Our previous studies showed there are at least two possible biological mechanisms accounting for these associations: an amino acid variation in exon 5 of CHRNA5 (rs16969968; D398N), which likely alters protein structure and receptor function and variation in CHRNA5 mRNA expression levels [8], [19], [20]. In European American populations, the nicotine dependence risk allele (minor allele) of the non-synonymous variant (rs16969968; D398N) primarily occurs on the haplotype containing the low mRNA expression allele of CHRNA5. The major allele at rs16969968 occurs on both high and low expression haplotypes. When the major allele occurs on the low mRNA expression haplotype of CHRNA5, the risk for nicotine dependence and lung cancer is significantly lower when compared to major alleles on the higher mRNA expression haplotype [19]. Lung cancer studies also demonstrated up-regulation of CHRNA5 mRNA expression in lung adenocarcinomas, compared to normal lung tissue [21], [22]. In addition, CHRNA5 mRNA expression in normal lung tissue was significantly associated with the genotype of rs16969968. mRNA expression level was about 2.5-fold lower in patients who are homozygous for the minor allele of rs16969968 than patients who are homozygous for the major allele [22].
