The CHRNA5-CHRNA3-CHRNB4 gene-cluster encodes for the nicotinic acetylcholine receptor subunits alpha five, three, and beta four. In this region, single nucleotide polymorphisms (SNPs) repeatedly associated with smoking include a non-synonymous (aspartic acid [D] to asparagine [N]; rs16969968) SNP at codon 398 of CHRNA5 and a synonymous SNP (rs1051730) in CHRNA3. The asparagine allele at CHRNA5-rs16969968 has been associated with nicotine dependence/heavy smoking(7, 8), pleasurable response to smoking(9), and decreased response to nicotine agonists in vitro(14). The CHRNA3-rs1051730[A] has been associated with nicotine dependence(3, 15), smoking quantity(3), and increased susceptibility to develop lung cancer and vascular disease among smokers(3–5). According to a recent meta-analysis, each copy of the CHRNA3-rs1051730[A] allele accounts only for ~0.5% of the variance in number of cigarettes smoked/day. Nevertheless the overall P value for this large meta-analysis including >74,000 participants was ~10−73, making this finding one of the most consistent across the entire panorama of genetic-association studies on human behavior(16). Of note, CHRNA3-rs1051730[A] is more common in heavy-smokers (≥10cigarette/day) than non-smokers. In contrast, frequency of this allele appears to be reduced, rather than increased, among light-smokers than non-smokers (3, 17).
