Influence of the NAT2 gene polymorphic markers on the effectiveness and safety of treatment in patients with newly diagnosed pulmonary tuberculosis based on peripheral red blood cell dynamics

Background. Individual sensitivity to isoniazid in tuberculosis patients is determined by the presence of N-acetyltransferase 2 (NAT2) enzyme gene allelic variants in genome. Evaluation of quantitative and qualitative alterations in peripheral blood can be used for diagnosis, disease severity estimation, or as a clue for estimation of anti-tuberculosis chemotherapy effectiveness and safety.Aim: Find associations between acetylation type and peripheral red blood cell (RBC) dynamics; determine the effect of NAT2 acetylation rate on the effectiveness and safety of treatment in patients with newly identified pulmonary tuberculosis (TB) residing in the Sakha Republic (Yakutia).Methods. This study included 146 patients with various clinical forms of newly diagnosed pulmonary TB. Oral isoniazid, rifampicin, pyrazinamide, and ethambutol were administered patients. Genotyping was performed via real time PCR.Results. Rapid and intermediate acetylators showed an increase in hemoglobin concentrations and RBC erythrocyte hemoglobin content by the end of chemotherapy (P<0.05). Incidence of anemia was lower in intermediate acetylators, compared to rapid or slow acetylators (P=0.013). Negative correlation was established between absolute RBC count and slow acetylation type (P=0.017). Patients with rapid acetylation type showed increased RBC distribution width indexes RDW-CV and RDW-SD (P<0.05).Conclusions. An adequate therapeutic effect was achieved with standard doses of anti-TB medications in patients with intermediate acetylation type. Rapid and slow acetylators required anti-TB medication dose correction. Genotyping for NAT2 gene in patients with pulmonary TB enables clinicians to choose the optimal dose of anti-TB medications, specifically, isoniazid dose.

Association study of NAT2 gene polymorphism and risk of oral cancer in Southern Punjab, Pakistan

Published in August 2021

N-acetyltransferase 2 (NAT2) and Cytochrome 2C9 (CYP2C9) Genes Polymorphisms in Type 2 Diabetes Mellitus Patients in Yaoundé, Cameroon

Although several environmental factors influence the onset of type 2 Diabetes Mellitus (T2DM), genetic factors contribute to an individual vulnerability to this disease. This study was aimed at studying CYP2C9*3 single nucleotide polymorphism (SNP) and NAT2 gene polymorphisms, and their correlation, if any, in the susceptibility to type 2 diabetes in Yaoundé, Cameroon. This was a case-control study involving 70 participants living in Yaoundé, Cameroon. DNA was extracted by Chelex 100 method. Polymorphisms of NAT2 gene and CYP2C9*3 SNP were assessed using Polymerase Chain Reaction – Restriction Fragment Length Polymorphism (PCR-RFLP). NAT2 gene characterization revealed the predominance of NAT2*5 alleles (35%) and slow metabolizing phenotype (72.9%). CYP2C9 gene characterization revealed the predominance of the wild-type allele (54%) and intermediate metabolizing phenotype (91%). Individuals with the “NAT2 slow metabolizer” phenotype were more likely to have T2DM while those with “intermediate metabolizer” phenotype were less likely to develop this disease (OR = 3.9740, P = 0.0009 and OR = 0.1406, P = 0.0044, respectively). CYP2C9*3 had no discernable predisposition to T2DM (OR= 0.1765, P= 0.1981). This study demonstrates that the NAT2 slow metabolizer phenotype could be associated with the development of T2DM in Yaoundé, Cameroon.

NAT2 and CYP1B1 genetic polymorphisms in patients with genital endometriosis depending on tolerability of melatonin

BACKGROUND: Genital endometriosis is one of the most pressing problems of modern gynecology. Melatonin is a promising drug with a potentially curative effect on endometriosis. AIM: The aim of this study was to conduct a comparative analysis of the genetic polymorphism of some genes encoding enzymes involved in melatonin metabolism. MATERIALS AND METHODS: The genetic polymorphism in the NAT2 and CYP1B1 genes encoding enzymes involved in melatonin metabolism in patients with different tolerance to this drug was analyzed by PCR-RFLP analysis. RESULTS: In patients with genital endometriosis, the presence of a wild-type allele (N) of the NAT2 gene was associated with poor tolerance of melatonin. The NAT2 (N / N) rapid acetylator phenotype combined with the low catalytic activity of CYP1B1 (C / C) occurred more frequently in endometriosis patients having poor melatonin tolerability compared to the group of patients who tolerated the therapy well. CONCLUSIONS: For patients with genital endometriosis with the wild-type (N) allele of the NAT2 gene, melatonin administration is inappropriate due to numerous side effects during the drug use.

Polymorphism of NAT2, PXR, ABCB1, and GSTT1 genes among tuberculosis patients of North Eastern States of India

Background: Anti-tuberculosis drug-induced liver injury (AT-DILI) in tuberculosis (TB) patients has been linked to polymorphisms in genes encoding drug metabolism enzymes and proteins. Objective: This study aimed to monitor polymorphisms of NAT2, PXR, ABCB1, and GSTT1 genes in TB patients from three states (Manipur, Tripura, and Nagaland) in the North Eastern Region of India. Methods: Genomic DNA was isolated from the whole blood samples of TB patients (n=219; Manipur:139; Tripura: 60; Nagaland: 20). The TaqMan allelic discrimination assay and statistical tools were used to investigate single nucleotide polymorphisms (SNP) patterns in NAT2, PXR, ABCB1, and GSTT1 genes. Results: In the study population, ten distinct genotypes of the NAT2 gene and single variation in the PXR, ABCB1, and GSTT1 genes were identified. A strong linkage disequilibrium (LD) was observed between rs1801280 and rs1799931 of the NAT2 gene. Majority of the study populations were intermediate (~46.1%), rest were either slow acetylators (~35.6%) or fast acetylators. Interestingly, ~55% of the TB patients in Tripura were slow acetylators and majority in Manipur and Nagaland were of intermediate acetylator genotypes. For all of the markers investigated, the population had a greater prevalence of ancestral alleles and genotypes. According to a combinational study of the genotypes linked to AT-DILI, ~26.1% of the population possessed the risk genotypes. Conclusion: These TB patients from north eastern states of India were found as carriers of the ancestral alleles and genotypes. And the risk for AT-DILI during TB treatment is low. Expanding such studies with additional markers and larger sample sizes will be useful to generate precise population-specific pharmacogenomics details for efficient TB management.

NAT2 Gene Polymorphisms and Plasma Isoniazid Concentration in Vietnamese Tuberculosis Patients

Isoniazid (INH) is one of the most common drugs for tuberculosis (TB) treatment and INH acetylation catalyzed by non-inducible hepatic enzyme arylamine N-acetyltransferase type 2 (NAT2). The isoniazid acetylation rates, which depend on NAT2 genotypes, is constant in an individual but can changes between patients. Phenotypic groups can be classified based on the genotype: slow, intermediate, and rapid acetylators. This study was performed to identify the relation between NAT2 gene polymorphisms and plasma INH concentrations among the different genotypes of Vietnamese tuberculosis patients. Blood samples of 136 adult TB patients treated with INH were collected and genotyped for NAT2 gene polymorphisms using Sanger sequencing. Two-hour post-dosing INH plasma concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). Among the 136 patients genotyped, there were 43 (31.62 %), 58 (42.65 %), and 35 (25.74 %) of slow, intermediate, and rapid acetylation phenotypes, with two-hour post dosing INH plasma concentrations of 3.4, 2.7, and 2.2 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P < 0.05). Genotyping of TB patients from Vietnam for NAT2 gene polymorphism revealed that 48 percent of the study population comprised slow acetylators. Two-hour INH levels were significantly different among CC and TT homozygous genotypes of NAT2(C282T), as 2.7 μg/ml and 3.9 μg/ml, respectively. This suggests that NAT2(C282T) could play a role in INH metabolism in TB patients. Methods: Blood samples of 136 adult TB patients treated with INH were collected and genotyped for NAT2 gene polymorphisms using Sanger sequencing. Two-hour post-dosing INH plasma concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). Results: Among the 136 patients genotyped, there were 43 (31.62%), 58 (42.65%) and 35 (25.74%) of slow, intermediate and rapid acetylation phenotypes with two-hour post dosing INH plasma concentration of 3.4, 2.7 and 2.2 μg/ml, respectively. The differences in INH concentrations among the three genotypes were significant (P<0.05). Conclusions: Genotyping of TB patients from Vietnam for NAT2 gene polymorphism revealed that 48 per cent of the study population comprised slow acetylators. Two-hour INH levels were significantly different among slow and rapid acetylators.