To better understand the genetic architecture of the CYP2A6 locus, we assessed the CPD association in terms of haplotypes underlying the CNP (rs8102683) and rs11878604 under the assumption of additive effect (Figure S7). Estimated haplotype frequencies revealed that the deletion (0 copies) at the CNP and the mutant allele rs11878604[C] are almost mutually exclusive (Table 1). Haplotypes including either of these variants showed a similar effect on CPD when compared with the reference haplotype (one copy at the CNP and the ancestral allele rs11878604[T]). Hence, individuals with a haplotype of the deletion (0 copies) and the ancestral allele rs11878604[T] (we refer to this as the “deletion haplotype”) require an average of four fewer cigarettes to maintain the same nicotine level as individuals who are homozygous for the reference haplotypes (). Likewise, individuals with a haplotype of the mutant allele rs11878604[C] and one copy at the CNP (we refer to this as the “mutant haplotype”) also require an average of three fewer cigarettes to maintain the same nicotine level as individuals who are homozygous for the reference haplotypes (). These patterns were completely replicated in the replication set (Table 1).
