SINGLE NUCLEOTIDE POLYMORPHISMS OF THE HUMANCYP2A13GENE: EVIDENCE FOR A NULL ALLELE

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Human CYP2A13 is believed to be important in the metabolic activation of tobacco-specific nitrosamines in the respiratory tract; therefore, genetic polymorphisms of the CYP2A13 gene may be associated with interindividual differences in the risks of tobaccorelated tumorigenesis. Our earlier studies identified a frequent single nucleotide polymorphism in CYP2A13 exon 5, Arg257Cys, which led to an approximate 50% decrease in metabolic activities. In the present study, three additional coding region mutations (Arg25Gln, Arg101Stop, and Asp158Glu) and several mutations in the introns and flanking regions were identified in a Chinese patient population. Of particular interest is the Arg101Stop mutation, which was due to a C > T change in exon 2. Thus, individuals homozygous for this nonsense mutation would not have a functional CYP2A13 protein and, therefore, might have reduced sensitivity to xenobiotic toxicity resulting from CYP2A13-mediated metabolic activation in the respiratory tract. The frequencies of the coding region mutations were further examined using random samples of white, black, Hispanic, and Asian newborns from New York. The frequency of the Arg25Gln mutation in Asian newborns (9.6%) was very similar to that found in the Chinese population (10.9%). On the other hand, the Arg101Stop mutation was not detected in 136 newborn samples examined (23 white, 21 black, 19 Hispanic, and 73 Asian), suggesting that this mutation may be unique for the Chinese patient population. Haplotype analysis indicated that the Arg25Gln and Arg257Cys mutations are parts of a common haplotype. However, an additional haplotype that consists of the 25Gln but not the 257Cys allele was also identified.

CYP2A13, CYP2A6, and the Risk of Lung Adenocarcinoma in a Japanese Population

“…22) Another nonsense mutation polymorphism, C301T (CYP2A13*7 allele, Arg101Stop), which was detected in a Chinese population, is likely to be functionally important since it entails a severely truncated protein lacking enzymatic activity. 20) Zhang et al reported that this variant allele also exhibits a protective effect against procarcinogens in the respiratory tract. 20) This CYP2A13 C301T polymorphism has been associated with the risk of small cell lung cancer.…”

“…18) Zhang et al 19,20) and Fujieda et al 21) have analyzed structural variations in the CYP2A13 gene. A C to T transition in exon 5 of the CYP2A13 (CYP2A13*7 allele, C3375T, Arg257Cys) has been shown to lead to a significant reduction in enzymatic activity (half the activity of the wild-type enzyme).…”

An Investigation of the Catalytic Activity of CYP2A13*4 with Coumarin and Polymorphisms of CYP2A13 in a Chinese Han Population

“…CYP2A13*3 and CYP2A13*7 were predicted to be null in function, and the other seven single nucleotide polymorphisms all resulted in missense variants (Table 1). The distribution frequencies of some CYP2A13 missense alleles have been investigated in Japanese, French Caucasian, and some other populations (Zhang et al, 2002(Zhang et al, , 2003Fujieda et al, 2003;Cauffiez et al, 2004Cauffiez et al, , 2005Cheng et al, 2004). However, to date, the distribution frequencies of all of the CYP2A13 missense alleles in Chinese Han population have not yet been reported.…”

“…Nine nonsynonymous single-nucleotide polymorphisms have been identified for human CYP2A13, including an insertional frame-shift mutation (133_134T insertion, CYP2A13*3) and a substitution of a stop codon (R101X, CYP2A13*7) (Zhang et al, 2002(Zhang et al, , 2003Fujieda et al, 2003;Cauffiez et al, 2004Cauffiez et al, , 2005Cheng et al, 2004). CYP2A13*3 and CYP2A13*7 were predicted to be null in function, and the other seven single nucleotide polymorphisms all resulted in missense variants (Table 1).…”

Multiplex Genotyping of Cytochrome P450 Single-Nucleotide Polymorphisms by Use of MALDI-TOF Mass Spectrometry

“…Fewer than 70 SNPs of the gene have been reported in the NCBI dbSNP and Human CYP allele databases combined, and only a few of those have been functionally characterized. Since CYP2A13 was characterized, there have been few studies involving SNPs of the gene using PCR single-strand conformation polymorphism or direct sequencing for SNP analysis (21 ). Because of wide applications in pharmacogenomics and environmental cancer studies, there is a need for genotyping SNPs of CYP2C9 and CYP2A13.…”