A CHRNA5 promoter study, that excluded rs2036527:G>A, found significantly more reporter activity was obtained from the T-G than the T-C (rs55853698:T>G-55781567:C>G) 5′UTR haplotype (Doyle et al., 2011). Additionally, individuals with the minor allele (‘T’) at CHRNA5 intronic SNP rs588765:C>T had 2–3-fold higher CHRNA5 mRNA expression (Wang et al., 2009b). The individual with the exon 2 frame-shift is homozygous ‘T’ at rs55853698:T>G, but heterozygous at rs55781567:C>G in the CHRNA5 5′UTR, and is heterozygous at intronic SNP rs588765:C>T raising the possibility of higher expression from one of the CHRNA5 alleles. If the exon 2 frame-shift occurs on a background allele that is rs55853698:T-rs55781567:C-rs588765:C, then we cannot exclude the possibility that, although the aberrant allele may undergo NMD, this individual has a normal level of α5 protein expression from higher mRNA expression from the other CHRNA5 allele that is rs55853698:T-rs55781567:G-rs588765:T. Therefore, the role of the exon 2 deletion in mediating this individual’s heavy smoking remains unclear.
