NAT2 Slow Acetylator Genotype Research Articles

Pharmacogenetic interactions of efavirenz or rifampin and isoniazid with levonorgestrel emergency contraception during treatment of HIV or tuberculosis.

In AIDS Clinical Trials Group study A5375, a pharmacokinetic trial of levonorgestrel emergency contraception, double-dose levonorgestrel (3 mg, versus standard dose 1.5 mg) offset the induction effects of efavirenz or rifampin on plasma levonorgestrel exposure over 8 h post-dose (AUC 0-8h ). We characterized the pharmacogenetics of these interactions. Cisgender women receiving efavirenz- or dolutegravir-based HIV therapy, or on isoniazid-rifampin for tuberculosis, were followed after a single oral dose of levonorgestrel. Linear regression models, adjusted for BMI and age, characterized associations of CYP2B6 and NAT2 genotypes (which affect plasma efavirenz and isoniazid exposure, respectively) with levonorgestrel pharmacokinetic parameters. Of 118 evaluable participants, 17 received efavirenz/levonorgestrel 1.5 mg, 35 efavirenz/levonorgestrel 3 mg, 34 isoniazid-rifampin/levonorgestrel 3 mg, and 32 (control group) dolutegravir/levonorgestrel 1.5 mg. There were 73 Black and 33 Asian participants. Regardless of genotype, women on efavirenz and isoniazid-rifampin had higher levonorgestrel clearance. In the efavirenz/levonorgestrel 3 mg group, CYP2B6 normal/intermediate metabolizers had levonorgestrel AUC 0-8h values similar to controls, while CYP2B6 poor metabolizers had AUC 0-8h values of 40% lower than controls. In the isoniazid-rifampin group, NAT2 rapid/intermediate acetylators had levonorgestrel AUC 0-8h values similar to controls, while NAT2 slow acetylators had AUC 0-8h values 36% higher than controls. CYP2B6 poor metabolizer genotypes exacerbate the efavirenz-levonorgestrel interaction, likely by increased CYP3A induction with higher efavirenz exposure, making the interaction more difficult to overcome. NAT2 slow acetylator genotypes attenuate the rifampin-levonorgestrel interaction, likely by increased CYP3A inhibition with higher isoniazid exposure.

Occupational exposures and genetic susceptibility to lung cancer and pleural mesothelioma: a systematic review


 Background
 The risk of occupationally related lung cancer, as well as pleural mesothelioma, in association with genetic polymorphisms, has been investigated with contradictory results.
 This systematic review aims to summarize the current knowledge on the relationship between genetic polymorphisms, occupational exposures, and lung cancer and pleural mesothelioma.
 Methods
 We searched MEDLINE, ISI Web of science, and SCOPUS online databases for all articles published in English language up to September 2016. Studies were considered eligible if they had assessed the association between occupational exposures and lung cancer/pleural mesothelioma in relation to genetic polymorphisms.
 Results
 Sixteen studies were included, of which eleven on lung cancer and six on mesothelioma, of which one was in common. NAT2 slow acetylator genotype confers an increased risk of pleural mesothelioma in subjects exposed to asbestos (OR=2.10; 95% CI=1.10-4.10), especially in combination with the GSTM1 null genotype (OR=3.60; 95% CI=1.30-9.60). GSTT1 null and CYP1A1 Msp1 T6235C (T/C+C/C) genotype carriers exposed to arsenic, uranium, asbestos and other chemical agents have an increased risk of lung cancer respect to not exposed wild type genotypes (OR=1.33; 95% CI=0.67-2.64, OR=2.20; 95% CI=1.11-4.35, respectively).
 Conclusion
 Genetic polymorphisms might modulate individual susceptibility to lung cancer and pleural mesothelioma in occupationally exposed subjects.

NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis.

NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group. We aim to prove an association of the NAT2 ultra-slow acetylators with the risk of ATDILI. Systematic review and meta-analysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultra-slow acetylators up to 31 October 2016. Meta-analysis of 18 studies with 822 ATDILI cases and 4630 controls was carried out in the RevMan software, version 5.3 with fixed-effect (low heterogeneity) and random effect (moderate to high heterogeneity) methods. The strong associations between each NAT2 slow acetylator genotypes and ATDILI were confirmed in meta-analysis except for NAT2*5B/*5B [odds ratio (OR): 1.69; 95% confidence interval (CI): 0.96-2.95; P=0.0679]. The NAT2 ultra-slow acetylators contribute to higher risk of ATDILI (OR: 3.60; 95% CI: 2.30-5.63; P=1.76E-08) than all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.20-3.57; P=5.73E-18) as well as fast acetylators. Additional in-vitro study using isoniazid as a substrate supports the existence of ultra-slow acetylator alleles (NAT2*6A and NAT2*7B). This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.

Genotype and allele frequencies of isoniazid-metabolizing enzymes NAT2 and GSTM1 in Latvian tuberculosis patients.

Pharmacogenomic testing of tuberculosis drug-metabolizing enzyme genes was proposed as a strategy to identify patients at risk for suboptimal responses to medications. However, variations of the genotype frequencies among ethnic groups exist and new alleles are been identified. The aim of this study was to identify polymorphisms of genes encoding metabolic enzymes NAT2 and GSTM1 in tuberculosis patients in Latvia and to estimate the frequency of NAT2 slow acetylator and GSTM1 null genotypes. In total, 85 DNA samples were genotyped, all individuals were Caucasian. An ethnic heterogeneity reflecting the multiethnic population of the country was observed. 49 patients were Latvians, 30 were Russians and 6 of other ethnicity. In total, 7 NAT2 alleles were identified: *4, *5, *6, *7, *11, *12, * and *13. The most frequent was the slow acetylation allele NAT2*6 (frequency 0.388) followed by the slow acetylation allele NAT2*5 and the rapid acetylation allele NAT2*4 (frequencies 0.306 and 0.194, respectively). The predominance of slow (51.8%) and intermediate (43.5%) acetylators compared with rapid acetylators (4.7%) was observed. The GSTM1 null genotype was detected in 48.2% of tuberculosis patients. When subgroup analysis was performed according to ethnicity, the results showed that neither NAT2 allele frequencies nor GSTM1 null genotype frequency did not differ significantly in TB patients of Latvian or Russian ethnicity. Overall, genotyping results were similar with previous reports of a NAT2 gene variation and GSTM1 null genotype frequency in Caucasians. Our findings have a contribution for the pharmacogenetics-based tuberculosis therapy in Latvia in future.

The role of genotypes that modify the toxicity of chemical mutagens in the risk for myeloproliferative neoplasms.

Background: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs.

Abstract 2222: Synergistic effects of NAT2 and GSTT1 null polymorphism in lung cancer: a study from North India

Abstract Purpose: Polymorphism in carcinogen detoxification enzymes, NAT2 and GSTT1, has been suggested as susceptibility factor for DNA damage and lung cancer. However, little information is available on DNA adduct burden in lung tissue and polymorphisms in NAT2 and GSTs gene. We investigated the independent and combined effect of metabolic gene polymorphisms NAT2 and GSTs in lung cancer north India patients. Aim: Present study was conducted to examine: 1) whether GSTT1 Null and NAT2 genotypes have combined risk factors for Lung cancer, 2) To study possible association of tobacco smoking with NAT2 and GSTT1 null genotype of these patients. Materials and Methods: This case control study was undertaken over a period of 19 months and included 100 Lung cancer patients and 145 controls. The GSTT1 Null and 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 X2 test and Binary Logistic regression. Results: The NAT2 slow acetylator genotype frequency of slow or fast acetylator genotypes was not significant in lung cancer patients alone (OR = 1.18, 95% CI: 0.69 - 2.03, p value = 0.583).when we combined GSTT1Null/NAT2 slow, then we found no significant association (OR = 0.85, 95% CI: 0.47 - 1.54, p value = 0.610) between case and controls. While on comparing data with smoker as well non-smoker NAT2 polymorphism have no association but GSTT1 null have significant association (P=0.004) in smoker patients. Conclusion: These data demonstrate that there have no combined affect GSTT1 Null NAT2 slow acetylator genotype did not associated with the risk of developing lung cancer in North Indian population when compared with controls. Note: This abstract was not presented at the meeting. Citation Format: Rajni Kant Shukla, Surya Kant, Sandeep Bhattacharya, Balraj K. Mittal. Synergistic effects of NAT2 and GSTT1 null polymorphism in lung cancer: a study from North India. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2222. doi:10.1158/1538-7445.AM2014-2222

382 Occupational and genetic risk factors for myeloproliferative neoplasms (MPN): A case-control study

ObjectivesThe aetiology of a rare category of myeloproliferative neoplasms (MPN), bone marrow diseases with an excess of blood cells, is currently unknown. An MPN cluster in northeastern Pennsylvania allowed investigation...

Pharmacogenetic & Pharmacokinetic Biomarker for Efavirenz Based ARV and Rifampicin Based Anti-TB Drug Induced Liver Injury in TB-HIV Infected Patients

BackgroundImplication of pharmacogenetic variations and efavirenz pharmacokinetics in concomitant efavirenz based antiviral therapy and anti-tubercular drug induced liver injury (DILI) has not been yet studied. We performed a prospective case-control association study to identify the incidence, pharmacogenetic, pharmacokinetic and biochemical predictors for anti-tubercular and antiretroviral drugs induced liver injury (DILI) in HIV and tuberculosis (TB) co-infected patients.Methods and FindingsNewly diagnosed treatment naïve TB-HIV co-infected patients (n = 353) were enrolled to receive efavirenz based ART and rifampicin based anti-TB therapy, and assessed clinically and biochemically for DILI up to 56 weeks. Quantification of plasma efavirenz and 8-hydroxyefaviernz levels and genotyping for NAT2, CYP2B6, CYP3A5, ABCB1, UGT2B7 and SLCO1B1 genes were done. The incidence of DILI and identification of predictors was evaluated using survival analysis and the Cox Proportional Hazards Model. The incidence of DILI was 30.0%, or 14.5 per 1000 person-week, and that of severe was 18.4%, or 7.49 per 1000 person-week. A statistically significant association of DILI with being of the female sex (p = 0.001), higher plasma efavirenz level (p = 0.009), efavirenz/8-hydroxyefavirenz ratio (p = 0.036), baseline AST (p = 0.022), ALT (p = 0.014), lower hemoglobin (p = 0.008), and serum albumin (p = 0.007), NAT2 slow-acetylator genotype (p = 0.039) and ABCB1 3435TT genotype (p = 0.001).ConclusionWe report high incidence of anti-tubercular and antiretroviral DILI in Ethiopian patients. Between patient variability in systemic efavirenz exposure and pharmacogenetic variations in NAT2, CYP2B6 and ABCB1 genes determines susceptibility to DILI in TB-HIV co-infected patients. Close monitoring of plasma efavirenz level and liver enzymes during early therapy and/or genotyping practice in HIV clinics is recommended for early identification of patients at risk of DILI.

Smoking and Polymorphisms in Xenobiotic Metabolism and DNA Repair Genes are Additive Risk Factors Affecting Bladder Cancer in Northern Tunisia

Cancer epidemiology has undergone marked development since the nineteen-fifties. One of the most spectacular and specific contributions was the demonstration of the massive effect of smoking and genetic polymorphisms on the occurrence of bladder cancer. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). DNA repair is essential to an individual's ability to respond to damage caused by tobacco carcinogens. Alterations in DNA repair genes may affect cancer risk by influencing individual susceptibility to this environmental exposure. Polymorphisms in NAT2, GST and DNA repair genes alter the ability of these enzymes to metabolize carcinogens or to repair alterations caused by this process. We have conducted a case-control study to assess the role of smoking, slow NAT2 variants, GSTM1 and GSTT1 null, and XPC, XPD, XPG nucleotide excision-repair (NER) genotypes in bladder cancer development in North Tunisia. Taken alone, each gene unless NAT2 did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotypes, the NAT2*5/*7 diplotype was found to have a 7-fold increased risk to develop bladder cancer (OR = 7.14; 95% CI: 1.30-51.41). However, in tobacco consumers, we have shown that Null GSTM1, Wild GSTT1, Slow NAT2, XPC (CC) and XPG (CC) are genetic risk factors for the disease. When combined together in susceptible individuals compared to protected individuals these risk factors give an elevated OR (OR = 61). So, we have shown a strong cumulative effect of tobacco and different combinations of studied genetic risk factors which lead to a great susceptibility to bladder cancer.

Genetic Susceptibility to Bladder Cancer Risk and Outcome

Bladder cancer is an excellent model for studying genetic susceptibility and gene-environment interaction in cancer etiology. The candidate gene approach found NAT2 slow acetylator and GSTM1-null genotypes to be bladder cancer susceptibility loci and also demonstrated interactions between these two genotypes and smoking in modulating bladder cancer risk. Recent genome-wide association studies identified at least eight novel genetic susceptibility loci for bladder cancer. Genetic determinants of clinical outcomes have been inconclusive. The future directions are to identify more genetic susceptibility loci for bladder cancer risk and outcome through a genome-wide association study approach, identify the causal genes and variants, study the biological mechanisms underlying the association between the causal variants and bladder cancer risk, detect gene-environment interactions and incorporate genetic knowledge into clinically applicable risk prediction models to benefit patients and public health.

Synergistic Effects ofNAT2slow andGSTM1null Genotypes on Carcinogen DNA Damage in the Lung

Polymorphisms in carcinogen detoxification enzymes, NAT2 and GSTM1, have been suggested as susceptibility factors for DNA damage and lung cancer. However, little information is available on DNA adduct burden in the lung tissue and polymorphisms in NAT2 and GST genes. We investigated the independent and combined effects of the metabolic gene polymorphisms of NAT2 and GSTs on DNA adduct formation in different tissues (lung and blood) in lung cancer patients. DNA adducts were measured in lung and blood by the (32)P-postlabeling assay. Multiple regression models were used to assess adjusted percent change in DNA adduct levels associated with GST and NAT2 genotypes. After adjusting for potential confounders, as well as for other GST gene variants, lung adduct levels significantly increased by 150.3% [95% confidence interval (95% CI), 35.4-362.6%] for the GSTM1 null and by 73.9% (95% CI, -3.2% to 212.4%) for the NAT2 slow acetylator genotype, respectively. No association was seen with polymorphisms of other GST genes such as GSTT1 and GSTP1. The high-risk group, the combined GSTM1 null plus NAT2 slow, had significantly enhanced levels of lung adducts by 295% (95% CI, 72.7-803.5%) over those associated with single genes, suggesting a synergistic effect on DNA damage in the target lung tissue. The increase in DNA adduct levels in lung is associated with the GSTM1 null and NAT2 slow genotypes alone or in combination. These results suggest that GSTM1 and NAT2 genotypes play an independent and interactive role in the formation of carcinogen DNA adduct in the lung.

Combined effect of smoking and inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 on bladder cancer in a Tunisian population

Cigarette smoking is the predominant risk factor for bladder cancer in males and females. The tobacco carcinogens are metabolized by various xenobiotic metabolizing enzymes, such as the super-families of N-acetyltransferases (NAT) and glutathione S-transferases (GST). Polymorphisms in NAT and GST genes alter the ability of these enzymes to metabolize carcinogens. We have conducted this case-control study to assess the role of smoking, slow NAT2 variants, and GSTM1 and GSTT1 null genotypes in bladder cancer development in North Tunisia. In all groups of patients, we have shown that GSTM1 and GSTT1 null genotypes did not appear to be a factor affecting bladder cancer susceptibility. For the NAT2 slow acetylator genotype, the NAT2∗5/∗7 diplotype was found to have a 7-fold increased risk of bladder (OR=7.14; 95% CI: 1.30–51.41). Furthermore, we found that NAT2 slow acetylator individuals temporarily carrying wild-type GSTT1 or GSTM1 null genotypes have a strong increased risk of bladder cancer (OR= 26 and 22.17, respectively). This cumulative effect was estimated at 12 for smokers harboring slow or an intermediate NAT2, GSTM1 null, and wild-type GSTT1 genotypes compared to non-smokers carrying rapid NAT2, wild-type GSTM,1 and GSTT1 null genotypes ( p=0.02; OR=12; CI 95% 1–323.76).

Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) Polymorphisms in Breast Carcinoma

BackgroundXenobiotic Metabolizing Enzymes (XMEs) contribute to the detoxification of numerous cancer therapy-induced products. This study investigated the susceptibility and prognostic implications of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene polymorphisms in breast carcinoma patients.MethodsThe authors used polymerase chain reaction and restriction enzyme digestion to characterize the variation of the CYP2E1, CYP2C19, CYP2D6, mEH and NAT2 gene in a total of 560 unrelated subjects (246 controls and 314 patients).ResultsThe mEH (C/C) mutant and the NAT2 slow acetylator genotypes were significantly associated with breast carcinoma risk (p = 0.02; p = 0.01, respectively). For NAT2 the association was more pronounced among postmenopausal patients (p = 0.006). A significant association was found between CYP2D6 (G/G) wild type and breast carcinoma risk only in postmenopausal patients (p = 0.04). Association studies of genetic markers with the rates of breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) revealed among all breast carcinoma patients no association to DFS but significant differences in OVS only with the mEH gene polymorphisms (p = 0.02). In addition, the mEH wild genotype showed a significant association with decreased OVS in patients with axillary lymph node-negative patients (p = 0.03) and with decreasesd DFS in patients with axillary lymph node-positive patients (p = 0.001). However, the NAT2 intermediate acetylator genotype was associated with decreased DFS in axillary lymph node-negative patients.ConclusionThe present study may prove that polymorphisms of some XME genes may predict the onset of breast carcinoma as well as survival after treatment.

Epidemiology of urinary bladder cancer: from tumor development to patient’s death

Urinary bladder cancer (UBC) ranks ninth in worldwide cancer incidence. It is more frequent in men than in women. We review the main established/proposed factors, both environmental and genetic, associated with bladder cancer etiology and prognosis. Data were extracted from previous reviews and original articles identified from PubMed searches, reference lists, and book chapters dealing with the reviewed topics. Evaluation and consensus of both the contribution of each factor in bladder cancer burden and the appropriateness of the available evidences was done during an ad hoc meeting held during the 18th Congress of the European Society for Urological Research. Cigarette smoking and specific occupational exposures are the main known causes of UBC. Phenacetin, chlornaphazine and cyclophosphamide also increase the risk of bladder cancer. Chronic infection by Schistosoma haematobium is a cause of squamous cell carcinoma of the bladder. NAT2 slow acetylator and GSTM1 null genotypes are associated with an increased risk of this cancer. Vegetables and fresh fruits protect against this tumor. Regarding prognosis, there is little knowledge on the predictive role of environmental exposures and genetic polymorphisms on tumor recurrence and progression and patient's death. Although active tobacco smoking is the most commonly studied factor, no definitive conclusion can be drawn from the literature. More research is needed regarding the effect of complex etiological factors in bladder carcinogenesis. Subgroup analysis according to stage, grade, and molecular features may help in identifying specific etiological and prognostic factors involved in different bladder cancer progression pathways.

分子疫学と尿路上皮がん

Tobacco smoking is the main cause of human urothelial cancer. It has been suggested that genetic susceptibility may contribute to the risk, because only a small portion of smokers develops urothelial cancer. Tobacco smoke contains many carcinogens which are activated or detoxified by phase-I or phase-II enzymes. The concentration of the ultimate carcinogen, which will react with DNA, is determined by the rate of activation and detoxification. Individuals with an increased rate of activation or a decreased rate of detoxification have a slightly higher level of bulky carcinogen-DNA adduct in the urothelial mucosa. Thus metabolic polymorphisms have been recognized as important determinants of carcinogen susceptibility, and recent efforts have shown that inter-individual differences in specific cytochrome P450 enzymes (CYPs), N-acetyltransferases (NAT), glutathione S-transferases (GST) and sulfotransferases (SULT) are often disproportionately represented in epidemiological studies between urothelial cancer cases and controls. It has been revealed that GSTM1 null genotype or NAT2 slow acetylator genotype may be associated with a small increase in urothelial cancer risk. Associations between other polymorphisms of metabolic enzymes and urothelial cancer are not well-known or are inconsistent. To reveal these associations, further well-designed and large-scale studies are needed.

CYP1A1 and CYP1B1 genetic polymorphisms, smoking and breast cancer risk in a Finnish Caucasian population

We investigated the associations between two CYP1A1 polymorphisms (Ile462Val and Thr461Asn) and one CYP1B1 polymorphism (Leu432Val) and breast cancer risk. The study population consisted of 483 breast cancer patients and 482 healthy population controls, all of homogenous Finnish origin. No statistically significant overall associations were found between the CYP1A1 and CYP1B1 genotypes and breast cancer risk. However, a significant increase in the breast cancer risk was seen for women who had smoked 1-9 cigarettes/day and carried the CYP1B1 432Val allele; the OR was 2.6 (95% CI 1.07-6.46) for women carrying the Leu/Val genotype and 5.1 (95% CI 1.30-19.89, P for trend 0.005) for women with the Val/Val genotype compared to similarly smoking women homozygous for the 432Leu allele. Furthermore, when CYP1B1 genotypes were combined with the previously analyzed N-acetyl transferase (NAT2) genotypes, a significant increase in breast cancer risk was found among women who had at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype (OR 1.52; 95% CI 1.03-2.24) compared to women carrying a combination of CYP1B1 Leu/Leu and NAT2 rapid acetylator genotypes. This risk was seen to be confined to ever smokers; the OR was 2.46 (95% CI 1.11-5.45) for ever smokers carrying at least one CYP1B1 432Val allele together with the NAT2 slow acetylator genotype compared to ever smokers with the CYP1B1 Leu/Leu and NAT2 rapid acetylator genotype combination. Our results suggest that the CYP1B1 polymorphism may be an important modifier of breast cancer risk in Finnish Caucasian women who have been exposed to tobacco smoke and/or carry the NAT2 slow acetylator genotype.

N‐acetyltransferase 2 polymorphism in patients with Diabetes Mellitus

The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. Human arylamine NATs are known to exist as two isoenzymes, NAT1 and NAT2. The objective of this study was to identify whether the genetic polymorphism of NAT2 plays a role in susceptibility to Diabetes Mellitus (DM). Ninety-seven patients with DM and 104 healthy controls were enrolled in the study. NAT2*5A, NAT2*6A, NAT2*7A/B and NAT2*14A polymorphisms were detected by using real time PCR with LightCycler (Roche Diagnostics GmbH, Mannheim, Germany). According to our data, the NAT2*5A and NAT2*6A mutant genotypes and NAT2*14A heterozygous genotype were associated with an increased risk of development of DM (OR = 47.06; 95%CI: 10.55-209.77 for NAT 2*5A, OR = 18.48; 95%CI: 3.83-89.11 for NAT2*6A and OR = 18.22; 95%CI: 6.29-52.76 for NAT2*14A). However, the NAT2*7A/B gene polymorphism carried no increased risk for developing DM disease. After grouping according to phenotypes as either slow or fast acetylators, NAT2*6A slow acetylator was found to be a significant risk factor for DM (OR = 6.09; 95%CI: 1.99-18.6, p = 0.02). The results indicate that NAT2 slow acetylator genotypes may be an important genetic determinant for DM in the Turkish population.

NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses

Many reported associations between common genetic polymorphisms and complex diseases have not been confirmed in subsequent studies. An exception could be the association between NAT2 slow acetylation, GSTM1 null genotype, and bladder-cancer risk. However, current evidence is based on meta-analyses of relatively small studies (range 23-374 cases) with some evidence of publication bias and study heterogeneity. Associations between polymorphisms in other NAT and GST genes and bladder-cancer risk have been inconsistent. We investigated polymorphisms in NAT2, GSTM1, NAT1, GSTT1, GSTM3, and GSTP1 in 1150 patients with transitional-cell carcinoma of the urinary bladder and 1149 controls in Spain; all the participants were white. We also carried out meta-analyses of NAT2, GSTM1, and bladder cancer that included more than twice as many cases as in previous reports. In our study, the odds ratios for bladder cancer for individuals with deletion of one or two copies of the GSTM1 gene were 1.2 (95% CI 0.8-1.7) and 1.9 (1.4-2.7) respectively (p for trend <0.0001). Compared with NAT2 rapid or intermediate acetylators, NAT2 slow acetylators had an increased overall risk of bladder cancer (1.4 [1.2-1.7]) that was stronger for cigarette smokers than for never smokers (p for interaction 0.008). No significant associations were found with the other polymorphisms. Meta-analyses showed that the overall association for NAT2 was robust (p<0.0001), and case-only meta-analyses provided support for an interaction between NAT2 and smoking (p for interaction 0.009). The overall association for GSTM1 was also robust (p<0.0001) and was not modified by smoking status (p=0.86). The GSTM1 null genotype increases the overall risk of bladder cancer, and the NAT2 slow-acetylator genotype increases risk particularly among cigarette smokers. These findings provide compelling evidence for the role of common polymorphisms in the aetiology of cancer. Although the relative risks are modest, these polymorphisms could account for up to 31% of bladder cancers because of their high prevalence.

N‐Acetyltransferase‐2, glutathione S‐transferase M1 and T1 genetic polymorphisms, cigarette smoking and hepatocellular carcinoma: A case‐control study

Our aim was to evaluate the role of N-acetyltransferase (NAT2) and glutathione S-transferase M1 and T1 (GSTM1 and GSTT1) polymorphisms in hepatocellular carcinoma (HCC) according to cigarette smoking, taking into account hepatitis B (HBV) and C (HCV) viral infection as well as alcohol consumption. A hospital-based case-control study was conducted in 2 areas of north Italy. Cases (n = 200) were patients hospitalized for HCC, and controls (n = 400) were patients admitted for reasons other than liver disease, neoplasms and tobacco- and alcohol-related diseases. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism-based method. The putative risk genotypes NAT2 slow acetylator, GSTM1 null and GSTT1 null were not associated with HCC (OR = 1.3, 95% CI 0.8-2.0; OR = 1.0, 95% CI 0.6-1.5; OR = 0.8, 95% CI 0.4-1.4, respectively). Although not statistically significant, an increase in HCC risk was observed among light smokers (1-20 pack-years) carrying GSTT1 null (OR = 1.7, 95% CI 0.6-4.7) and NAT2 slow acetylator (OR = 1.3, 95% CI 0.6-3.0) genotypes. In conclusion, there was no evidence for a gene-environment interaction in HCC risk for GSTM1, GSTT1 and NAT2 genotypes.

Effects of N-acetyl transferase 1 and 2 polymorphisms on bladder cancer risk in Caucasians

Cigarette smoking is the predominant risk factor for bladder cancer (BC). Major carcinogens present in tobacco smoke include a number of aromatic and heterocyclic amines. Two distinct N-acetyl transferase (NAT) enzymes, NAT1 and NAT2, play important roles in the bio-activation and detoxification of these carcinogens. Genes encoding NAT1 and NAT2 are highly polymorphic among human populations, and these polymorphisms result in rapid or slow acetylator phenotypes. Recent studies have suggested that variant alleles leading to slow acetylation by the NAT2 enzyme or rapid acetylation by the NAT1 enzyme constitute possible risk factors for bladder cancer. In this case–control study, we sought to determine whether NAT1 and NAT2 polymorphisms are associated with bladder cancer risk in the largest sample size to date. PCR-RFLP assay was used to determine the presence of NAT1 and NAT2 polymorphisms in 507 Caucasian BC patients and 513 age-, gender-, and ethnicity-matched healthy controls. Overall, we found no significant association between BC risk and NAT1 NAT1 * 10 allele (OR = 0.95; 95% CI 0.73–1.25). However, our data suggested that NAT2 slow acetylator genotypes were associated with a significant increased risk of BC (OR = 1.31; 95% CI, 1.01–1.70). This elevated risk appeared more evident in older individuals (OR = 1.41; 95% CI, 1.01–1.98) than in younger individuals (OR = 1.15; 95% CI, 0.76–1.74). Moreover, the risk was greater for heavy smokers (OR = 2.11; 95% CI, 1.33–3.35) than light smokers (OR = 0.96; 95% CI, 0.61–1.53) and never smokers (OR = 1.23; 95% CI, 0.79–1.90). Finally, a joint effect between NAT2 slow acetylators and heavy smokers was observed. Using never smokers with NAT2 rapid acetylator genotypes as a reference group, heavy smokers with NAT2 slow acetylator genotypes showed an over six-fold increase in BC risk. In a multiplicative interaction model, the interaction term was statistically significant ( P = 0.02). Our data suggest that having a NAT2 slow acetylator genotype is a significant risk factor for BC, particularly in smokers and older individuals.