SIR – Two recent studies in high-ranking journals have reported results on the association between CYP2A6 polymorphism and tobacco smoking.1, 2 Our data, derived from a novel and specific genotyping method3 that was applied to a large and racially homogenous representative population sample, strongly suggest that CYP2A6 alleles expressing decreased enzymatic activity are not associated with a reduced risk of tobacco dependence or lower levels of cigarette smoking.
Nicotine is metabolized to cotinine by the CYP2A6 enzyme, which is genetically variable. In a recent issue of Nature, Pianezza et al reported that subjects who lacked fully functional CPY2A6 and had decreased nicotine metabolism were protected against becoming tobacco-dependent smokers, and that those smokers having at least one defective CYP2A6 allele (null allele) smoked significantly fewer cigarettes than those with the normal gneotype.1 To the contrary, in a recent study, London et al reported that smokers with at least one CYP2A6-null allele smoked slightly more than those with the normal genotype, and that there was no difference between these two groups concerning the risk of becoming a smoker.2 However, they found a trend which suggested that subjects with two CYP2A6-null alleles may have a lower risk of becoming tobacco smokers. In both of the aforementioned studies, the CYP2A6 genotype was identified by the method of Fernandez-Salguero et al,4 which was recently reported to give erroneous results relative to coumarin hydroxylase phenotype, a probe reaction for the CYP2A6 enzyme.3 Therefore, we decided to study the association between the CYP2A6 genotype and tobacco smoking by using a new allele-specific PCR genotyping method that identifies the major defective CYP2A6 allele and accurately predicts the phenotype.3 We have used PCR-primers which specifically amplified exons 1–4 of the CYP2A6 gene without amplifying highly homologous CYP2A13 genes or CYP2A7 genes or CYP2A7 pseudogenes. This 1.8-kb PCR fragment was subsequently used as a template for an allele-specific PCR reaction as described in detail by Oscarson et al.3
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