NAT2 Polymorphisms Research Articles

Lack of association between NAT2 polymorphism and prostate cancer risk: a meta-analysis and trial sequential analysis.

Previous studies have investigated the association between NAT2 polymorphism and the risk of prostate cancer (PCa). However, the findings from these studies remained inconsistent. Hence, we performed a meta-analysis to provide a more reliable conclusion about such associations. In the present meta-analysis, 13 independent case-control studies were included with a total of 14,469 PCa patients and 10,689 controls. All relevant studies published were searched in the databates PubMed, EMBASE, and Web of Science, till March 1st, 2017. We used the pooled odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association between NAT2*4 allele and susceptibility to PCa. Subgroup analysis was carried out by ethnicity, source of controls and genotyping method. What's more, we also performed trial sequential analysis (TSA) to reduce the risk of type I error and evaluate whether the evidence of the results was firm. Firstly, our results indicated that NAT2*4 allele was not associated with PCa susceptibility (OR = 1.00, 95% CI= 0.95–1.05; P = 0.100). However, after excluding two studies for its heterogeneity and publication bias, no significant relationship was also detected between NAT2*4 allele and the increased risk of PCa, in fixed-effect model (OR = 0.99, 95% CI= 0.94–1.04; P = 0.451). Meanwhile, no significant increased risk of PCa was found in the subgroup analyses by ethnicity, source of controls and genotyping method. Moreover, TSA demonstrated that such association was confirmed in the present study. Therefore, this meta-analysis suggested that no significant association between NAT2 polymorphism and the risk of PCa was found.

Vitamin K epoxide reductase complex subunit 1 (VKORC1): A pharmacogenomic predictor of response and survival in patients (pts) on triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-Cet) for initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU trial OPTILIV).

2569 Background: The HAI of Irinotecan-Oxaliplatin-5-Fluorouracil (IFO) with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts (Lévi, Ann Oncol 2016). Methods: To identify pharmacogenomic predictors of outcomes, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA). Relations between SNPs and tumor response, R0+R1, survival, and toxicities were tested using adjusted Mann Whitney, Fisher Exact, Log Rank tests and Hardy-Weinberg Equilibrium. Results: Pts (16F;36M; 33-76 yo; WHO performance status 0-1) received protocol treatment as 2nd (21 pts) or 3-4thline (31 pts). VKORC1 SNPs in promoter (rs9923231) and intron (rs9934438) were consistently associated with early and objective responses, and overall survival. For rs9923231, T/T (N = 8) as compared to C/T (N = 21) had greatest chance of achieving early response (50% vs 5%, p = 0.029) or 4-y survival (46% vs 0%, p = 0.006). VKORC1 SNPs also related to HA thrombosis (rs992331, T/T, 77% vs C/C, 30%, p = 0.04). In contrast, NAT2 SNPs (rs1041983 and rs1801280) were associated with up to 5-fold differences in R0-R1 resection rate. Statistically significant associations (p < 0.05) of SNPs with clinical outcomes were found for oxydo-reduction (CYP2E1 and HA thrombosis; CYP2C9 and diarrhea; CYP2C19 and diarrhea, fatigue, and early response), conjugation (UGT1A1 and diarrhea; NAT2 and fatigue); and transport (ABCB1 or SLC0B3 and neutropenia; SLC22A1 and diarrhea; SLC 15A2 and early response). Conclusions: VKORC1 was highlighted for the first time, as a pharmacogenomic predictor of HAI efficacy for LM-CRC. Conversion-to-resection was associated with NAT2 polymorphism. VKORC1 γ-carboxylates vitamin K-dependent proteins. Its polymorphism guides personalized warfarin dosing. VKORC1 SNPs determination could help identify the uLM-CRC pts who best benefit from intensive HAI therapy. Clinical trial information: NCT00852228.

Association Between NAT2 Polymorphisms and Prostate Cancer

Background: NAT2 enzyme involved in bioconversion of aromatic amines, heterocyclic arylamines and certain drugs into electrophilic ions that can be important initiators in tumorigenesis process. Objectives: The aim of this study was to assess the possible association between NAT2 polymorphisms (857 G > A, 481 T > C, and 590 G > A) and risk of prostate cancer (PC). Methods: Totally, 207 benign prostate hyperplasia (BPH) and 147 PC Iranian patients were evaluated. NAT2 genotypes were detected by restriction fragment length polymorphism (RFLP). Multiple logistic regression models were used to estimate the odds ratios for the association between presence of each genotype and developing PC. Results: For NAT2 G857A, the frequency of AA and AG genotypes was lower among PC patients compared to those without it (1.01% vs. 0 and 55.88% vs. 54.55%, respectively; P = 0.7). For NAT2 T481c, the odds ratios for the association of TT and CT genotypes with PC were 0.65 and 0.55, respectively, which were not statistically significant (P = 0.5 and P = 0.09, respectively). For NAT2 G590a, both AA (11.11% vs. 12.87%) and AG (45.83% vs. 52.48%) genotypes were significantly more common among PC patients compared to BPC patients (P = 0.008). However, none of the relevant odds ratios were statistically significant (OR = 2.2, P = 0.2 and OR = 1.72, P = 0.1, respectively). Among PC patients, CT genotype of T481C caused more than 4-fold significant increase in the risk of developing advanced stages of PC. Conclusions: Our study represented credible evidence that carrying G857A, G590A and T481C polymorphisms of NAT2 may not affect developing PC, its grading or invasion, but heterozygote genotype of T481C polymorphism (Rapid acetylator) can be associated with more advanced stages of cancer earlier in life. Further longitudinal studies with larger sample sizes are needed to more precisely assess the genetic risk factors of PC.

Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil

Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p=0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR=26.0; 95%CI:3.1-217.6; OR=3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR=10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes.

Genetic associations of S282T polymorphism of the gene Nat2 with parkinsonism: clinical and molecular comparisons

Genetic associations of S282T polymorphism of the gene Nat2 with parkinsonism: clinical and molecular comparisons

Lifestyle and clinical determinants of skin autofluorescence in a population-based cohort study.

BackgroundSkin autofluorescence (SAF) is a noninvasive marker of advanced glycation end products (AGEs). In diabetes, higher SAF levels have been positively associated with long‐term complications, cardiovascular morbidity and mortality. Because little is known about the factors that influence SAF in nondiabetic individuals, we assessed the association of clinical and lifestyle parameters with SAF as well as their interactions in a large‐scale, nondiabetic population and performed the same analysis in a type 2 diabetic subgroup.MethodsIn a cross‐sectional study in participants from the LifeLines Cohort Study, extensive clinical and biochemical phenotyping, including SAF measurement, was assessed in 9009 subjects of whom 314 (3·5%) subjects with type 2 diabetes.ResultsMean SAF was 2·04 ± 0·44 arbitrary units (AU) in nondiabetic individuals and 2·44 ± 0·55 AU in type 2 diabetic subjects (P < 0·0001). Multivariate backward regression analysis showed that in the nondiabetic population, SAF was significantly and independently associated with age, BMI, HbA1c, creatinine clearance, genetic polymorphism in NAT2 (rs4921914), current smoking, pack‐years of smoking and coffee consumption. In the type 2 diabetic group, a similar set of factors was associated with SAF, except for coffee consumption.ConclusionsIn addition to the established literature on type 2 diabetes, we have demonstrated that SAF levels are associated with several clinical and lifestyle factors in the nondiabetic population. These parameters should be taken into consideration when using SAF as a screening or prediction tool for populations at risk for cardiovascular disease and diabetes.

GENOTYPE POLYMORPHISMS OF NAT2 AND CYP2E1 GENES ASSOCIATED WITH DRUG INDUCED LIVER INJURY (DILI) IN INDONESIAN TUBERCULOSIS PATIENTS

Currently, Indonesia is in the fifth rank of highest TB prevalence over the world. One of the TB problem is low patients’ adherence due to the oral antituberculosis induced hepatotoxicity. Polymorphisms of NAT2 and CYP2E1 genes had important role in the isoniazid (INH)-induced hepatotoxicity. The aim of this study was to evaluate the polymorphisms profile of NAT2 and CYP2E1 genes associated with hepatotoxicity induced by INH. We used cohort design in Public Health Centers and Lung Clinics of Yogyakarta and Lampung. The inclusion criteria were adult subjects (> 18 yo), newly diagnosed TB and treated by oral antituberculosis, normal function of renal and live and willingness to participate in this study. Subjects were excluded when having positive reaction of HbsAg test, history of HIV and abnormality of renal and liver function. The SNPs of NAT2 and CYP2E1 were designed using IPlex method of DNA sequenom. Among 57 TB patients, we found 14 patients with higher INH serum concentration and experienced increase of ALT-AST. Subjects with SNPs of rs 2070676, rs 1329149, rs 3813867, rs 6413432, rs 8192772, rs 2031920, rs 2515641, rs 8192775, rs 915908 of CYP2E1 experienced increase of ALT and AST . Subjects with SNPs of rs 1799930, rs1799931, rs1801279, rs1801280, rs1799929 , rs1208, rs1041983 of NAT2 are associated with the increase of ALT and AST . The polymorphisms of CYP2E1 and NAT2 may have a role in the mechanisms of INH induced DILI. Keywords: CYP2E1, NAT2, tuberculosis, isoniazid, Indonesia

Association Between NAT2 Polymorphisms and Lung Cancer Susceptibility.

To further investigate the association between NAT2 polymorphisms and lung cancer susceptibility.In terms of phenotypes, we investigated the acetylator status of NAT2 polymorphisms associated with lung cancer risk. Additionally, in view of genotypes, we mainly analyzed 5 single nucleotide polymorphisms (SNPs) in NAT2 gene, namely C282T, A803G, C481T, G590A, and G857A. Twenty-six eligible studies were included in our meta-analysis by searching PubMed, Embase, and CNKI databases. We used odds ratios (ORs) with corresponding 95% confidence intervals (CIs) to evaluate the susceptibility to lung cancer associated with NAT2 polymorphisms.Overall, based on phenotypes, the pooled ORs showed no significant association between NAT2 polymorphisms and lung cancer susceptibility. In the subgroup analyses by ethnicity and source of control, there was still no significant association. In terms of genotypes, overall, no obvious relationship was observed between NAT2 polymorphisms and lung cancer risk. But increased risk of lung cancer was found in association with NAT2 C282T polymorphism (TT vs. CC + TC: OR = 1.58, 95% CI = 1.11–2.25).Our meta-analysis demonstrates that TT genotype in NAT2 C282T polymorphism may be a risk factor for lung cancer susceptibility. Additionally, the acetylator status of 5 SNPs in NAT2 gene may not be associated with lung cancer risk.

Abstract A10: Exposure to heterocyclic aromatic amines, genetic susceptibility and bulky DNA adduct levels in blood leukocytes

Abstract Background: There is compelling evidence to suggest that aspects of diet influence cancer risk; specifically, high meat consumption is associated with elevated risks. Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, is a hypothesized explanation for the meat-cancer relationship. Reactive HAA metabolites form adducts with DNA; left unrepaired, adducts can induce mutations which may initiate/promote carcinogenesis. Genetic differences in the ability to biotransform HAAs (as conferred by polymorphisms in CYP1A1, CYP1A2, CYP1B1, NAT1 and NAT2) and repair DNA adducts (as conferred by polymorphisms in XPA, XPD and XRCC1) is postulated to modify the dietary HAAs-DNA adduct relationship. Methods: In a cross-sectional study of 99 healthy volunteers recruited from Kingston, Ontario, Canada, dietary exposure to HAAs and bulky DNA adduct levels in blood leukocytes was investigated. A detailed questionnaire was used in combination with a mutagen database to estimate average intake of dietary HAAs. Specifically, the detailed questionnaire obtained the average frequency of consumption, usual level of doneness and usual serving size of nine commonly consumed meats items with high HAA content. Bulky DNA adduct levels were measured in blood collected after an overnight fast using 32P-postlabelling. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. Results: No main effects of dietary exposure to HAAs on bulky DNA adduct levels were observed. However, polymorphisms in NAT1 were found to associate with bulky DNA adduct levels. Specifically, those with the putative NAT1*10 rapid acetylator phenotype had a lower adduct level than those with the slow acetylator phenotype (p=0.02). Furthermore, having five or more ‘at-risk’ genotypes was associated with higher bulky DNA adduct levels (p=0.03). Gene-diet interactions were also observed between the NAT1*10 allele and dietary HAAs (p&amp;lt;0.05); specifically, among the slow acetylator phenotype, higher intakes of dietary HAAs were associated with an increase in DNA adduct levels compared to lower intakes. Conclusions: This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. The lack of a strong independent association between dietary HAAs and DNA adducts suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this Canadian population; future studies should consider relevant gene-diet interactions to clarify the potential role of HAAs in carcinogenesis. Citation Format: Vikki Ho, Sarah Peacock, Thomas E. Massey, Roger W. L. Godschalk, Frederik-Jan van Schooten, Jian Chen, Will D. King. Exposure to heterocyclic aromatic amines, genetic susceptibility and bulky DNA adduct levels in blood leukocytes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A10.

Associations of polymorphisms in NAT2 gene with risk and metastasis of osteosarcoma in young Chinese population.

Osteosarcoma is the most common primary malignancy of bone in young individuals. Genetic factors may play an important role in the tumorigenesis of osteosarcoma. Here we carried out a case-control study to investigate seven NAT2 single-nucleotide polymorphisms (rs1799929, rs120, rs1041983, rs1801280, rs1799930, rs1799931, and rs1801279) on the risk and prognosis of osteosarcoma. This study included 260 young osteosarcoma cases and 286 controls. The TaqMan method was used to determine genotypes. We found that rs1799931 G>A polymorphisms were associated with a decreased risk of osteosarcoma in young Chinese population, and rs1041983 CT genotype seemed to play a protective role in the risk of osteosarcoma. However, further analysis showed that rs1041983 polymorphisms were associated with an elevated risk of tumor metastasis, predicting poor prognosis. This study provided the first evidence for the associations between NAT2 polymorphisms and osteosarcoma risk and metastasis in Chinese population.

Genotoxic Effects of GSTP1 Gene Polymorphisms with Respect to Respiratory Problems among Traffic Police

Genetic susceptibility is likely to play a role in response to vehicular pollution of GSTP1 and NAT2 (C481T). Genotoxic effects due to respiratory problems in traffic police occupationally exposed to vehicular exhaust have particular importance in the detoxification of inhaled toxicants since it is the most abundant in the lung function and the association.161 male traffic policemen and 170 control subjects were selected for this study. Gene polymorphism was studied using PCR and RFLP method. The results on gene polymorphism of GSTP1 and NAT2 (C481T) showed significant association of homozygous mutant genotype (GG) in GSTP1 gene and homozygous mutant genotype (CC) in NAT2 gene with traffic police having respiratory problems. However, no such association was observed in traffic police without respiratory problems and control group also. Our results suggest that long term exposure to urban air pollution (with traffic as the main contributor) polymorphisms in genetic susceptibility provides evidence to suggest a role in determining the respiratory problems in GSTP1 and NAT2 (C481T) variants associated with reduced detoxification ability, increase susceptibility to such damage and appears to be associated with occupationally exhaust vehicular exhaust in traffic policemen.

Gene-diet interactions in exposure to heterocyclic aromatic amines and bulky DNA adduct levels in blood leukocytes.

Heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, are an emerging biologic explanation for the meat-colorectal cancer relationship. HAAs form DNA adducts; left unrepaired, adducts can induce mutations, which may initiate/promote carcinogenesis. The purpose of this research was to investigate the relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct levels. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood measured using (32)P-postlabeling among 99 healthy volunteers. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. No main effects of dietary HAAs on bulky DNA adduct levels was found. However, those with the putative NAT1 rapid acetylator phenotype had lower adduct levels than those with the slow acetylator phenotype (P = 0.02). Furthermore, having five or more 'at-risk' genotypes was associated with higher bulky DNA adduct levels (P = 0.03). Gene-diet interactions were observed between NAT1 polymorphisms and dietary HAAs (P < 0.05); among the slow acetylator phenotype, higher intakes of HAAs were associated with an increase in DNA adduct levels compared to lower intakes. This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. However, the lack of a strong main effect of HAAs suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this population; future studies should consider relevant gene-diet interactions to clarify the role of HAAs in carcinogenesis.

Genetic susceptibility in childhood acute leukaemias: a systematic review.

Acute leukaemias (AL) correspond to 25–35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene–gene and gene–environment interactions.

N-acetyltransferase 1 and 2 polymorphisms and risk of diabetes mellitus type 2 in a Saudi population.

BACKGROUND AND OBJECTIVESThere have been inconsistent reports on N-acetyltransferase (NAT) gene polymorphism in type 2 diabetes mellitus (T2DM), and data is particularly limited in the Arab population. Therefore, the main objective of this study was to identify whether the genetic polymorphisms of NAT1 and NAT2 play a role in susceptibility to T2DM in the Saudi population.DESIGN AND SETTINGA population-based, prospective genetic association case-control study on a Saudi population.PATIENTS AND METHODSWhole blood, anthropometric measurements and biochemistry data were collected from 369 Saudi individuals (186 T2DM patients and 183 healthy controls). DNA was isolated from the blood. Polymorphism of NAT1 and NAT2 SNPs [NAT2*7B, rs1041983(C>T); NAT2*7, rs1799931(G>A); NAT2*6A, rs1799930(G>A); NAT2*5A, rs1799929(C>T); and NAT1*11A, rs4986988(C>T)] were evaluated by allelic discrimination using real-time PCR.RESULTSSubjects with T2DM had a significantly increased body mass index (BMI), waist circumference, systolic and diastolic blood pressure, glucose, triglycerides, and LDL-cholesterol compared with healthy controls (P<.05). The rs1799931(G>A) genotype was detected in the control population but not in the T2DM population (P<.001). The wild type (G) allele frequency was higher in T2DM than controls (P=.038). The mutant allele (A) in rs1799931(G>A) had a protective effect for T2DM (OR 0.32, 95% CI 0.16–0.62; P=.001). Regression analysis showed that BMI, systolic BP and triglycerides are potential risk factors for T2DM.CONCLUSIONThe genotypes as well as the individual alleles of rs1799931(G>A) differed significantly between the case and control populations. The variation in the data reported so far suggest that polymorphism of the NAT gene may vary among different geographical areas. Environmental or dietary factors may also contribute to disease manifestation.

NAT1 and NAT2 genetic polymorphisms and environmental exposure as risk factors for oesophageal squamous cell carcinoma: a case-control study.

BackgroundTobacco smoking and red meat consumption are some of the known risk factors associated with the development of oesophageal cancer. N-acetytransferases (NAT1 and NAT2) play a key role in metabolism of carcinogenic arylamines present in tobacco smoke and overcooked red meat. We hypothesized that NAT1 and NAT2 genetic polymorphisms may influence the risk of oesophageal cancer upon exposure to environmental carcinogens.MethodsSingle nucleotide polymorphisms (SNPs) in the NAT1 and NAT2 genes were investigated by genotyping 732 cases and 768 healthy individuals from two South African populations to deduce the acetylator phenotype (slow, intermediate or rapid) from the combination of the genotyped SNPs.ResultsThe 341 CC genotype (rs1801280) was significantly associated with a reduced risk for oesophageal cancer in the Mixed Ancestry population (OR = 0.31; 95% CI 0.11-0.87). The NAT2 slow/intermediate acetylator status significantly increased the risk among cigarette smokers in the Black population (OR = 2.76; 95% CI 1.69-4.52), as well as among alcohol drinkers in the Mixed Ancestry population (OR = 2.77; 95% CI 1.38-5.58). Similarly, the NAT1 slow/intermediate acetylator status was a risk factor for tobacco smokers in the Black population (OR = 3.41; 95% CI 1.95-5.96) and for alcohol drinkers in the Mixed Ancestry population (OR = 3.41; 95% CI 1.70-6.81). In a case-only analysis, frequent red meat consumption was associated with a significantly increased cancer risk for NAT2 slow/intermediate acetylators in the Mixed Ancestry population (OR = 3.55; 95% CI 1.29-9.82; P = 0.019), whereas daily white meat intake was associated with an increased risk among NAT1 slow/intermediate acetylators in the Black population (OR = 1.82; 95% CI 1.09-3.04; P = 0.023).ConclusionsOur findings indicate that N-acetylation polymorphisms may modify the association between environmental risk factors and oesophageal cancer risk and that N-acetyltransferases may play a key role in detoxification of carcinogens. Prevention strategies in lifestyle and dietary habits may reduce the incidence of oesophageal cancer in high-risk populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1105-4) contains supplementary material, which is available to authorized users.

Interaction between Dietary and Lifestyle Risk Factors and N-Acetyltransferase Polymorphisms in B-Cell Lymphoma Etiology

Background: Gene-environment interactions are suggested to play a role in lymphomagenesis. Methods: We tested the interaction between the NAT1/NAT2 phenotype, as inferred by the respective genotypes, and exposure to dietary and lifestyle risk factors, in 199 incident lymphoma cases and 188 population controls. We used unconditional logistic regression to calculate the odds ratio (OR) and its 95% confidence interval for lymphoma (all subtypes combined) and B cell lymphoma, associated to the rapid NAT1 phenotype and to the intermediate and slow NAT2 phenotype, and to the estimated dietary intake of heterocyclic amines and folate, current smoking, coffee, and use of permanent hair dyes, as well as the respective interaction terms. We adjusted the ORs by age, gender, and education, and we used the likelihood ratio test to test the interaction between the NAT1, NAT2 phenotype and the dietary and lifestyle variables. Results: We observed an increase in risk of lymphoma (all subtypes combined) and B-cell lymphoma in particular associated with the estimated above median dietary intake of heterocyclic amines (OR = 4.2, 95%CI 1.2 – 14.8) and folate (OR = 4.1, 95%CI 0.7 – 22.4) among subjects with the NAT1 rapid acetylator phenotype, but not independent on the NAT1 phenotype. The test for interaction was significant for heterocyclic amines, but not for folate (p for interaction = 0.026 and 0.076 respectively). Ever use of permanent hair dyes was associated with an elevated risk independent on the NAT1, NAT2 phenotypes; risk decreased to null among intermediate and slow NAT1 acetylators (p for interaction = 0.010). Conclusions: Our results suggest that NAT1, NAT2 polymorphisms interact with dietary and lifestyle exposures in modulating risk of lymphoma and particularly B-cell lymphoma.

Association of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region.

To explore associations of CYP2E1 and NAT2 polymorphisms with lung cancer susceptibility among Mongolian and Han populations in the Inner Mongolian region. CYP2E1 and NAT2 polymorphisms were detected by PCR-RFLP in 930 lung cancer patients and 1000 controls. (1) Disequilibrium of the distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations (p=0.031). (2) Lung cancer risk was higher in individuals with c1, D allele of CYP2E1 RsaI/PstI, DraI polymorphisms and slow acetylation of NAT2 (c1 compared with c2, OR=1.382, 95%CI: 1.178- 1.587, p=0.003; D compared with C, OR=1.241, 95%CI: 1.053-1.419, P<0.001; slow acetylation compared with rapid acetylation, OR=1.359, 95%CI:1.042-1.768, p=0.056) (3) Compared with c2/c2 and rapid acetylation, c1/c1 together with slow acetylation synergetically increased risk of lung cancer 2.83 fold. (4) Smokers with CYP2E1 c1/c1, DD, and NAT2 slow acetylation have 2.365, 1.916, 1.841 fold lung cancer risk than others with c2/c2, CC and NAT2 rapid acetylation, respectively. (5) Han smokers with NAT2 slow acetylation have 1.974 fold lung cancer risk than others with rapid acetylation. Disequilibrium distribution of NAT2 polymorphism was found in lung cancer patients among Han and Mongolian populations. Besides, Han smokers with NAT2 slow acetylation may have higher lung cancer risk compared with rapid acetylation couterparts. CYP2E1 c1/ c1, DD and NAT2 slow acetylation, especially combined with smoking, contributes to the development of lung cancer. CYP2E1 c1/c1 or DD genotype and NAT2 slow acetylation have strong synergistic action in increasing lung cancer risk.

Genetic polymorphisms of phase I and phase II metabolic enzymes as modulators of lung cancer susceptibility.

Tobacco exposure remains the main etiologic factor for lung cancer (LC). Interactions between environment and individual genetic profile are particularly important for this disease. The aim of this study was to evaluate the contribution of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 polymorphisms for the susceptibility to LC in a Portuguese population considering their demographic and clinical characteristics. A total of 200 LC and 247 controls subjects from the Centre of Portugal were studied. Clinical and demographic characteristics were collected from clinical files and by individual questionnaires. Polymorphisms of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 were genotyped using PCR-RFLP, PCR multiplex, ARMS and real time. Gender, family history of cancer, smoke cessation and alcohol consumption were independent risk factors (p < 0.05). Associations found between phases I and II genes and LC population reveal a sex dependent distribution. Logistic regression analysis demonstrates that enhanced activation by CYPs, associated by reduced or loss of function of phase II enzymes, can lead to a greater risk. GSTP1 and NAT2 polymorphisms studied have a significant contribution for the histological tumour types and the presence of metastases, at time of diagnosis, respectively, when males with smoking habits were considered. Multiple interactions between environment and individual characteristics are clearly associated to this disease. Variants of the detoxification genes may act synergistically contributing to this disease and modifying the risk posed by smoking and sex. The GSTT1*0 and GSTP1 (Ile462Val) might contribute to the malignant phenotype through different mechanisms.

Tuberculose : intérêt du dosage de l’isoniazide dans la prévention des effets hépatotoxiques

Several recent studies have established a correlation between NAT2 polymorphism and hepatotoxicity induced by isoniazid. The objective of this work was to assess the place of isoniazid dosage, marker of acetylation phenotype, in clinical practice in the department of Haute-Garonne. Data from reportable disease of tuberculosis and the results of isoniazid dosage performed at the pharmacokinetics and clinical toxicology laboratory were used during the period 2009-2012. The current practice of dosage is far from being systematical: only 3.9% of patients who developed tuberculosis have benefited from isoniazid dosage. The isoniazid initial posology was adapted to the acetylation capacity for only 33.3% of patients. A decision tree was realized and used to identify populations (low metabolism) liable to benefit from isoniazid dosage.

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