Single nucleotide polymorphisms of the human cyp2a13 gene: evidence for a null allele.

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 tobacco-related 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.