N-Acetyltransferase 1 ( NAT1 ) Genotype: A Risk Factor for Urinary Bladder Cancer in a Lebanese Population (original) (raw)
Related papers
Asian Pacific journal of cancer prevention : APJCP, 2017
Background: In Lebanon, bladder cancer (BC) has an unusually high prevalence. Individuals who are exposed to aromatic amines from smoking or certain occupations and carrying the slow N-acetyl transferase 2 (NAT2) acetylator’ phenotype may be at a higher risk. Methods: Data and DNA from 115 Lebanese BC cases and 306 controls were examined. Ten NAT2 single nucleotide polymorphisms were genotyped, seven of which were then included in haplotype and phenotype analysis. Results: BC patients were more likely to be males (87.8% vs. 54.9%) and current smokers (60.9% vs. 26.5%) when compared to controls. In both groups, most participants had the slow NAT2 acetylator phenotype (66.1% of BC cases vs 62.7% of controls; P=0.302) with the NAT2*5B and *6A haplotypes being the most common. The odds ratio (95%CI) of having BC among slow NAT2 acetylators was 1.157 (0.738-1.815) and remained non-significant after adjustment [1.097 (0.666-1.806)]. Sensitivity analysis with a subgroup of 113 cases and 84...
BioTechnologia, 2019
Background. Toxic compounds are detoxified by several xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2). The role for NAT2 genetic polymorphisms in different malignancies risk has been the subject of numerous studies. In the current study we investigated the association of genetic NAT2 variants or their corresponding acetylator phenotypes with bladder cancer risk. The relationship between NAT2 genotype/phenotype and smoking status was also evaluated as potential risk factor of urinary bladder cancer. Material and methods. As few data on the association between genetic polymorphisms of NAT2 and bladder cancer are available in the Algerian population, we performed an extensive identification of NAT2 variants in 175 bladder cancer patients and 189 healthy controls by direct PCR sequencing of the coding region. Results. Thirteen previously described SNPs were identified in this study; only T341C and G590A were associated with increased risk of bladder cancer (P < 0.05). NAT2 slow acetylator phenotype is at higher risk (OR = 2.45, 95% CI = 1.41-4.35) with the greatest risk noted for the allele NAT2*5. When combined to smoking status, T341C and G590A SNPs were of significant correlation with bladder cancer risk (P < 0.05) among non smokers. A correlation that increased among smokers. However, a relationship emerged only when smoking habit was considered between C345T, C481T and A803G SNPs and bladder cancer risk (P < 0.05). Our study showed a strong interaction between NAT2 slow acetylator phenotype and smoking (P = 7.20e !6). Conclusions. These findings provided evidence of an additive effect between smoking status and NAT2 slow acetylation in influencing bladder cancer risk.
Oncogene, 2006
A role for the N-acetyltransferase 2 (NAT2) genetic polymorphism in cancer risk has been the subject of numerous studies. Although comprehensive reviews of the NAT2 acetylation polymorphism have been published elsewhere, the objective of this paper is to briefly highlight some important features of the NAT2 acetylation polymorphism that are not universally accepted to better understand the role of NAT2 polymorphism in carcinogenic risk assessment. NAT2 slow acetylator phenotype(s) infer a consistent and robust increase in urinary bladder cancer risk following exposures to aromatic amine carcinogens. However, identification of specific carcinogens is important as the effect of NAT2 polymorphism on urinary bladder cancer differs dramatically between monoarylamines and diarylamines. Misclassifications of carcinogen exposure and NAT2 genotype/phenotype confound evidence for a real biological effect. Functional understanding of the effects of NAT2 genetic polymorphisms on metabolism and genotoxicity, tissue-specific expression and the elucidation of the molecular mechanisms responsible are critical for the interpretation of previous and future human molecular epidemiology investigations into the role of NAT2 polymorphism on cancer risk. Although associations have been reported for various cancers, this paper focuses on urinary bladder cancer, a cancer in which a role for NAT2 polymorphism was first proposed and for which evidence is accumulating that the effect is biologically significant with important public health implications.
N-acetyltransferase 2 phenotype, occupation, and bladder cancer risk: results from the EPIC cohort
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2013
An association between N-acetyltransferase 2 (NAT2) slow acetylation and bladder cancer has been consistently observed in epidemiologic studies. However, evidence has been mainly derived from case-control studies and was sparse from cohort studies. We evaluated the association between NAT2 slow acetylation and bladder cancer in a case-control study nested in the European Prospective Investigation into Cancer and Nutrition. Exposure to aromatic amines and polycyclic aromatic hydrocarbons (PAH) could be assessed for 754 cases and 833 controls for whom occupational information was documented. A semiquantitative job-exposure matrix was applied to at-risk occupations to estimate the exposure as low, medium, or high based on tertiles of the distribution of the exposure score in controls. Using a comprehensive genotyping, NAT2 acetylation status could be categorized from 6-single-nucleotide polymorphism genotypes as slow or fast in 607 cases and 695 controls with DNA from archived blood sa...
2023
Background: AnassociationbetweenN-acetyltransferase2(NAT2)slowacetylationandbladdercancerhasbeen consistently observed in epidemiologic studies. However, evidence has been mainly derived from case-control studies and was sparse from cohort studies. We evaluated the association between NAT2 slow acetylation and bladder cancer in a case-controlstudy nested in the European Prospective Investigation into Cancer and Nutrition. Methods: Exposure to aromatic amines and polycyclic aromatic hydrocarbons (PAH) could be assessed for 754 cases and 833 controls for whom occupational information was documented. A semiquantitative jobexposure matrix was applied to at-risk occupations to estimate the exposure as low, medium, or high based on tertiles of the distribution of the exposure score in controls. Using a comprehensive genotyping, NAT2 acetylation status could be categorized from 6-single-nucleotide polymorphism genotypes as slow or fast in 607 cases and 695 controls with DNA from archived blood samples. Results: Occupational exposure to aromatic amines and PAH was associated with an increased bladder cancer risk [upper tertile of the distribution of the exposure score: OR ¼ 1.37; 95% confidence interval (CI), 1.02-1.84, and OR ¼ 1.50; 95% CI, 1.09-2.05, respectively]. NAT2 slow acetylation did not modify these risk estimates and was not itself associated with bladder cancer risk (OR ¼ 1.02; 95% CI, 0.81-1.29). Conclusions: These findings confirm established or suspected occupational risk factors but not the anticipated role of NAT2 slow acetylation in bladder cancer. No interaction was detected between NAT2 and any exposure of interest, including smoking. Impact: Genetic testing for NAT2 would be inappropriate in occupational settings. Cancer Epidemiol Biomarkers Prev; 22(11); 2055-65. Ó2013 AACR.
International Journal of Cancer, 2004
Tobacco smoking and occupation are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. Glutathione S-transferase (GST) M1, T1 and P1 are involved in the detoxification of PAH reactive metabolites. Two N-acetyltransferase isozymes, NAT2 and NAT1, have major roles in catalyzing the N-acetylation and O-acetylation of aromatic amines. Cytochrome P450 1B1 (CYP1B1) and sulfotransferase 1A1 (SULT1A1) are also involved in the metabolism of PAHs and aromatic amines. It is hypothesized that the genetic polymorphisms of these metabolic enzymes have an effect on the individual susceptibility to bladder cancer in particular by interacting with relevant environmental exposures. A hospital-based case-control study among men in Brescia, Northern Italy recruited 201 incidence cases and 214 controls from 1997–2000. Occupational exposures were blindly coded by occupational physicians. Genotyping of polymorphisms were carried out with PCR-RFLP method. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk. Effect modifications by age of onset, smoking and occupational exposures to PAHs and aromatic amines were evaluated. We also conducted an analysis of interaction between genetic factors. GSTM1 and GSTT1 null genotype were associated with an increased risk of bladder cancer with an odds ratio (OR) of 1.69 (95% confidence interval [CI] = 1.11–2.56) and 1.74 (95% CI = 1.02–2.95), respectively. The effect of GSTM1 null was seen particularly in heavy smokers, and there was a combined effect with occupational exposure of aromatic amines (OR = 2.77, 95% CI = 1.08–7.10). We observed a trend (p-value < 0.01) of increasing cancer risk comparing subjects with normal GSTM1 and T1 activity to subjects with one (OR = 1.82, 95% CI = 1.16–2.85) or both null genotypes (OR = 2.58, 95% CI = 1.27–5.23). NAT2 slow acetylator was associated with marginally increased risk of bladder cancer (OR = 1.50, 95% CI = 0.99–2.27), and the OR for the joint effect with occupational exposure of aromatic amines was 3.26 (95% CI = 1.06–9.95). SULT1A1 Arg213His polymorphism showed a marginal protective effect. These findings suggest that individual susceptibility to bladder cancer may be modulated by GSTM1, GSTT1 and NAT2 polymorphisms. © 2004 Wiley-Liss, Inc.
Acta Biochimica Polonica
Smoking is a main risk factor for bladder cancer (BC). NAT2 is a drug-metabolizing enzyme that catalyses the detoxification of many xenobiotics and carcinogens. Single nucleotide polymorphism (SNP) in NAT2 results in different acetylation phenotypes (fast, intermediate or slow). Certain NAT2 SNPs were associated with BC and/or modified the association of BC with smoking. However, limited evidence is available among BC patients or smokers from Jordan. This study aimed to discover novel SNPs in NAT2 and to assess the association with BC. This was a case-control study among 120 BC patients and 120 controls. Amplification of a 446 bp fragment of NAT2 encoding the N-catalytic domain was conducted using a polymerase chain reaction. Gene sequencing was done using Sanger-based technology. A total of 40 SNPs were detected. Two variants were significantly associated with BC (p<0.05); namely a novel c.87G>A and the reported c.341T>C. Regarding c.87G>A, genotype distribution was sig...
Cancer Letters, 2004
We investigated the role of glutathione S-transferase (GST) enzymes (M1, T1), methylenetetrahydrofolate (MTHFR) 677 and 1298, and the NAD(P)H:quinone oxidoreductase (NQO1) polymorphisms in a population-based bladder cancer casecontrol study in Argentina. Buccal cell DNA was obtained from 106 cases and 109 controls. The strongest evidence was for an interaction between NQO1 genotype and smoking. For ever smoking vs. never smoking the odds ratio was 8.6 (95% confidence interval (CI) 2.7-27), in the CC genotype, and 1.3 (95% CI 0.5-3.5) in the CT and TT genotypes combined. Also, elevated bladder cancer risks associated with GSTM1 and GSTT1 null genotypes were found in smokers. Having both null polymorphisms conferred the highest risks. The MTHFR 677 CT and TT polymorphisms appeared protective against bladder cancer.
CYP2E1 and NQO1 genotypes and bladder cancer risk in a Lebanese population
International journal of molecular epidemiology and genetics, 2013
Urinary bladder cancer incidence in Lebanon ranks among the highest in the world. Cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase1 (NQO1), and N-Acetyltransferase1 (NAT1), are drug-metabolizing enzymes (DMEs) involved in the metabolism of carcinogens, such as arylamines and heterocyclic amines, implicated in bladder cancer. The present study attempts to investigate the role of these DMEs genetic polymorphism in bladder cancer risk among Lebanese men. 54 cases and 106 controls were recruited from two hospitals in Beirut. An interview-based questionnaire was administered to assess suspected environmental and occupational risk factors. PCR-RFLP was performed on blood-based DNA samples to determine DMEs genotypes. Associations between bladder cancer and putative risk factors were measured using adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Results showed CYP2E1 c1/c1, NAT1*14A, and smoking, to be risk factors for bladder cancer. No significant differe...