The Association Between NAT2 Genetic Polymorphism And Genetic Susceptibility Of Adult Acute Myeloid Leukemia

Background:Acute myeloid leukemia (AML) is a kind of hematological malignancy. The pathogenesis of AML is closely associated with the environmental, occupational, and genetic factors. The ability of carcinogens metabolizing is different from each other, and the difference is depend on the polymorphisms of the metabolic enzymes. Therefore, the polymorphisms of metabolic enzyme gene are important factors to the genetic susceptibility of tumor. The phase â…¡ metabolism enzyme, N-acetyltransferase 2 (NAT2) is one of the important metabolism enzymes in human bodies which is encoding by the NAT2 gene. The frequency of every single nucleotide polymorphisms (SNPs) of NAT2 gene is different in different regions and ethnic groups. The SNPs affect the function of NAT2 gene directly, and then reduce the stability of the enzyme and change the affinity to the substrate. However, a single SNP in a gene carries less information. Human beings are diploid organisms, haplotype and diplotype analysis is more effective than the allele and genotype analysis. At present, research on the association of NAT2 haplotype and adult AML genetic susceptibility in China is lack. Detecting and identifying the genetic risk factors of the tumor effectively, and then guiding the treatment of AML patients as well as the early tumor detection and prevention of the carriers of the genetic risk factors is very important.Objective:To determine the association of N-acetyltransferases 2 (NAT2) genetic polymorphisms (rs 1041983, rs 1801280, rs1799929, rs 1799930, rs1208, rs 1799931) and the susceptibility to acute myeloid leukemia.Methods:This case control study that we conducted included 98 histological confirmed AML patients and 1993 control subjects. We applied the method of SNaPshot genotyping to explore the genetic polymorphism of NAT2 gene. Haploview4.1 software was used to construct haplotypes of the NAT2 gene. PHASE2.0 software was used to construct diplotypes. The logistic regression analysis was carried out to estimate the association between genetic polymorphism of NAT2 gene and AML risk which is manifested by Odds Ratio (OR) and 95% confidential interval (95%CI). Further stratification analysis by smoking and drinking status were also conducted.Results:1. The genotype and allele frequency of rs 1799930 and rs 1799931 polymorphisms are significantly different between the group of AML and control.2. In the total study group, the genotype of six SNPs in NAT2 gene was unrelated to the risk of AML (P>0.05). But NAT2* 5B decreased the risk of AML (OR=0.22,95%CI:0.05-0.88, P=0.03).3. In the group of smoker and nonsmoker, the genotype of six SNPs and the mutated haplotype in NAT2 gene were unrelated to the risk of AML (P>0.05).4. In the group of nonsmoker and nondrinker, the homozygous mutated genotype (AA) of rs 1799930 decreased the risk of AML (OR=0.32,95%CI:0.10-0.98, P=0.046). NAT2*6A decreased the risk of AML (OR=0.59,95%CI:0.37-0.94, P=0.03).5. In the total study group, the phenotype of NAT2 was unrelated to the risk of AML (P>0.05). In the group of nonsmoker and nondrinker, the slow-acetylator phenotypes significantly decreased the risk of AML (OR=0.05,95%CI:0.03-0.11, P<0.001). 6. In the group of smoker and nonsmoker, the phenotype of NAT2 was unrelated to the risk of AML (P>0.05).Conclusions:1. The genotype and allele frequency of rs 1799930 and rs 1799931 polymorphisms may be different between the group of AML and normal people. The genotype and allele frequency of rs 1799931 polymorphism in AML patients may be higher than the normal ones, and the genotype and allele frequency of rs 1799930 polymorphism may be lower than the normal ones. 2. There are five common haplotype of NAT2 in the study population, namely the wild-type haplotype (NAT2* 4) and the mutated haplotype (NAT2* 5B, NAT2*6A, NAT2*7B, NAT2*13). The frequency of NAT2*5B may be different between the group of AML and normal people. The frequency of NAT2*5B in AML patients may be lower than the normal ones.3. The homozygous mutated genotype (AA) of rs 1799930 may decrease the risk of AML. NAT2*6A may be the protective factor in AML. The slow acetylator phenotype may decrease the risk of AML.