It has previously been suggested that the deletion of the CYP2A6 gene strongly down-regulates nicotine metabolism [12], and it is very common only in the Japanese population [14]. This allele is often referred to as CYP2A6*4, a classical CYP2A6 functional allele (Human Cytochrome P450 Allele Nomenclature Committee; see URLs), which has been captured by the CNP (rs8102683) in our study. However, the secondary SNP (rs11878604) located in an intergenic region has been unknown a priori in any previous study and may not have any direct functional impact on the CYP2A6 gene. Therefore, we investigated the LD between rs11878604 and the CYP2A6 functional alleles using phased haplotype data from the imputation reference panel (Table S5), which included several known deleterious SNPs in the CYP2A6 gene. Consequently, we found that the mutant haplotype is linked to the functional alleles CYP2A6*7 (or possibly *36 or *37), *9 (or possibly *15) and *10, all of which are known to strongly down-regulate nicotine metabolism [12]. This observation is not surprising because the mutant haplotype strongly reduced daily cigarette consumption (Table 1).
