N-乙酰基转移酶 1（NAT1）多态性与口腔白斑病和癌症风险的关联。
Association between polymorphisms at N-acetyltransferase 1 (NAT1) & risk of oral leukoplakia & cancer.
机构信息
Biological Sciences Division, Indian Statistical Institute, Kolkata, India.
出版信息
Indian J Med Res. 2012 Oct;136(4):605-13.
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 (r 2 =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.
背景与目的
N-乙酰基转移酶 1 和 2（NAT1 和 NAT2）是烟草致癌物代谢的重要酶。由于多态性，这些酶的活性不当可能导致 DNA 加合物的形成，从而可能调节与烟草相关的口腔癌前病变和癌症的风险。以前的研究表明，NAT2 多态性不会调节口腔癌前病变和癌症的风险。我们进行这项研究是为了检查 NAT1 多态性是否单独或与 NAT2 联合调节口腔白斑病和癌症的风险。
方法
通过 TaqMan 方法在 389 名对照、224 名白斑病和 310 名癌症患者中确定了 NAT1 上四个 SNP 的基因型。分析基因型数据以了解个体的单倍型和乙酰化状态，然后估计疾病的风险。使用我们之前发表的 NAT2 数据，还分析了患者和对照的 NAT1 和 NAT2 乙酰化基因型的组合，以估计疾病的风险。
结果
NAT1 基因型数据的分析表明，1088T 和 1095C 等位基因存在强连锁不平衡（r2=0.97，P<0.0001），并且 SNP 处于 Hardy-Weinberg 平衡（P=0.1）。野生型或正常乙酰化和变异型或快速乙酰化等位基因是对照人群中主要的两种等位基因（频率分别为 0.62 和 0.36）。NAT1 快速乙酰化不能调节白斑病和癌症的风险（OR=0.9，95%CI：0.6-1.3；OR=1.0，95%CI：0.7-1.4，分别）。分析联合的 NAT1 和 NAT2 乙酰化数据也没有显示疾病风险的显著增强。
解释与结论
在我们的患者人群中，NAT1 快速乙酰化单独以及 NAT1 快速-NAT2 缓慢乙酰化的组合都不能调节口腔癌前病变和癌症的风险。因此，NAT1/NAT2 代谢的致癌物产物可能不参与与烟草相关的口腔癌前病变和癌症。可以解释为，大样本量以及其他候选基因座的多态性组合对于估计像口腔癌这样的复杂疾病的风险可能很重要。
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