Association of SCN2A, ABCB1 and CYP2C19*3 with genetic susceptibility to major depressive disorder / 中华预防医学杂志

Objective: Due to genetic factors might increase the risk of depression, this study investigated the genetic risk factors of depression in Chinese Han population by analyzing the association between 13 candidate genes and depression. Methods: 439 depression patients and 464 healthy controls were included in this case-control study. Case group consisted of 158 males and 281 females, aged (29.84±14.91) years old, who were hospitalized in three departments of the affiliated Brain Hospital of Guangzhou Medical University including Affective Disorders Department, Adult Psychiatry Department and Geriatrics Department, from February 2020 to September 2021. The control group consisted of 196 males and 268 females, aged (30.65±12.63) years old. 20 loci of 13 candidate genes in all subjects were detected by MALDI-TOF mass spectrometry. Age difference was compared using the student's t-test, the distributions of gender and genotype were analyzed with Pearson's Chi-square test. The analyses of Hardy-Weinberg equilibrium, allele frequency and the genetic association of depression were conducted using the corresponding programs in PLINK software. Results: PLINK analysis showed that SCN2A rs17183814, ABCB1 rs1045642, CYP2C19*3 rs4986893 and NAT2*5A rs1799929 were associated with depression before Bonferroni correction (χ2=10.340, P=0.001; χ2=11.010, P=0.001; χ2=9.781, P=0.002; χ2=4.481, P=0.034). The frequencies of minor alleles of above loci in the control group were 12.07%, 43.64%, 2.59% and 3.88%, respectively. The frequencies of minor alleles of loci mentioned above in the case group were 17.43%, 35.99%, 5.47% and 6.04%, respectively. OR values were 1.538, 0.726, 2.178 and 1.592, respectively. After 1 000 000 permutation tests using Max(T) permutation procedure, the four loci were still statistically significant, the empirical P-value were 0.002, 0.001, 0.003 and 0.042, respectively. However, only three loci including SCN2A rs17183814, ABCB1 rs1045642 and CYP2C19 rs4986893 had statistical significance after Bonferroni correction, the adjusted P-value were 0.026, 0.018 and 0.035, respectively. Conclusion: SCN2A rs17183814, ABCB1 rs1045642 and CYP2C19*3 rs4986893 were associated with depression's susceptibility in Chinese Han population. The A allele of SCN2A rs17183814 and CYP2C19*3 rs4986893 were risk factors for depression, while the T allele of ABCB1 rs1045642 was a protective factor for depression.

Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

Clinical Pharmacogenetic Testing and Application: Laboratory Medicine Clinical Practice Guidelines

Pharmacogenetic testing for clinical applications is steadily increasing. Correct and adequate use of pharmacogenetic tests is important to reduce unnecessary medical costs and adverse patient outcomes. This document contains recommended pharmacogenetic testing guidelines for clinical application, interpretation, and result reporting through a literature review and evidence-based expert opinions for the clinical pharmacogenetic testing covered by public medical insurance in Korea. This document aims to improve the utility of pharmacogenetic testing in routine clinical settings.

Polymorphisms in NAT2 (N-acetyltransferase 2) gene in patients with systemic lupus erythematosus / Polimorfismos no gene NAT2 (N-acetiltransferase 2) em pacientes com lúpus eritematoso sistêmico

ABSTRACT Objective: To investigate potential associations of four substitutions in NAT2 gene and of acetylator phenotype of NAT2 with systemic lupus erythematosus (SLE) and clinical phenotypes. Methods: Molecular 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 conclusions: The 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).

RESUMO Objetivo: Investigar potenciais associações de quatro substituições do gene NAT2 (N-acetiltransferase 2) e do fenótipo acetilador de NAT2 com o lúpus eritematoso sistêmico (LES) e os fenótipos clínicos. Métodos: A análise molecular das substituições 481C > T, 590G > A, 857G > A e 191G > A do gene NAT2 foi feita com a técnica de PCR-RFLP, usando DNA extraído de amostras de sangue periférico obtidas de pacientes com LES (n = 91) e controles (n = 97). Resultados e conclusões: O genótipo 857GA foi mais prevalente entre pacientes com LES não brancas (OR = 4,01, IC 95% = 1,18-13,59). O alelo 481 T apresentou associação positiva com as alterações hematológicas que envolvem mecanismos autoimunes, especificamente anemia hemolítica autoimune ou trombocitopenia autoimune (OR = 1,97; IC 95% = 1,01-3,81).

Asociación entre polimorfismos del gen NAT2 y fisura labiopalatina no sindrómica en Argentina / Association between NAT2 polymorphisms with non-syndromic cleft lip with or without cleft palate in Argentina

Background: NAT genes are considered candidate genes for the genetic predisposition to non-syndromic Cleft lip with or without cleft palate (NSCLP), since they codify for N-acetyltransferases, enzymes responsible for the biotransformation of arylamines, hydrazine drugs, and a great number of toxins and carcinogens present in diet, cigarette smoke, and environment. Aim: To determine the association between alleles determining slow acetylator phenotype and the risk of NSCLP. Material and Methods: We analyzed *5 (481C>T), *6 (590G>A) and *7 (857G>A) alleles which determine the slow acetylator phenotype and *4 (wild type) allele by polymerase chain reaction/restriction fragment length polymorphism in 97 progenitor-case trios of NSCLP in Argentinian Obstetric Wards. We evaluated the transmission disequilibrium (TDT). Results: TDT showed a positive association between allele *5 and NSCLP (odds ratio = 1,6; p = 0,03). Conclusions: The presence of *5 allele is significantly higher in cases with congenital NSCLP.

NAT2 gene polymorphisms in three indigenous groups in the Colombian Caribbean Coast region / Polimorfismo del Gen NAT2 en tres grupos indígenas de la región Caribe Colombiana

Objective: To study the NAT2 gene polymorphisms 481T, 590A and 857A in the Chimila, Wiwa and Wayuu indigenous groups of the Colombian Caribbean to determine the frequencies of the alleles NAT2*4, NAT2*5, NAT2*6, and NAT2*7 and to determine the types of acetylators present in these populations. Methods: A total of 202 subjects were studied: 47 Chimila, 55 Wiwa, and 100 Wayuu. The polymorphisms were identified using a real-time PCR method for allelic discrimination designed using Taqman of Applied Biosystems. Results: The following alleles were found at the highest frequency in the following groups: the NAT2*4 allele (wild type) in the Wayuu group (55.3%), the NAT2*5 allele in the Wiwa group (34.5%), and the NAT2*7 allele in the Chimila group (24.2%). A higher frequency of the rapid acetylator status was found in the Wayuu group (31.3%) and Chimila group (29.5%) compared with the Wiwa group (12.7%). The intermediate acetylator status distribution was very similar in all three groups, and the frequency of the slow acetylator status was higher in the Wiwa group (32.7%) compared with the Chimila and Wayuu groups (20.5% and 21.2%, respectively). Conclusion: The results demonstrated the allelic distribution and pharmacogenetic differences of the three groups studied and revealed the most frequent acetylator status and phenotype. Because of the high prevalence of slow acetylators, a greater incidence of tuberculosis (TB) drug-induced hepatotoxicity is predicted in these populations, with a higher frequency in the Wiwa group.

Objetivo: Estudiar los polimorfismos tipo SNP (del inglés- single nucleotide polymorphism) 481T, 590A y 857A del gen NAT2, en los grupos indígenas Chimila, Wiwa y Wayúu del Caribe Colombiano para determinar las frecuencias de los alelos NAT2*4, NAT2*5, NAT2*6 y NAT2*7 y caracterizar el tipo de acetiladores presentes en estas poblaciones. Métodos: Se estudiaron 202 individuos en total, 47 Chimila, 55 Wiwa y 100 Wayúu. Los polimorfismos se determinaron mediante la técnica de PCR en tiempo real por el método de discriminación alélica Taqman de Applied Biosystems. Resultados: El alelo NAT2*4 (wild type) mostró una mayor frecuencia en el grupo Wayúu (55.3%), el alelo NAT2*5 en el grupo Wiwa (34.5%) y el alelo NAT2*7 en el grupo Chimila (24.2%). Se encontró una mayor frecuencia del estado acetilador rápido en el grupo Wayúu (31.3%) y en el grupo Chimila (29.5%) al compararse con el grupo Wiwa (12.7%). La distribución del estado acetilador intermedio es muy similar en los tres grupos, y para el estado acetilador lento observamos que en el grupo Wiwa la frecuencia es mayor (32.7%) con respecto a Chimila y Wayúu con 20.5% y 21.2% respectivamente. Conclusiones: Los resultados permitieron conocer la distribución alélica y el componente farmacogenético de los tres grupos estudiados; igualmente, deducir el estado acetilador y/o fenotipo más frecuente. Debido a la alta prevalencia de acetiladores lentos, se podría predecir un aumento de la incidencia de hepatotóxicidad inducida por medicamentos antituberculosos como la Isoniacida indicados en estas poblaciones y en mayor frecuencia en el grupo Wiwa.

N-acetyltransferase and cytochrome P450 2E1 gene polymorphisms and susceptibility to antituberculosis drug hepatotoxicity in an Indian population.

Background. Antituberculosis drug hepatotoxicity (ATDH) is common in India. Isoniazid, a constituent of most antituberculosis drug regimens, is metabolized by N-acetyltransferase (NAT2) and cytochrome P450 2E1 (CYP2E1) enzymes. We therefore studied the association of some single-nucleotide polymorphisms (SNPs) in these enzyme genes with ATDH. Methods. Allelic and genotypic frequencies at three SNP loci in the NAT2 gene (rs1799929, rs1799930 and rs1799931) and one locus (rs2031920) in the CYP2E1 gene were studied using restriction fragment length polymorphism in 33 patients who developed ATDH following an isoniazidcontaining antituberculosis drug regimen and 173 healthy blood donors. After confirming adherence of the control data to the Hardy–Weinberg equilibrium model, genotype and allele frequencies in the two groups were compared. Results. For SNP rs1799930 in the NAT2 gene, 7 (21%), 21 (64%) and 5 (15%) patients, and 93 (54%), 62 (36%) and 18 (10%) controls had GG, GA and AA genotypes, respectively (p=0.003; odds ratio [OR] for GA v. GG=4.50 [95% CI 1.80–11.22] and for AA v. GG=3.69 [1.05–12.93]). Allele frequency for G nucleotides for this SNP was 0.53 among patients and 0.72 among controls (OR 2.24 [1.31–3.84], p=0.007). The allele and genotype frequencies of the other NAT2 SNPs and the CYP2E1 SNP showed no significant difference between cases and controls. All the 33 patients and 151 (87%) of 173 controls had mutant allele at one or more of the three NAT2 SNP loci (p=0.03). The presence of two or more mutant alleles, a marker of slow acetylator status, was more frequent in patients (23/33 [70%]) than in controls (73/173 [42%]; OR 3.23 [95% CI 1.45–7.19], p=0.004). Conclusion. In India, the risk of ATDH is increased in persons with ‘A’ allele at SNP rs1799930 in the NAT2 gene, but is not associated with rs2031920 polymorphism in the CYP2E1 gene.

Association between polymorphisms at N-acetyltransferase 1 (NAT1) & risk of oral leukoplakia & cancer.

Background & objectives: N-acetyltransferases 1 and 2 (NAT1 and NAT2) are important enzymes for metabolism of tobacco carcinogens. Due to polymorphisms, improper activities of these enzymes might lead to the formation of DNA adducts that may modulate risk of tobacco related oral precancer and cancer. Previously, it was shown that NAT2 polymorphisms did not modulate the risk of oral precancer and cancer. We undertook this study to check whether polymorphisms at NAT1 can modulate the risk of oral leukoplakia and cancer either alone or in combination with NAT2. Methods: Genotypes at four SNPs on NAT1 were determined by TaqMan method in 389 controls, 224 leukoplakia and 310 cancer patients. Genotype data were analyzed to know haplotypes and acetylation status of individuals and, then to estimate the risk of diseases. Using our previously published NAT2 data, combination of NAT1 and NAT2 acetylation genotypes of patients and controls were also analyzed to estimate the risk of diseases. Results: Analysis of NAT1 genotype data revealed that 1088T and 1095C alleles exist in strong linkage disequilibrium (r2=0.97, P<0.0001) and SNPs are in Hardy-Weinberg Equilibrium (P=0.1). Wild type or normal acetylating and variant or rapid acetylating alleles were two major alleles (frequencies 0.62 and 0.36, respectively) present in the control population. NAT1 rapid acetylation could not modulate the risk of leukoplakia and cancer (OR=0.9, 95% CI: 0.6-1.3; OR=1.0, 95% CI: 0.7-1.4, respectively). Analysis of combined NAT1 and NAT2 acetylating data also showed no significant enhancement of the risk of diseases. Interpretation & conclusions: NAT1 rapid acetylation alone as well as combination of NAT1 rapid-NAT2 slow acetylation did not modulate the risk of oral precancer and cancer in our patient population. So, NAT1/NAT2 metabolized carcinogen products may not be involved in tobacco related oral precancer and cancer. It may be interpreted that large sample size as well as combination of polymorphisms at other candidate loci may be important to estimate the risk of a complex disease like oral cancer.

Tabaquismo, Glutation S-Transferasa, N-Acetiltransferasa 2 y riesgo de cáncer de vejiga / Tabaquism, S-Transferase Glutation, N-Acetiltrasferase 2 and bladder cancer risk

El hábito tabáquico es el factor de riesgo más conocido para cáncer de vejiga. Ciertas arilaminas presentes en el cigarrillo han sido identificadas como carcinógenos para la vejiga en humanos. El objetivo de nuestro estudio es establecer el riesgo de padecer de cáncer de vejiga en individuos fumadores, acetiladores lentos para NAT2 y genotipos nulos de GSTM1 y GSTT1. Materiales y métodos: Se reunieron en total 150 pacientes, 75 pertenecientes al grupo de carcinoma urotelial de vejiga y 75 del grupo control, en este último no se incluyeron pacientes con enfermedad neoplásica de ninguna índole. El ADN se aisló de la muestra de sangre a partir de linfocitos utilizando un kit disponible comercialmente (QIAmp DNA Blood Mini and Maxi Kit, QIAGen GMBH). Mediante el uso de técnicas de reacción en cadena de polimerasa y de restricción/ fragmentación se determinaron los polimorfismos de las enzimas: NAT2, GSTT1 y GSTM1.Resultados: Se incluyeron un total de 150 pacientes, de los cuales 75 pertenecían al grupo controly 75 al grupo de cáncer de vejiga, la media de edad del grupo de cáncer de vejiga fue 60,5 +/-11,4 y del grupo control fue 51,3 +/- 11,4. En cuanto al género en grupo de cáncer de vejiga 64 por ciento pertenecían al sexo masculino. En el grupo control 41 por ciento pertenecían al sexo masculino. Al estudiar el hábito tabáquico se halló que 51 por ciento de los pacientes del grupo de cáncer de vejiga continuaban siendo fumadores, mientras que sólo 21 por ciento fumaba en el grupo control. En el análisis de los genotipos de la enzima NAT2 en el grupo de los pacientes con cáncer de vejiga 52 por ciento resultaron acetiladores lentos, y 4 por ciento acetiladores rápidos. En el grupo control 45 por ciento de los pacientes eran acetiladores lentos y 12 por ciento acetiladores rápidos. En cuanto a la determinación de GSTT1 19 por ciento de los pacientes del grupo de cáncer de vejiga y 24 por ciento del grupo control exhibieron el genotipo nulo...

Introduction: Smoking is the most studied risk factor for bladder cancer. Certain arilamines present in cigarettes have been identified as carcinogenic for the bladder in humans. The purpose of this study is to establish the risk of bladder cancer in smokers, slow acetilators for NAT2 and none active genotypes for GSTM1 and GSTT1. Material and methods: 150 patients were studied, 75 in the group of urothelial carcinoma of the bladder and 75 in the control group. The DNA was isolated from lymphocytes of blood samples using commercially available kit (QIAmp DNA Blood Mini and Maxi Kit, QIAG en GMBH). Enzyme polymorphisms of NAT2, GSTT1 and GSTM1 were determined using techniques of polymerase chain reaction and restriction/fragmentation. Results: 150 patients were included, of who 75 belonged to the control group and 75 had bladder cancer, the average of age of the bladder cancer group was 60.5 +/- 11.4 and of the control group 51.3 +/- 11.4. Regarding gender, in the bladder cancer group 64 percent were males. In the control group 41percent were males. 51 percent of the patients in the bladder cancer group continued being smokers, whereas only 21 percent smoked in control group. In NAT2 enzyme genotype analysis the bladder cancer group 52 percent were slow acetilators, and 4 percent fast acetilators. In the control group 45 percent were slow acetilators and 12 percent fast acetilators. Regarding GSTT1 determination, 19 percent of the bladder cancer group and 24 percent of the control group showed the non-active genotype. GSTM1 showed its non-active form in 44 percent of the bladder cancer group and 48 percent of the control group. Discussion: Bladder cancer is clearly related with smoking habit. We observed a very significant relationship when evaluating smoking habit, slow acetilators for NAT2, and none-active genotypes of GSTM1 and bladder cancer...

Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22 percent (18/82) vs. 9.8 percent (6/61), odds ratio (OR), 2.86, 95 percent confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95 percent CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

Association of CYP1A1, CYP1A2, GSTM1 and NAT2 gene polymorphisms with colorectal cancer and smoking.

We investigated CYP1A1*2A, CYP1A1*2C, CYP1A2*1C, CYP1A2*1F, GSTM1 and NAT2 gene polymorphisms, involving enzymes which metabolize many carcinogens, with reference to colorectal cancer risk. The distribution of these genotypes was not associated with risk overall. However, the CYP1A1*2A T/C genotype showed a significant association with colorectal cancer risk in never-smokers (odds ratio [OR], 3.06; 95% confidence interval [95% CI], 1.11-8.40; p = 0.030). The risk of the NAT2 rapid genotype in never-smokers was also statistically significantly increased (OR, 5.38; 95%CI, 1.80-16.1; p = 0.003). Furthermore, the joint effects of NAT2 rapid plus other genotypes were associated with colorectal cancer overall (OR, 3.12; 95%CI, 1.15-8.51; p = 0.026, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, OR, 3.25; 95%CI, 1.09-9.74; p = 0.035, for NAT2 rapid plus CYP1A2*1C G/G, and OR, 4.20; 95%CI, 1.09-16.1; p = 0.037, for NAT2 rapid plus GSTM1 null, respectively). In never-smokers, the joint effects of NAT2 rapid plus other genotypes were remarkable (OR, 15.9; 95%CI, 1.87-135.8; p = 0.011, for NAT2 rapid plus combined CYP1A1*2A T/C and C/C, OR, 5.71; 95%CI, 1.49-21.9; p = 0.011, for NAT2 rapid plus combined CYP1A1*2C Ile/Val and Val/Val, and OR, 9.14; 95%CI, 2.05-40.7; p = 0.004, for NAT2 rapid plus CYP1A2*1F A/A, respectively). The joint effect of CYP1A2*1F A/A plus CYP1A2*1C G/G genotypes was also increased in never-smokers (OR, 6.16; 95%CI, 1.26-30.1; p = 0.025). Our findings suggest that the CYP1A1*2A T/C and NAT2 rapid genotypes is associated with colorectal cancer susceptibility without smoking exposure. These results also indicate that the NAT2 in combination with CYP1A1*2C, CYP1A2*1C, or GSTM1 genotypes may strongly confer susceptibility to colorectal cancer. In particular, the combination of NAT2 plus CYP1A1*2A, CYP1A1*2C, or CYP1A2*1F genotypes, and that of CYP1A2*1F plus CYP1A2*1C genotype may define a group of persons who are genetically susceptible to colorectal cancer in never smokers.

NAT2 and CYP1A2 polymorphisms and lung cancer risk in relation to smoking status.

We investigated the associations between lung cancer and the gene polymorphisms of the drug metabolizing enzymes, containing cytochrome P450 1A1 (CYP1A1), cytochrome P450 1A2 (CYP1A2), glutathione S-transferase class mu (GSTM1), and N-acetyltransferase 2 (NAT2). The study involved 113 lung cancer patients and 121 non-cancer controls divided into never, light and heavy smokers according to pack-years of smoking in Japanese by using PCR-RFLP. For light smokers, the lung cancer risk of NAT2 intermediate-slow was significantly increased [the adjusted odds ratio (OR): 10.9, 95% confidence intervals (95%CI): 1.75-67.5, P-value: 0.010]. Moreover, never smokers having joint genotypes of NAT2 intermediate-slow and CYP1A2*1F A/A was also associated with increased the lung cancer risk (OR: 4.95, 95% CI: 1.19-20.6, P-value: 0.028). We suggested that light smokers with intermediate-slow NAT2 activity were at highest risk for lung cancer and the gene-gene interaction based on intermediate-slow NAT2 activity and high CYP1A2 activity would be increased a lung cancer risk among never smokers.

Gene amplification using DNA from human spot urine samples.

The purpose of this study was to test the amplification of DNA from human urinary sediment for molecular epidemiological studies. Twenty-six urine samples were obtained from healthy volunteers. Polymerase chain reactions (PCR) for methylenetetrahydrofolate reductase (MTHFR), beta-globin, and N-acetyltransferase 2 (NAT2) was conducted using genomic DNA isolated from the urine. The MTHFR and beta-globin genes were amplified successfully from all the urine DNA samples while the NAT2 gene was amplified in 88.5% of cases. The median yield of DNA was 0.28 microg from the 10 ml urine samples, sufficient amounts of DNA being contained in urinary sediments for amplification of all three genes. This result indicates that urine can be used as a DNA source for PCR-based molecular epidemiological studies.

NAT2 gene polymorphism in bladder cancer: a study from North India

PURPOSE: This study was conducted to examine: 1) whether the NAT2 genotypes are risk factors for bladder cancer, 2) to study possible association of tobacco usage with NAT2 genotype of these patients. MATERIALS AND METHODS: This case control study was undertaken over a period of 19 months and included 101 bladder cancer patients and 110 controls. The NAT2 genotypes were identified by PCR-RFLP method in peripheral blood DNA samples. Genotypes frequencies and the association of the genotypes among patients and controls group were assessed by chi2 test and Fisher exact test. RESULTS: The NAT2 fast acetylator genotype frequency of slow or fast acetylator genotypes was not significant in bladder cancer patients alone (OR = 1.18, 95 percent CI: 0.69 - 2.03, p value = 0.583) or combination with tobacco users (OR = 0.84, 95 percent CI: 0.328 - 2.125, p value = 0.813) when compared with controls. CONCLUSION: These data demonstrate that the NAT2 fast or slow acetylators genotype did not associated with the risk of developing bladder cancer in North Indian population when compared with controls.

Antituberculosis drug-induced hepatitis: risk factors, prevention and management.

Apart from infectious or viral hepatitis, other most common non-infectious causes of hepatitis are alcohol, cholestatic, drugs and toxic materials. The most common mode that leads to liver injuries is antituberculosis drug-induced hepatitis. The severity of drug-induced liver injury varies from minor nonspecific changes in hepatic structure to fulminant hepatic failure, cirrhosis and liver cancer. Patients receiving antitubercular drug frequently develop acute or chronic hepatitis. The time required for the metabolites to reach hepatotoxic levels is much earlier with isoniazid plus rifampicin treatment than isoniazid alone and this has been shown to be synergistic rather than additive. Antituberculosis drug (ATT)-inducible cytochrome P-4502E1 (CYP2E1) is constitutively expressed in the liver. Recent studies show that polymorphism of the N-acetyltransferase 2 (NAT2) genes and glutathione-S-transferase (GST) are the major susceptibility risk factors for ATT-induced hepatitis. The hepatic NAT and GST are involved in the metabolism of several carcinogenic arylamines and drugs. The NAT2 enzyme has a genetic polymorphism in human. N-acetyltransferase 2 genes (NAT2) have been identified to be responsible for genetic polymorphism of slow and rapid acetylation in humans. Slow acetylators of NAT2 prove to develop more severe hepatotoxicity than rapid acetylators making it a significant risk factor. Deficiency of GST activity, because of homozygous null mutations at GSTM1 and GSTT1 loci, may modulate susceptibility to drug and xenobiotic-induced hepatotoxicity. Polymorphisms at GSTM1, GSTT1 and NAT2 loci had been linked to various forms of liver injury, including hepatocellular carcinoma.

Acetylator status, drug metabolism and disease.

Acetylation polymorphism, although discovered 40 years ago, still holds interest not only because many drugs and carcinogens are metabolized by acetylation in the liver but also because advances have been made in the understanding of the molecular genetics of acetylation. It is this genetic variation of drug metabolism that is one of the causes of inter-individual variation of the effect of a drug. Acetylation polymorphism relates to the metabolism of a number of arylamine and hydrazine drugs and carcinogens by cytosolic N-acetyltransferase--NAT2. In humans, 2 genes--NAT1 and NAT2--are responsible for the N-acetyltransferase activity. Studies have revealed several allelic variants of both NAT1 and NAT2. It has been suggested that some of these variants modify the individual susceptibility to disease.

N-acetyltransferase activity--a susceptibility factor in human bladder carcinogenesis.

A higher proportion of slow acetylator phenotypes has previously been found among bladder cancer patients. In the present study carried out among 77 male bladder cancer patients and 80 non-cancer controls, 59.74% of the patients and 35% of the controls were slow acetylator phenotypes (p < 0.01). The odds of developing bladder cancer was also observed to be significantly higher among smokers than non-smokers (p < 0.01). The findings suggest that slow N-acetyl phenotype is a susceptibility factor in bladder carcinogenesis.