with extensive acetylator phenotype did not experience DILI (odds ratio [OR]: 0.46; 95% confidence interval [CI]: 0.23-0.94). The G carriership of HLA rs1063355 could protect the patients from the DILI (OR: 0.39; 95% CI: 0.14-0.9). Furthermore, the C carriership of HLA rs1041981 can protect the patients from DILI (OR: 0.38; 95% CI: 0.15-0.50). The genotype of HLA-DQB*0302 significantly affects the isoniazid concentration., Conclusion: The NAT2 genotype was significantly associated with DILI. Furthermore, the absence of G carriership of HLA-DQA*0102 could protect the patients from DILI without being associated with an effect on the isoniazid concentration., Competing Interests: None