N-acetyltransferase 2 Slow Genotype Research Articles

NAT2 polymorphisms combining with smoking associated with breast cancer susceptibility: a meta-analysis

To derive a more precise estimation of the relationship between the slow or rapid acetylation resulting from N-acetyltransferase 2 (NAT2) polymorphisms and breast cancer risk, a meta-analysis was performed. PubMed, Medline, Embase, and Web of Science were searched. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess strength of association. The pooled ORs were performed for slow versus rapid acetylation genotypes. A total of 26 studies including 9,215 cases and 10,443 controls were included in the meta-analysis. Overall, no significantly elevated breast cancer risk was associated with NAT2 slow genotypes when all studies were pooled into the meta-analysis (OR = 1.026, 95% CI = 0.968-1.087). In the subgroup analysis by ethnicity, increased risks were not found for either Caucasians (OR = 1.001, 95% CI = 0.938-1.068) or Asians (OR = 1.155, 95% CI = 0.886-1.506). When stratified by study design, statistically significantly elevated risk associated with NAT2 slow genotypes was only found among hospital-based studies (OR = 1.178, 95% CI = 1.037-1.339). In the subgroup analysis by menopausal status, no statistically significantly increased risk was found in either premenopausal (OR = 1.053, 95% CI = 0.886-1.252) or postmenopausal women (OR = 0.965, 95% CI = 0.844-1.104). When stratified by cumulative smoking exposure, in the subgroup of smokers with high pack-years, NAT2 slow genotypes were significantly associated with increased breast cancer risk (OR = 1.400, 95% CI = 1.099-1.784). In conclusion, this meta-analysis suggested that there is overall lack of association between NAT2 genotypes and breast cancer risk, however, NAT2 polymorphisms when combining with heavy smoking history may contribute to breast cancer susceptibility.

Cigarette Smoking, N-Acetyltransferase 2 Genotypes, and Breast Cancer Risk: Pooled Analysis and Meta-analysis

Approximately 10 years ago, it was noted that smoking increased risk of breast cancer among women with N-acetyltransferase 2 (NAT2) slow acetylation genotypes. This report was followed by a number of studies to address this question. We pooled data from 10 existing studies and also conducted a meta-analysis of 13 studies published from 1996 to October 2006 that were conducted among women, were published in English, and had adequate information on smoking and NAT2 genotyping. Raw data were requested from authors. Unconditional logistic regression was done for pooled analysis, and random effect models was done for meta-analysis. Study heterogeneity was assessed, and sensitivity tests were done when subgroups were excluded from the analysis. In the pooled analysis, there was a significant interaction between smoking, NAT2 genotype, and risk of breast cancer [pack-years (continuous variable, P(interaction) = 0.03)], with higher pack-years significantly associated with an increased risk of breast cancer among women with NAT2 slow genotypes (pooled analysis relative risk, 1.49; 95% confidence interval, 1.08-2.04). These findings were supported by the meta-analysis including all studies; pack-years were significantly associated with risk among slow acetylators in a dose-dependent fashion (meta-analysis relative risk, 1.44; 95% confidence interval, 1.23-1.68 for > or =20 pack-years versus never smokers), but not among rapid acetylators. Similar relationships were noted for smoking status (ever, never) and duration of smoking. Our results show that cigarette smoking is associated with an increase in breast cancer risk among women with NAT2 slow acetylation genotypes. Because slow NAT2 genotypes are present in 50% to 60% of Caucasian populations, smoking is likely to play an important role in breast cancer etiology.

Association of Genetic Polymorphisms of N-Acetyltransferase 2 and Susceptibility to Esophageal Cancer in North Indian Population

Esophageal cancer is multifactorial disease involving environmental and genetic risk factors. Tobacco smoke and alcohol are strong environmental risk factors. N-acetyltransferase 2 (NAT2) is known to metabolize heterocyclic amine carcinogens in tobacco smoke. The purpose of this study was to determine whether genetic polymorphism in the NAT2 and their interaction with environmental factors influence the susceptibility for esophageal cancer. For our study, 126 patients and 164 controls were genotyped for NAT2 2 * 5, 2 * 6 and 2 * 7 polymorphisms using PCR-RFLP method. In a case-control study, NAT2 slow acetylator genotype was not significantly associated with risk of esophageal cancer (OR 1.3, 95%CI = 0.78–2.2, P = 0.28). There was significant linkage disequilibrium between 2 * 5–2 * 6 and 2 * 5–2*7 (P < 0.05). Using expectation maximization algorithm, 6 haplotypes were obtained but none of them revealed any significant contribution to disease susceptibility. In case only analysis, the smokers with rapid acetylator were at slightly higher risk of esophageal cancer (OR 1.3, 95%CI = 0.62–3.0, P = 0.43) which was not statistically significant. NAT2 slow or fast genotypes did not affect the risk of esophageal cancer in patients with alcohol consumption or occupational exposure. These results suggest that NAT2 acetylator genotypes did not influence the susceptibility to esophageal cancer. NAT2 polymorphism did not significantly modulate the cancer risk after interaction with environmental factors like tobacco, alcohol or occupational exposure.

N-Acetyltransferase 2 status and gastric cancer risk: a preliminary meta-analysis

In recent studies N- Acetyltransferase 2 (NAT2) genotype has been considered as a risk factor for developing gastric cancer, however with conflicting results among Asian and Caucasian populations. In order to clarify the influence of NAT2 slow acetylation status on gastric cancer risk, a preliminary meta-analysis of published case-control studies was undertaken. The primary outcome measure was the odds ratio (OR) for the risk of gastric cancer associated with the NAT2 slow genotype using a random effects model. Pooling the results from the 5 studies identified (771 cases, 1083 controls), an overall OR for gastric cancer risk associated with the NAT2 slow genotype of 0.91 emerged (95% CI: 0.54-1.55). The result suggests that the NAT2 slow genotype has probably no effect on the risk of gastric cancer. Additional epidemiological studies, based on sample sizes that are commensurate with the detection of small genotypic risks, are required to confirm these findings. Future studies may also help to clarify whether geographic differences exist.

Glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) polymorphisms and urothelial cancer risk with tobacco smoking

The objective of this study was to examine the association between the genetic polymorphism of glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) genes and urothelial cancer risk in relation to smoking status. In this study, 325 Japanese patients with urothelial transitional cell carcinoma and 325 healthy controls were compared for frequencies of GSTM1, T1 and NAT2 genotypes. The frequencies of GSTM1 null genotype and NAT2 slow genotype were significantly higher in the cases than in the controls (adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.01-1.87, adjusted OR 3.09, 95% CI 1.69-5.63, individually). Furthermore, the risk of GSTM1 null genotype and NAT2 slow genotype was higher among smokers (adjusted OR 1.48, 95% CI 1.01-2.15, adjusted OR 4.28, 95% CI 1.96-9.36, individually). The regression analysis of cancer risk as a function of the amount of smoking showed that the susceptibility of people who had GSTM1 null genotype increased from 45 pack-years, while the susceptibility of people with NAT2 intermediate or slow genotype increased rapidly from 25 pack-years, compared with non-smokers. A multiplicative interaction between NAT2 intermediate or slow genotype and pack-years of smoking was found (P<0.001), but GSTM1 null genotype was not (P=0.06). Our results indicate that the GSTM1 null genotype and NAT2 intermediate or slow genotype are associated with an increased risk of urothelial cancer in relation to smoking amounts. Furthermore, the interaction between NAT2 intermediate or slow genotype and pack-years of smoking has a strong impact on urothelial cancer.