N-acetyltransferase 2 Gene Polymorphisms Research Articles

ISONIAZID-INDUCED LIVER INJURY: PHARMACOGENETIC ASPECTS

Inter-individual differences in anti-tuberculosis chemotherapy outcomes have been demonstrated in clinical practice, such as, achievement of intended therapeutic effect in some patients, and insufficiency or absence of response to treatment in others, with development of adverse drug reactions, especially, isoniazid-induced liver injury. Isoniazid-induced liver injuries are the main reason for isoniazid discontinuation, which further leads to considerably reduced effectiveness of anti-tuberculosis chemotherapy, increased relapse risk, and secondary drug-resistance of M. tuberculosis. Hepatotoxic reactions to chemotherapy are predicated by mutations in genes encoding enzymes participating in isoniazid biotransformation: N-acetyltransferase 2 (NAT2), cytochrome P450 2Е1, and glutathione-S-transferase. NAT2 gene polymorphism has been identified as risk factor for isoniazid hepatotoxicity. Nucleotide substitutions in NAT2 gene cause modification of enzyme protein structure, reduction of enzyme synthesis and alteration of its activity. Based on genetically-determined isoniazid acetylation rate, patients are referred to three acetylator types: rapid, intermediate, and slow. Correlations have been established in meta-reviews and systematic reviews between slow acetylator type and frequency of hepatotoxic reactions to isoniazid. Based on study findings, interrelation was shown between cytochrome P450 CYP2E1 gene polymorphism and increased risk of liver injury during chemotherapy with isoniazid. Contribution of GSTM1 and GSTT1 genotypes to isoniazid toxicity requires further exploration, as the obtained results were ambiguous and controversial.

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.

Prevalence of polymorphisms in N-acetyltransferase 2 gene among patients of Yakut ethnicity newly diagnosed with pulmonary tuberculosis

Background. Tuberculosis therapy can lead to considerably dissimilar outcomes among individual patients. Some patients benefit from anti-tuberculosis chemotherapy leading to a desired therapeutic effect, while other patients show insufficient or absent response, or develop adverse side effects. Individual response to isoniazid is affected by mutations in the gene encoding N-acetyltransferase 2 (NAT2). Wide variations were observed in distributions of polymorphic NAT2 alleles in human populations depending on race, ethnicity, or geographical origin. No data are available to date on prevalence of NAT2 gene polymorphic variants and acetylation types in Yakut (Sakha) patients with newly diagnosed pulmonary tuberculosis.
 Aims: the frequencies of NAT2 polymorphic SNPs as well isoniazid acetylation phenotypes were evaluated in the patients cohort of Yakut ethnicity with newly diagnosed pulmonary tuberculosis (PTB). The comparison with, other ethnic groups of Asian origin was done.
 Methods. Cross-sectional study was conducted among Yakut patient cohorts with newly identified pulmonary tuberculosis. Using real-time PCR the following SNPs were explored: NAT2*5 (rs1801280, Т341С), NAT2*6 (rs1799930, G590A), NAT2*7 (rs1799931, G857A), NAT2*11 (rs1799929, C481T), NAT2*12 (rs1208, A803G), NAT2*13 (rs1041983, C282T). Genetically determined metabolic rates were calculated using NATpred online tool.
 Results. NAT2 SNPs were assessed, namely *5, *6, *7, *11, *12, and *13. The most frequent in Yakut patients were NAT2*6 and NAT2*13 SNPs (40.9% and 64.4%, respectively). Significant differences were detected in frequencies of NAT2 *5, *11, *12 polymorphisms; all studied NAT2 gene polymorphisms showed meaningful differences in genotype and minor allele prevalence rates after comparison between Yakut population and other Mongoloid ethnic groups (populations of China, Japan, Vietnam). High prevalence of intermediate acetylation type among ethnic Yakuts (58.3%) was established.
 Conclusions. Certain distinct differences in allelic variants of NAT2 gene and acetylation type prevalence in patients of Yakut ethnic origin newly diagnosed with pulmonary tuberculosis let conclude that the existing genotyping and phenotyping data from studies among other Mongoloid populations cannot be implicitly extrapolated on Yakut people. Pharmacogenetic data on individual response to drugs in Yakut patients should be made use of in clinical practice, to develop personalized isoniazid administration algorithms, with a final goal to make treatment more effective and safe.

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.

The role of NAT2 polymorphism and methylation in anti-tuberculosis drug-induced liver injury in Mongolian tuberculosis patients.

Anti-tuberculosis drug-induced liver injury (ATLI) is one of the most significant adverse reactions for this line of therapy. N-acetyltransferase 2 (NAT2) is an important metabolic enzyme involved in drug metabolism and detoxification. Genetic polymorphism and DNA methylation have been proven to be key factors that affect the expression of NAT2. Therefore, the objective of the study was to investigate the relationship between NAT2 gene polymorphism and DNA methylation in the promoter region with ATLI risk in Mongolian tuberculosis patients. Our study is a case-control design. Chi-square test, Mann-Whitney U non-parametric test and Pearson test were all used to analyse existing relationships. The association between NAT2 gene acetylation phenotype and the total methylation of the NAT2 promoter region was analysed by means of binary logistic regression analysis. The general situation of the patients was evaluated by questionnaire, and the NAT2 genotyping of the three major polymorphism loci of gene coding was carried out by a gene sequencing technique. The methylation status of the NAT2 gene promoter region was detected by bisulphite sequencing and mass spectrometry. Our study found that the detection rate of ATLI in Mongolian tuberculosis patients was 27.6%. There were no significant differences in demographic characteristics and living habits amongst the two groups, while significant differences were observed in the polymorphism of the NAT2 genes 481 (rs1799929) and 590 (rs1799930) and the acetylation phenotype. Moreover, the composition and distribution of the NAT2*4/4 and NAT2*4/5 genotypes were found in the two groups. The risk of ATLI in the slow acetylation type was 3.56 times higher than that of the fast acetylation type. Compared with the control group, the CpG5, CpG10, CpG11.12 and total methylation of the NAT2 promoter region in the ATLI group showed a hypermethylated pattern (P<.05). However, on performing binary logistic regression, neither the slow acetylation, intermediate acetylation nor rapid acetylation were found to be associated with ATLI (P>.05). It was found that the total methylation of NAT2 gene promoter region was an independent influencing factor of ATLI in Mongolian tuberculosis patients. With the increase of the total methylation level of NAT2 gene promoter region, the risk of ATLI increased gradually. (OR=8.371, 95% CI: 2.391~29.315). CpG1, CpG4, CpG9, CpG10 and CpG11.12 were positively correlated with a total methylation level in the ATLI group. The detection rate of ATLI in Mongolian tuberculosis patients was 27.6%, and there were differences in the NAT2 genotypes and acetylated phenotypes. The slow acetylated type was the risk factor for ATLI. Methylation in the promoter region of the NAT2 gene has an effect on the risk of ATLI. After adjusting for the interference of three acetylation types, it was found that the total methylation of the promoter region of NAT2 gene in Mongolian tuberculosis patients is an independent influencing factor of ATLI. Furthermore, there is a moderate to high correlation between some sites and the overall level of methylation.

Risk of congenital heart diseases associated with NAT2 genetic polymorphisms and maternal polycyclic aromatic hydrocarbons exposure

N-Acetyltransferase 2 (NAT2) is a phase II xenobiotic-metabolizing enzyme participating in the detoxification of toxic arylamines and aromatic amines. The present study was designed to investigate whether maternal NAT2 genetic polymorphisms are associated with fetal susceptibility to congenital heart diseases (CHDs) and to assess whether the risk is modified by polycyclic aromatic hydrocarbons (PAHs) exposure. We conducted a hospital-based case-control study to investigate the association of NAT2 gene polymorphisms (rs1799930 G/A, rs1208 A/G, and rs1799931 G/A) and the combinations of PAHs exposure and genetic variants with the risk of CHDs. Three hundred fifty-seven mothers of CHDs fetuses and 270 control mothers were recruited. Logistic regression models for the risk of CHDs were applied to determine the effect of NAT2 polymorphisms, as well as gene-exposure interactions. Our study did not demonstrate an association of maternal NAT2 genetic polymorphisms alone with CHDs occurrence. However, we found that certain genetic polymorphisms of NAT2 in the present of high PAHs exposure have a higher risk of CHDs. Our study suggests that the risk of CHDs associated with maternal NAT2 gene polymorphisms is potentiated by PAHs exposure.

Assessment of N-acetyltransferase 2 (NAT2) gene polymorphisms in bladder cancer patients

Introduction: Bladder cancer is the most common cancer of the urinary tract. Aromatic amines are incriminated in the pathogenesis of bladder cancer. While many people are exposed to it, only a small proportion of the exposed individuals develop bladder cancer indicating the contribution of genetic variation, namely N-acetyltransferases (NATs) phenotypes (slow and fast acetylator) which are involved in detoxification of aromatic amines and other carcinogenic toxins. Slow acetylators are less efficient in metabolizing aromatic amines, increased toxic burden and subsequently carcinogenesis. Objectives: The aim of this study was to determine whether NAT2 gene polymorphisms (M1, M2 and M3) are associated with bladder cancer formation and with high stage and grade of the tumor. Patients and Methods: This study was conducted on 35 Egyptian bladder cancer patients. Patients further subdivided according to tumor stage and grade. Fifteen patients with benign renal diseases as a pathological control group, in addition to 15 apparently healthy subjects as a healthy control group included in the study. Assay of NAT2 gene single nucleotide polymorphisms (SNPs) was conducted by polymerase chain reaction and restriction fragment length polymorphism (PCRRFLP) technique. Results: Regarding the frequency of NAT2 gene polymorphism, our study revealed that M1 (C481T) mutation was significantly more frequent in patients than controls groups, however no significant differences with M2 or M3 was seen. Conclusion: This investigation implies that NAT2 genotype exhibit no association with the risk of developing bladder cancer, either alone or with smoking. Moreover, there was no association between NAT2 polymorphism and different stages and grades of bladder cancer.

Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence.

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100–1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137–1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052–1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug–enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.

Study of N-acetyl transferase 2 single-gene polymorphism (rs1799931) in patients with acute myeloid leukemia

Background The genetic background has emerged as a risk factor for acute myeloid leukemia (AML) progression. N-acetyl transferase 2 (NAT2), as an enzyme, plays a pivotal role in detoxifying the carcinogenic compounds. The NAT2 gene is highly polymorphic and is found to be associated with the process of tumorigenesis and the progression of many cancers.Objective This was a case–control study adopted to explore the possible association of NAT2 gene polymorphism rs1799931 (G857A) with the susceptibility of AML progression in the Egyptian cohort.Patients and methods This study was performed during the period spanning from February 2017 to December 2018 on 60 AML cases and 80 controls. NAT2 gene rs1799931 (G857A) polymorphism was genotyped by real-time PCR technique. The NAT2 genotype and allele distributions between the cases and controls were compared by χ2-test. Association strength between NAT2 gene single-gene polymorphism (rs1799931) and AML susceptibility was expressed by odds ratios (ORs) and 95% confidence intervals (CIs) and adjusted to the confounding variables.Results The NAT2 rs1799931 genotypes’ and alleles’ distribution frequencies were significantly different between AML cases and controls (P<0.05). The GG genotype and G allele frequencies were significantly higher than those of the AA genotype (P=0.027) and A allele (P=0.003) in AML cases if compared with the controls. GG genotype presents a higher susceptibility to AML than the AA genotype (OR: 3.765; 95% CI: 1.167–12.15), and the G allele exhibited 2.365-folds increased adjusted risk for AML if compared with the A allele (OR: 2.365; 95% CI: 1.344–4.163).Conclusion NAT2 gene rs1799931 (G857A) is associated with increased susceptibility to AML in the Egyptian population with the GG genotype and G allele carrying a higher risk for AML. Further studies should be performed to verify the present results.

NAT2 Gene Polymorphisms in Turkish Patients with Psoriasis Vulgaris.

Psoriasis is a common, chronic, and autoimmune skin disease. Factors that play a role in etiopathogenesis of psoriasis include internal factors such as genetic susceptibility and immunological factors and external factors such as stress, infection, trauma, drug, and environmental compounds. N-acetyltransferase 2 (NAT2) is a xenobiotic enzyme that is involved in the metabolism of drugs, environmental toxins, and carcinogens. In this study, we aimed to demonstrate whether the variations in the NAT2 gene lead to a predisposition to psoriasis by affecting the enzyme's ability to metabolize drugs and environmental components or not. Three polymorphisms (rs1799929, rs1799930, and rs1799931) in NAT2 gene were genotyped and compared by real-time PCR method in 260 psoriasis vulgaris patients and 200 healthy controls. There was no difference in the genotype distributions and allele frequencies of polymorphisms between psoriasis vulgaris patients and controls. When the effects of polymorphisms on the clinical features of the disease, such as onset age and severity, are assessed, it has been found that rs1799930 and rs1799929 are, respectively, associated with early onset age and severity of the disease. In conclusion, rs1799929, rs1799930, and rs1799931 polymorphisms of the NAT-2 gene do not appear to be a risk factor for the development of psoriasis. Conversely, they may have an effect on either more severe or early onset cases of the disease.

Distribution of rs1801279 and rs1799930 Polymorphisms in NAT2 Gene among Population in Kupang, Nusa Tenggara Timur, Indonesia

BACKGROUND: N-acetyltransferase-2 (NAT2) enzyme, encoded by NAT2 gene, plays a key role in metabolism of anti-tuberculosis (TB) drug isoniazid. Polymorphisms in NAT2 gene may result in different responses to TB therapy. Since TB prevalence in the eastern part of Indonesia is high, the aim of this study is to explore the distribution of NAT2 gene polymorphisms among population from Kupang, Nusa Tenggara Timur.METHODS: A total of 234 respondents were included from Kupang in 2012. Polymorphisms of NAT2 gene were examined using mass screening platform and the genotypes distribution were presented in percentage. To confirm NAT2 gene polymorphisms, polymerase chain reaction (PCR)-sequencing was performed in a subset of population.RESULTS: The polymorphisms of NAT2 gene showed that the distribution of rs1801279 for GG genotype was 100%; whereas the genotype distribution of rs1799930 for GG, GA and AA was 57%, 35.1% and 7.9%, respectively. In a subset of individuals (n13), acetylator status was well determined by PCR-sequencing, resulting in individual with wild type fast acetylator (NAT2*4; n4), intermediate (NAT2*4/*5 or NAT2*4/*6 or NAT2*4/*7; n7) and poor acetylators (NAT2*6/*6 or NAT2*7/*7; n2).CONCLUSION: The amino acid change in rs1799930 result in intermediate and poor acetylator status in Kupang population. This may lead to suboptimal response of TB therapy. Assessing acetylator status before TB therapy is important and may serve as personalized INH therapy.KEYWORDS: NAT2 gene, polymorphism, acetylator status, Kupang

Genetic polymorphisms of NAT2 and risk of acute myeloid leukemia: A case-control study.

Our purpose was to investigate the possible associations between N-acetyltransferase-2 (NAT2) gene polymorphisms and the risk of acute myeloid leukemia (AML) in Chinese Han population.A case-control study was conducted including 98 AML cases and 112 healthy controls. NAT2 gene 2 polymorphisms rs1799930 and rs1799931 were genotyped using direct sequencing. Chi-square test was performed to compare the genotype and allele distribution differences between groups. Odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between NAT2 gene polymorphisms and AML onset.A remarkable decrease trend of rs1799931 GA genotype was detected in AML patients compared with controls, whereas the ancestral GG genotype frequency increased in cases (P < .05). And the mutant A allele of rs1799931 significantly reduced the risk of AML by 0.585-fold versus the ancestral G allele carriers (OR = 0.585, 95% CI = 0.361–0.950). But the distributions of rs1799930 genotype and allele were similar between groups (P > .05).Our findings suggested that NAT2 gene polymorphism rs1799931 was associated with decreased risk of AML and was likely to be a protective factor against AML development.

Arylamine N-acetyltransferase 2 gene polymorphism in an Algerian population

Background: The arylamine N-acetyltransferase 2 (NAT2) is a key enzyme in the biotransformation of xenobiotics. NAT2 gene polymorphisms have been associated with the risk of isoniazid hepatotoxicity and these polymorphisms change among different populations.Aim: The objective of this study is to investigate NAT2 polymorphisms in order to predict the prevalence of NAT2 phenotype in an Algerian population.Subjects and methods: Genotyping of NAT2 was done using a PCR-RFLP method. Haplotype was analysed using the software package PHASE, version 2.0.Results: The major haplotypes were NAT2*5B (23.72%), NAT2*6 A (18.61%), NAT2*4 (14.60%) and NAT2*5 F (10%). The average of the expected slow acetylator phenotype was 53%.Conclusion: Our results suggest that the high frequency of slow acetylator phenotype requires investigation into its possible association with ATDH.

Polymorphisms in NAT2 (N-acetyltransferase 2) gene in patients with systemic lupus erythematosus

ObjectiveTo investigate potential associations of four substitutions in NAT2 gene and of acetylator phenotype of NAT2 with systemic lupus erythematosus (SLE) and clinical phenotypes. MethodsMolecular analysis of 481C>T, 590G>A, 857G>A, and 191G>A substitutions in the NAT2 gene was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique, from DNA extracted from peripheral blood samples obtained from patients with SLE (n=91) and controls (n=97). Results and conclusionsThe 857GA genotype was more prevalent among nonwhite SLE patients (OR=4.01, 95% CI=1.18–13.59). The 481T allele showed a positive association with hematological disorders that involve autoimmune mechanisms, specifically autoimmune hemolytic anemia or autoimmune thrombocytopenia (OR=1.97; 95% CI=1.01–3.81).

N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.

Background & objectives:Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously.Methods:Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR.Results:The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group.Interpretation & conclusions:Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.

Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity.

Background & objectives:The N-acetyltransferase 2 (NAT2) gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH).Methods:In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs.Results:Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8%) and non-DIH (77.2%) patients. However, the genotypic distribution of variant NAT2*5/*7 amongst slow-acetylator genotypes was significantly higher in DIH (56%) group as compared to non-DIH (39%) group (odds ratio 2.02; P=0.006).Interpretation & conclusions:The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

Active cigarette smoking and the risk of breast cancer at the level of N-acetyltransferase 2 (NAT2) gene polymorphisms.

The aim of our study was to assess the correlation between the tobacco exposure and NAT2 gene (rs1041983 C/T, rs1801280 T/C, rs1799930 G/A) polymorphisms in association with breast cancer development. We wanted to determine the prognostic clinical importance of these polymorphisms in association with smoking and breast cancer. For the detection of possible association between smoking, NAT2 gene polymorphisms, and the risk of breast cancer, we designed a case-controlled study with 198 patients enrolled, 98 breast cancer patients and 100 healthy controls. Ten milliliters of peripheral blood from the cubital vein was withdrawn from every patient. The HRM (high resolution melting) analysis was used for the detection of three abovementioned NAT2 gene polymorphisms. When comparing a group of women smoking more than 5 cigarettes a day with the patients smoking fewer than 5 cigarettes a day, we found out that if women were the carriers of aberrant AA genotype for rs1799930, the first group of women had higher risk of breast carcinoma than the second group. If patients were the carriers of aberrant TT genotype for rs1041983, for rs1801280CC genotype, and rs1799930AA genotype and they smoked more than 5 cigarettes a day, they had higher risk of malignant breast disease than never-smoking women. Our results confirm the hypothesis that NAT2 gene polymorphisms (rs1041983 C/T, rs1801280 T/C, and rs1799930 G/A) in association with long-period active smoking could be the possible individual risk-predicting factors for breast cancer development in the population of Slovak women.

N-Acetyltransferase 2 (NAT2) polymorphism as a risk modifier of susceptibility to pediatric acute lymphoblastic leukemia.

N-Acetyltransferases (NAT) have been known to modify the risk to a variety of solid tumors. However, the role of NAT2 polymorphism in risk susceptibility to childhood acute lymphoblastic leukemia (ALL) is still not well known. We performed a case-control study to determine if the common NAT2 polymorphisms play a role in altering susceptibility to pediatric ALL. DNA of 92 pediatric ALL patients and 312 healthy controls was analyzed for the NAT2 polymorphisms using the PCR-RFLP method. The wild-type NAT2*4 was encountered in 8.6 % of patients versus 11.8 % of controls (P = 0.23). The rapid acetylators NAT2*12 803A>G, AG, GG, and AG/GG were overrepresented in controls (P = 0.0001; odds ratio (OR) 0.22, 0.19, and 0.21 respectively). NAT2*5D 341T>C and NAT2*11A 481C>T were of comparable frequencies. For their combination, NAT2*5A, a slow acetylator, both TCTT and CCCT were overrepresented in patients (P < 0.001; OR 15.8 and 17.9 respectively). NAT2*5B (803A>G, 341T>C, 481C>T) was overrepresented in controls (P < 0.001; OR 0.12). Apparently, 803A>G ameliorated the combined effect of 341T>C and 481C>T. A similar effect was obtained with NAT2*5C (341T>A, 803A>G) (P < 0.0001; OR 0.11). For slow acetylator NAT2*7A 857G>A, GA and GA/AA were overrepresented in patients (P = 0.009 and 0.01; OR 2.74 and 2.72 respectively). NAT2*13 282C>T, NAT2*6B 590G>A, and NAT2*14A 191G>A were of comparable frequencies. NAT2 282C>A in combination with NAT2 857G>A (NAT2*7B) showed a synergistic effect in patients versus controls (P < 0.0001; OR 3.51). In conclusion, NAT2 gene polymorphism(s) with slow acetylator phenotype is generally associated with the risk of development of ALL in children.

Correlation between NAT2 gene polymorphism and cirrhotic portal hypertension in the Chinese population.

Our study aims to discuss the correlation between N-acetyltransferase 2 (NAT2) gene polymorphism and cirrhotic portal hypertension in the Chinese population for the purpose of exploring the functional significance of NAT2 gene polymorphism. From June 2010 to February 2014, a total of 212 posthepatitis B cirrhosis patients (the observation group) from the affiliated Shandong Province-owned Hospital of Shandong University diagnosed by needle biopsy of the liver, B ultrasound, or surgical operation were recruited. These 212 patients were divided into a cirrhotic portal hypertension group (PHT(+) group) (130 patients) and a simple liver cirrhosis (LC) group (PHT(-) group) (82 patients), and 172 healthy blood donors were enrolled into the control group. The polymerase chain reaction-restriction fragment length polymorphism method was adopted to detect NAT2 gene polymorphism and some related statistical analysis. In these 212 patients, four mutation alleles in the NAT2 gene (WT, M1, M2, and M3) were detected. The frequency of patients carrying NAT2 slow acetylator genotype in the observation group was higher than that in the control group, but there was no significant difference (p>0.05). However, there was a significant difference in the NAT2 slow acetylator genotype frequency between the PHT(+) group and the control group (p<0.05). The risk for the occurrence of PHT in NAT2 slow acetylator genotype carriers was more frequent than that in NAT2 rapid acetylator genotype carriers. In addition, the diameters of the portal vein and splenic vein as well as spleen thickness in NAT2 rapid acetylator genotype were obviously bigger than that in the NAT2 slow acetylator genotype. Our study provided empirical evidence that NAT2 gene polymorphism may be correlated to the formation of cirrhotic portal hypertension, and it might be used as a potential biomarker for genetic susceptibility to PHT in Chinese population.

Expression of NAT2 in immune system cells and the relation of NAT2 gene polymorphisms in the anti-tuberculosis therapy in Mexican mestizo population.

Arylamine N-acetyltransferase 2 (NAT2) metabolizes isoniazid (INH) and Single Nucleotide Polymorphisms (SNP) responsible for its activity has been reported. The aim of this study in the Mexican mestizo population was to evaluate NAT2 expression at the protein level in immune cells, as well as the distribution and frequency of six NAT2 SNPs and their association with anti-TB therapy, by measuring the plasma levels of INH and Acetyl-INH (AcINH). We performed genotyping assays of NAT2 SNPs in 40 TB patients and 121 healthy volunteers by real-time PCR. A method for detecting NAT2 in immune cells using flow cytometry was developed. Plasma concentrations of INH and AcINH were obtained by HPLC in TB patients and the Metabolic Ratio (MR) was calculated. The phenotypes obtained in the healthy volunteers were as follows; 18.87 % of subjects had the rapid acetylator phenotype, 45.45 % had the intermediate phenotype and 39.66 % exhibited the slow acetylator phenotype. In the TB patient group, 35 % of patients had the rapid acetylator phenotype, 32.5 % were intermediate and 32.5 % showed the slow acetylator phenotype. A higher expression level of NAT2 in innate immune cells from TB patients compared to those from healthy volunteers was detected (P < 0.013). In TB patients the MR showed a bimodal distribution with an antimode of 0.7, which was used as a threshold value for acetylator classification. A high correspondence between the rapid and slow acetylator phenotype with MR was demonstrated. In conclusion, the 282C>T, 341T>C, 481C>T, 590G>A, 803A>G, 857G>A SNPs of NAT2 gene provides accurate for prediction of the acetylator phenotype in Mexican mestizo population. A statistical difference was found in frequency of rapid metabolizer phenotype, which was higher in TB patients. In addition, the expression of NAT2 protein in immune cells can lead to further studies related to its functional role in the innate immune response against M. tuberculosis and other xenobiotics metabolized by this enzyme.