Characterisation and PCR‐based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population

Abstract

Cytochrome P450 2A6 is an important human hepatic P450 which activates pre-carcinogens, oxidises some drugs and constitutes the major nicotine C-oxidase. In fact, results have been presented in the literature which suggested a relationship between the distribution of defective CYP2A6 alleles and smoking behaviour as well as cigarette consumption. In the present report, we describe the structure of a novel CYP2A locus where the whole CYP2A6 gene has been deleted, resulting in an abolished cytochrome P450 2A6-dependent metabolism. The origin of this locus is apparently due to an unequal crossover event between the 3P-flanking region of the CYP2A6 and CYP2A7 genes. A rapid PCR-based method for the detection of the CYP2A6del allele was developed and the allele frequency was 15.1% among 96 Chinese subjects, but only 1.0% in Finns (n = 100) and 0.5% in Spaniards (n = 100). In the Chinese population, we did not detect any CYP2A6*2 alleles using an improved genotyping procedure, in contrast to the 11^20% previously reported. It is concluded that genotyping for the CYP2A6del allele is of great importance in studies correlating, for example, smoking behaviour, pre-carcinogen activation or drug metabolism to the CYP2A6 genotype, in particular when oriental populations are investigated.z 1999 Federation of European Biochemical Societies.

Effects of cytochrome P450 (CYP) 2A6 gene deletion and CYP2E1 genotypes on gastric adenocarcinoma

“…Table I shows the CYP2A6 genotype frequencies of our control group and the reported ethnic population. 5,9,13,15,20,21 Electrophoretic patterns of CYP2A6 *1/*1 and *1/*4 by polymerase chain reaction were the same pattern in our analysis method and did not discriminate CYP2A6 *1/*1 from *1/*4. There were significant interethnic differences in certain CYP2A6 genotype frequencies.…”

Implications of gene copy-number variation in health and diseases

“…Frequency of the deletion variant (CYP2A6del) when studied in 96 Chinese subjects, was found to be 15.1%, but only 1% in Finns (n¼100) and 0.5% in Spaniards (n¼100). 60 Apart from deletion, a novel duplication was reported in the African-American population and was found to increase nicotine metabolism and may affect smoking behavior in contrast to the European-American, Korean or Japanese populations. 61 Another gene studied in the Caucasian-American and in the African-American population is SULT1A1 gene, which catalyzes the sulfate conjugation of a wide variety of drugs and is found to be genetically polymorphic.…”

CYP2A7 polymorphic alleles confound the genotyping of CYP2A6*4A allele

“…In the genotyping method by Oscarson et al, 8 the CYP2A6*4 allele was detected with a two-step PCR analysis. In the first PCR reaction (PCR I), the primer set of 2Aex7F and 2A6R1 was used (Figure 6b).…”

“…However, this genotyping method cannot distinguish between CYP2A6*4 and CY-P2A7*1D alleles, as the primer of 2A6R1 can anneal to the CYP2A7*1D allele (Figure 6b). Oscarson et al 8 reported that the allele frequencies of CYP2A6*4 in Finns (n ¼ 100) and Spaniards (n ¼ 100) were 1.0 and 0.5%, respectively. Owing to the presence of the CYP2A7*1D alleles, the allele frequencies of CYP2A6*4 in these populations might be actually lower than those values.…”

“…8 In the CYP2A6*4 (CYP2A6*4A, CYP2A6*4B, and CYP2A6*4D) alleles, the entire CYP2A6 gene is deleted and the enzymatic activity is lacking. [8][9][10][11] The CYP2A6*1X2 allele has a duplication of the CYP2A6 gene as the reciprocal product of the CYP2A6*4D allele after an unequal crossover event. 12 The CYP2A6*12 is a CYP2A7/CYP2A6 hybrid allele created by an unequal crossover in intron 2.…”