N-acetyltransferase 2 Slow Acetylator Research Articles

Pharmacogenomic insights into tuberculosis treatment shows the NAT2 genetic variants linked to hepatotoxicity risk: a systematic review and meta-analysis

BackgroundTuberculosis (TB) patients undergoing anti-tuberculosis treatment often face serious adverse drug reactions, such as hepatotoxicity. Genetic variants of the N-acetyltransferase 2 (NAT2) gene have been linked to an increased risk of these toxic events.ObjectiveThis study aims to provide a comprehensive evaluation of the evidence linking NAT2 genetic variants to anti-tuberculosis drug-related hepatotoxicity (ATDH).MethodA comprehensive review and meta-analysis was performed by accessing databases such as PubMed, Scopus, and Web of Science. A total of 24 articles were incorporated into the dataset. Meta-analyses were conducted to gather estimates of the association between the slow acetlylators (SA) genotype and ATDH. The studies were stratified by ethnicity, regimen, genotyping methods, criteria for liver toxicity, and dosage. Also, meta-analysis for the specific SA type that was most likely responsible for the ATDH was also conducted.ResultsThe included studies showed individuals with a slow NAT2 acetylator had a significantly greater risk of experiencing hepatotoxicity ATDH (odds ratio [OR] 2.52 (95% CI: 1.95–3.27; p value < 0.001) compared to individuals with other types of acetylator (i.e., rapid and immediate). Among individuals with slow acetylator NAT2*5/7, NAT2*5/6, and NAT2*6/6 genotypes, there is a greater likelihood of association compared to other variations.ConclusionOur meta-analysis confirms a significant association between slow NAT2 acetylator and increased hepatotoxicity risk. The findings from the present underscore the potential of pharmacogenomic testing to improve TB treatment outcomes. By identifying patients with the slow acetylator NAT2 genotype, healthcare providers can predict an increased risk of anti-tuberculosis drug-induced hepatotoxicity. This allows for personalized treatment strategies, such as adjusting drug dosages or selecting alternative therapies, to minimize adverse effects and optimize efficacy.

Influence of N-acetyltransferase 2 polymorphisms and clinical variables on liver function profile of tuberculosis patients

ABSTRACT Background Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase 2 (NAT2) gene as well as several other clinical factors can contribute to the elevation of liver function test values in tuberculosis (TB) patients receiving antitubercular therapy (ATT). Research design and methods A prospective study involving dynamic monitoring of the liver function tests among 130 TB patients from baseline to 98 days post ATT initiation was undertaken to assess the influence of pharmacogenomic and clinical variables on the elevation of liver function test values. Genomic DNA was extracted from serum samples for the assessment of NAT2 SNPs. Further, within this study population, we conducted a case control study to identify the odds of developing ATT-induced drug-induced liver injury (DILI) based on NAT2 SNPs, genotype and phenotype, and clinical variables. Results NAT2 slow acetylators had higher mean [90%CI] liver function test values for 8–28 days post ATT and higher odds of developing DILI (OR: 2.73, 90%CI: 1.05–7.09) than intermediate acetylators/rapid acetylators. Conclusion The current study findings provide evidence for closer monitoring among TB patients with specific NAT2 SNPs, genotype and phenotype, and clinical variables, particularly between the period of more than a week to one-month post ATT initiation for better treatment outcomes.

Human N-acetyltransferase 2 (NAT2) gene variability in Brazilian populations from different geographical areas.

Introduction: Several polymorphisms altering the NAT2 activity have already been identified. The geographical distribution of NAT2 variants has been extensively studied and has been demonstrated to vary significantly among different ethnic population. Here, we describe the genetic variability of human N-acetyltransferase 2 (NAT2) gene and the predominant genotype-deduced acetylation profiles of Brazilians. Methods: A total of 964 individuals, from five geographical different regions, were genotyped for NAT2 by sequencing the entire coding exon. Results: Twenty-three previously described NAT2 single nucleotide polymorphisms (SNPs) were identified, including the seven most common ones globally (c.191G>A, c.282C>T, c.341T>C, c.481C>T, c.590G>A, c.803A>G and c.857G>A). The main allelic groups were NAT2*5 (36%) and NAT2*6 (18.2%), followed to the reference allele NAT2*4 (20.4%). Combined into genotypes, the most prevalent allelic groups were NAT2*5/*5 (14.6%), NAT2*5/*6 (11.9%) and NAT2*6/*6 (6.2%). The genotype deduced NAT2 slow acetylation phenotype was predominant but showed significant variability between geographical regions. The prevalence of slow acetylation phenotype was higher in the Northeast, North and Midwest (51.3%, 45.5% and 41.5%, respectively) of the country. In the Southeast, the intermediate acetylation phenotype was the most prevalent (40.3%) and, in the South, the prevalence of rapid acetylation phenotype was significantly higher (36.7%), when compared to other Brazilian states (p < 0.0001). Comparison of the predicted acetylation profile among regions showed homogeneity among the North and Northeast but was significantly different when compared to the Southeast (p = 0.0396). The Southern region was significantly different from all other regions (p < 0.0001). Discussion: This study contributes not only to current knowledge of the NAT2 population genetic diversity in different geographical regions of Brazil, but also to the reconstruction of a more accurate phenotypic picture of NAT2 acetylator profiles in those regions.

Application of a physiologically based pharmacokinetic model to predict isoniazid disposition during pregnancy.

Pregnancy can increase the risk of latent tuberculosis infection (LTBI) progression to tuberculosis (TB) disease. Isoniazid (INH) is the preferred preventative treatment for LTBI in pregnancy. INH is mainly cleared by N-acetyltransferase 2 (NAT2) but the pharmacokinetics (PK) of INH in different NAT2 phenotypes during pregnancy is not well characterized. To address this knowledge gap, we used physiologically based pharmacokinetic (PBPK) modeling to evaluate NAT2 phenotype-specific effects of pregnancy on INH disposition. A whole-body PBPK model for INH was developed and verified for non-pregnant NAT2 fast (FA), intermediate (IA), and slow (SA) acetylators. Model predictive performance was assessed using a drug-specific model acceptance criterion for mean plasma area under the curve (AUC) and peak plasma concentration (Cmax ), and the absolute average fold error (AAFE) for individual plasma concentrations. The verified model was extended to simulate INH disposition during pregnancy in NAT2 SA, IA, and FA populations. A sensitivity analysis was conducted using the verified PBPK model and known changes in INH disposition during pregnancy to determine whether NAT2 activity changes during pregnancy or other INH clearance pathways are altered. This analysis suggested that NAT2 activity is unchanged while other INH clearance pathways increase by ~80% during pregnancy. The model was applied to explore the effect of pregnancy on INH disposition in two ethnic populations with different NAT2 phenotype distributions and with high TB burden. Our PBPK model can be used to predict INH disposition during pregnancy in diverse populations and expanded to other drugs cleared by NAT2 during pregnancy.

Correlation of N-acetyltransferase 2 genotype and acetylation status with plasma isoniazid concentration and its metabolic ratio in ethiopian tuberculosis patients

Unfavorable treatment outcomes for tuberculosis (TB) treatment might result from altered plasma exposure to antitubercular drugs in TB patients. The present study investigated the distribution of the N-Acetyltransferase 2 (NAT2) genotype, isoniazid acetylation status, genotype–phenotype concordance of NAT2, and isoniazid plasma exposure among Ethiopian tuberculosis patients. Blood samples were collected from newly diagnosed TB patients receiving a fixed dose combination of first-line antitubercular drugs daily. Genotyping of NAT2 was done using TaqMan drug metabolism assay. Isoniazid and its metabolite concentration were determined using validated liquid chromatography-tandem mass spectrometry (LC–MS/MS). A total of 120 patients (63 male and 57 female) were enrolled in this study. The mean daily dose of isoniazid was 4.71 mg/kg. The frequency of slow, intermediate, and fast NAT2 acetylators genotypes were 74.2%, 22.4%, and 3.3% respectively. The overall median isoniazid maximum plasma concentration (Cmax) was 4.77 µg/mL and the AUC0–7 h was 11.21 µg.h/mL. The median Cmax in slow, intermediate, and fast acetylators were 5.65, 3.44, and 2.47 μg/mL, respectively. The median AUC0–7 h hour in slow, intermediate, and fast acetylators were 13.1, 6.086, and 3.73 mg•h/L, respectively. The majority (87.5%) of the study participants achieved isoniazid Cmax of above 3 µg/mL, which is considered a lower limit for a favorable treatment outcome. There is 85% concordance between the NAT2 genotype and acetylation phenotypes. NAT2 genotype, female sex, and dose were independent predictors of Cmax and AUC0–7 h (p < 0.001). Our finding revealed that there is a high frequency of slow NAT2 genotypes. The plasma Cmax of isoniazid was higher in the female and slow acetylators genotype group. The overall target plasma isoniazid concentrations in Ethiopian tuberculosis patients were achieved in the majority of the patients. Therefore, it is important to monitor adverse drug reactions and the use of a higher dose of isoniazid should be closely monitored.

Induction of glucose production by heterocyclic amines is dependent on N-acetyltransferase 2 genetic polymorphism in cryopreserved human hepatocytes

Heterocyclic amines (HCAs) are mutagenic compounds found in cooked meat. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes, and we recently reported that HCAs induce insulin resistance and glucose production in human hepatocytes. It is well known that HCAs require hepatic bioactivation by cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans that, depending on the combination of NAT2 alleles, correlates to rapid, intermediate, or slow acetylator phenotype that exhibits differential metabolism of aromatic amines and HCAs. No previous studies have examined the role of NAT2 genetic polymorphism in the context of HCA-mediated induction of glucose production. In the present study, we assessed the effect of three HCAs commonly found in cooked meat (2-amino-3,4-dimethylimidazo[4,5-f]quinoline [MeIQ], 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline [MeIQx], and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [PhIP]) on glucose production in cryopreserved human hepatocytes with slow, intermediate, or rapid NAT2 acetylator phenotype. HCA treatment did not affect glucose production in slow NAT2 acetylator hepatocytes, while a slight increase in glucose production was observed in intermediate NAT2 acetylators treated with MeIQ or MeIQx. However, significant increases in glucose production were observed in rapid NAT2 acetylators following each HCA. The current findings suggest that individuals who are rapid NAT2 acetylators may be at a greater risk of developing hyperglycemia and insulin resistance following dietary exposure to HCAs.

Effect of N-acetyltransferase 2 genetic polymorphism on 4,4'-methylenebis(2-chloroaniline)-induced genotoxicity and oxidative stress.

4,4'-Methylenebis(2-chloroaniline) or MOCA is an aromatic amine used primarily in polyurethane and rubber industry. MOCA has been linked to hepatomas in animal studies while limited epidemiologic studies reported the association of exposure to MOCA and urinary bladder and breast cancer. We investigated MOCA-induced genotoxicity and oxidative stress in DNA repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human metabolizing enzymes CYP1A2 and N-acetyltransferase 2 (NAT2) variants as well as in rapid, intermediate, and slow NAT2 acetylator cryopreserved human hepatocytes. N-acetylation of MOCA was highest in UV5/1A2/NAT2*4 followed by UV5/1A2/NAT2*7B and UV5/1A2/NAT2*5B CHO cells. Human hepatocytes showed a NAT2 genotype-dependent response with highest N-acetylation in rapid acetylators followed by intermediate and slow acetylators. MOCA induced higher levels of mutagenesis and DNA damage in UV5/1A2/NAT2*7B compared to UV5/1A2/NAT2*4 and UV5/1A2/NAT2*5B cells (p < 0.0001). MOCA also induced higher levels of oxidative stress in UV5/1A2/NAT2*7B cells. MOCA caused concentration-dependent increase in DNA damage in cryopreserved human hepatocytes (linear trend p < 0.001) which was NAT2 genotype dependent i.e., highest in rapid acetylators, lower in intermediate acetylators, and lowest in slow acetylators (p < 0.0001). Our findings show that N-acetylation and genotoxicity of MOCA is NAT2 genotype dependent and suggest that individuals possessing NAT2*7B are at higher risk to MOCA-induced mutagenicity. DNA damage, and oxidative stress. They confirm significant differences in genotoxicity between the NAT2*5B and NAT2*7B alleles, both of which are associated with slow acetylator phenotype.

NAT2 and CYP2E1 polymorphisms and antituberculosis drug-induced hepatotoxicity in Peruvian patients.

BackgroundIn Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%–13% is associated with significant adverse drug reactions (ADR), considering drug‐induced liver injury (DILI) as the most prevalent. Among the first‐line anti‐TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N‐acetyltransferase‐2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients.MethodsIn this cross‐sectional study, all 377 participants completed their anti‐TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1.ResultsWe found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population.ConclusionWe propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent. A retrospective nested hospital-based case–control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates. Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH. Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

Development of population pharmacokinetics model of isoniazid in Indonesian patients with tuberculosis

ObjectivesNo population pharmacokinetics (PK) model of isoniazid (INH) has been reported for the Indonesian population with tuberculosis (TB). Therefore, we aimed to develop a population PK model to optimize pharmacotherapy of INH on the basis of therapeutic drug monitoring (TDM) implementation in Indonesian patients with TB. Materials and methodsINH concentrations, N-acetyltransferase 2 (NAT2) genotypes, and clinical data were collected from Dr. Soetomo General Academic Hospital, Indonesia. A nonlinear mixed-effect model was used to develop and validate the population PK model. ResultsA total of 107 patients with TB (with 153 samples) were involved in this study. A one-compartment model with allometric scaling for bodyweight effect described well the PK of INH. The NAT2 acetylator phenotype significantly affected INH clearance. The mean clearance rates for the rapid, intermediate, and slow NAT2 acetylator phenotypes were 55.9, 37.8, and 17.7 L/h, respectively. Our model was well-validated through visual predictive checks and bootstrapping. ConclusionsWe established the population PK model for INH in Indonesian patients with TB using the NAT2 acetylator phenotype as a significant covariate. Our Bayesian forecasting model should enable optimization of TB treatment for INH in Indonesian patients with TB.

N-Acetyltransferase 2, Glutathione S-transferase gene polymorphisms and susceptibility to hepatocellular carcinoma in an Algerian population

ABSTRACT This study was conducted to investigate the potential association of genetic polymorphisms of glutathione S-transferase M1/T1 (GSTM1, GSTT1), and N-acetyltransferase 2 (NAT2) genes and epidemiological parameters with the risk of HCC in the Algerian population. A case-control study including 132 confirmed HCC patients and 141 cancer-free controls was performed. Genotyping analysis was performed using conventional multiplex PCR and PCR-RFLP. Statistical analysis was performed using the Chi-square test. Logistic regression analysis was used to estimate odds ratios and 95% confidence intervals (95% CI). GSTM1 null and NAT2 slow acetylator genotypes confer an increased risk to HCC (OR =1.88, 95% CI 1.16–3.05; OR =2.30, 95% CI 1.26–4.18, respectively). This association was prevalent in smokers (OR =2.00, 95% CI 1.05–3.8 and OR =2.55, 95% CI 1.22–5.34, respectively). No significant association was observed for GSTT1 null genotype in the contribution to HCC risk (OR =0.76, 95% CI 0.46–1.27). In conclusion, the GSTM1 and NAT2 gene polymorphisms are positively associated with the risk of HCC in older men and especially in smokers.

Influence of N-acetyltransferase 2 gene polymorphisms on the in vitro metabolism of the epidermal growth factor receptor inhibitor rociletinib.

Rociletinib showed activity in T790M-positive non-small cell lung cancer patients. It undergoes amide hydrolysis to form M502, followed by N-acetylation to M544 or amide hydrolysis to M460. We identified the enzymes responsible for rociletinib metabolism, and investigated the relationship between M544 formation and N-acetyltransferase 2 (NAT2) polymorphisms. Rociletinib and metabolites were incubated with carboxylesterase (CES)1b, CES1c, CES2, NAT1, NAT2, arylacetamide deacetylase, inhibitors, pooled human liver microsomes (HLM) and cytosols (HLC). Cytosols (n =107) were genotyped for NAT2 polymorphisms (rs1041983 and rs1801280) and incubated with M502. Human hepatocytes from intermediate (NAT2*6/*12A) and slow (NAT2*5B/*5B) acetylators were incubated with 10μM rociletinib and metabolites for 24 hours. Metabolites were measured by high-performance liquid chromatography. M502 was formed from rociletinib and M544 by CES2 and HLM; M544 and N-acetyl-M460 were formed by NAT2 and HLC; M460 was not formed by CES or arylacetamide deacetylase. M502 formation by HLM was inhibited by bis-(4-nitrophenyl)phosphate and eserine (10μM). M544 formation in HLC was inhibited by 100 μM quercetin and was associated with NAT2 genotype (P <.0001). M460 formation in HLM was inhibited by eserine, and M460 was N-acetylated in HLC. Hepatocytes formed M502, M544 and M460. The intermediate acetylator showed higher production (range: 3.4-5.1-fold) of N-acetylated metabolites than the slow acetylator. Results indicate that NAT2 and CES2 are involved in rociletinib metabolism, and polymorphic NAT2 could alter drug exposure in patients. Slow NAT2 acetylators would have higher exposure to M502 and M460 and consequently, be at increased risk of experiencing hyperglycaemia and QTc prolongation.

Functional Characterization of the Effects of N-acetyltransferase 2 Alleles on N-acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity.

Variability in the enzymatic activity of N-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in N-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated NAT2 genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated in vitro kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for N-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced N-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 NAT2 genotypes were categorized into three or four clusters. According to the results of in vitro metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.

Population pharmacokinetic model of isoniazid in patients with tuberculosis in Tunisia

AimsTo develop a pharmacokinetic model of isoniazid (INH) concentration taking into account demographic factors and genetic variables [N-acetyltransferase 2 (NAT2) genotype], and to propose an initial INH dosage that could maximize the probability of achieving the desired INH concentration. MethodsA retrospective analysis was undertaken of INH concentration data collected from patients with tuberculosis in Tunisia. ResultsIn total, 118 patients were included in this study. The one-compartment model [volume of distribution (V), elimination rate (Ke)] was found to have good predictive performance. Multi-variate analysis showed that NAT2 affected both V and Ke significantly, but age, gender and weight did not. Internal validation of the final model showed correlation of 0.95 between individual predicted INH concentration 3 h after drug intake (C3) and observed C3. External validation showed that percentage mean absolute prediction error and percentage root mean squared error were 9.11% (range 0.62–35.8%) and 11.6%, respectively. Monte-Carlo simulation showed that doses of at least 225 mg/24 h and at least 450 mg/24 h attained a therapeutic concentration in >80% of patients in the NAT2 slow acetylator group and the NAT2 rapid/intermediate acetylator group, respectively. ConclusionThe pharmacokinetic model allowed optimization of individual dosing regimens of INH in patients with tuberculosis in Tunisia. This tool may facilitate improved efficacy of INH and prevent its toxicity in this population.

A pilot study to investigate the utility of NAT2 genotype-guided isoniazid monotherapy regimens in NAT2 slow acetylators.

Isoniazid is a therapeutic agent for the treatment of latent tuberculosis infection. Genetic variants in the N-acetyltransferase 2 (NAT2) are associated with the safety and pharmacokinetics of isoniazid. The study aimed to evaluate the safety and pharmacokinetics of a NAT2 genotype-guided regimen of isoniazid monotherapy. A randomized, open-label, parallel-group and multiple-dosing study was performed in healthy subjects. The subjects received isoniazid for 29 days. The NAT2 slow acetylators (NAT2*5/*5, -*5/*6, -*5/*7, -*6/*6, -*6/*7, -*7/*7) randomly received standard dose (300 mg, standard-treatment group) or reduced dose (200 mg, PGx-treatment group) of isoniazid. Also, all the NAT2 rapid acetylators (NAT2*4/*4) received isoniazid 300 mg (reference group). The safety and pharmacokinetics were evaluated during the study. The PGx-treatment group showed a more stable serum liver enzyme profile and a lower incidence of adverse drug reactions (ADRs) than the standard-treatment group. The emergence rates of ADRs were 12.5, 60 and 33.3% in the reference, standard-treatment and PGx-treatment groups, respectively. The PGx-treatment group showed higher plasma isoniazid concentrations than the reference group, although the PGx-treatment group received a reduced dose of isoniazid. Our results showed that a NAT2 genotype-guided regimen may reduce ADRs during isoniazid monotherapy without concern over insufficient drug exposure.

The association between NAT2 acetylator status and adverse drug reactions of sulfasalazine: a systematic review and meta-analysis

N-acetyltransferase 2 (NAT2) acetylator status can be classified into three groups depending on the number of rapid alleles (e.g., NAT2*4): rapid, intermediate, and slow acetylators. Such acetylator status may influence the occurrence of adverse drug reactions (ADRs) during sulfasalazine treatment. This systematic review and meta-analysis aimed to evaluate the association between NAT2 acetylator status and ADRs of sulfasalazine. We searched for qualified studies in PubMed, Web of Science, Embase, and the Cochrane Library. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between NAT2 acetylator status and ADRs of sulfasalazine. Nine cohort studies involving 1,077 patients were included in the meta-analysis. NAT2 slow acetylators were associated with an increase in overall ADRs (OR 3.37, 95% CI: 1.43 to 7.93; p = 0.005), discontinuation due to overall ADRs (OR 2.89, 95% CI: 1.72 to 4.86; p < 0.0001), and dose-related ADRs (OR 5.20, 95% CI: 2.44 to 11.08; p < 0.0001), compared with rapid and intermediate acetylators. In conclusion, NAT2 slow acetylators are at risk of ADRs during sulfasalazine treatment. Based on our findings, NAT2 genotyping may be useful to predict the occurrence of ADRs during sulfasalazine treatment.

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

BackgroundThere 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.MethodsWe 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.ResultsIn 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.ConclusionsIsoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India.

Is NAT2 Gene Polymorphism Associated with Vitiligo?

Background:N-acetyltransferase-2 (NAT2) is a phase II xenobiotic enzyme that plays an important role against oxidative stress-mediated reactive oxygen species protection. Polymorphism in specific genotypes of NAT2 may lead to increase an imbalance in antioxidant systems and may influence the pathogenesis of vitiligo. We conducted this study to see the association between NAT2 gene polymorphism and risk of vitiligo. We looked into whether single-nucleotide polymorphisms (SNP) at positions 857, 481 and 590 of the coding region of the NAT2 gene play as a risk factor for vitiligo among north Indian people.Methods:In this study, we assessed 100 patients with vitiligo and 160 healthy individuals as controls. Genomic DNA was extracted from human peripheral blood and polymerase chain reaction–restricted fragment length polymorphism was done to identify the single nucleotide polymorphism at positions 857, 481, and 590 of the coding region of the NAT2 gene.Results:In this study, we observed a significant higher risk with slow acetylator genotypes of NAT2 (OR = 2.85; 95% CI = 1.68-4.84, P value < 0.001) for the vitiligo. Furthermore, in the association between NAT2 acetylator genotypes with percentage of body surface area (BSA) of disease, we observed that slow acetylator genotypes of NAT2 has significant higher risk with low grade of disease (1%–10% >11%–30% >30% of BSA).Limitations:A major limitation of this study was the small sample size and warrants further investigation on a large epidemiological study to confirm these findings.Conclusions:Our preliminary data indicate that NAT2 slow acetylator genotype exhibits significant association for the risk of vitiligo, especially in disease predisposition and initiation.

NAT2 gene polymorphisms and endometriosis risk: A PRISMA-compliant meta-analysis.

ObjectiveEndometriosis is a common chronic, gynecological disease. Despite many studies on the role of N-acetyltransferase 2 (NAT2) in endometriosis, its clinical significance is unclear. In this study, associations between NAT2 phenotypes as well as single nucleotide polymorphisms (SNPs) within NAT2 (i.e. rs1799929, rs1799930, rs1208, and rs1799931) and endometriosis risk were evaluated using a meta-analysis approach.MethodsEmbase, PubMed, ClinicalTrials.gov, CNKI (China National Knowledge Infrastructure), Wanfang databases, Cochrane Library for clinical trials, and Web of Science were searched to identify relevant articles. ORs (odds ratios) and 95% CIs (95% confidence intervals) were used to estimate the associations between NAT2 polymorphisms and endometriosis risk. Heterogeneity among included studies was also assessed. In addition, a subgroup analysis of NAT2 phenotypes and endometriosis risk based on ethnicity was performed.ResultsNine case-control studies met the inclusion criteria. The odds ratio was 2.30 (95% CI: 1.61–3.28) for the NAT2 slow acetylation phenotype versus the intermediate + fast acetylation phenotype in the Asian population. These results suggest that Asian individuals with the NAT2 slow acetylation phenotype have a 130% increased risk of endometriosis. A significant association was also found for rs1799930 (OR = 0.74; 95% CI, 0.59–0.92), suggesting that individuals with this mutant genotype have a 26% decreased risk of endometriosis.ConclusionsThe rs1799930 mutant genotypes are associated with a decreased risk of endometriosis. No statistically significant associations were found between rs1799931, rs1208, or rs1799929 and endometriosis. Based on a subgroup analysis based on ethnicity, the NAT2 slow acetylation phenotype was found to increase the risk of endometriosis in Asians. No statistically significant associations were found between the NAT2 slow acetylation phenotype and endometriosis risk in Caucasians. Accordingly, NAT2 phenotypes and SNPs are potential biomarkers for the diagnosis and treatment of endometriosis.

Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis

ObjectivesThe objective of this study was to investigate the association between genetic polymorphisms of N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase (GST) and solute carrier organic anion transporter...