There is consistent selleck chem inhibitor evidence from twin and adoption studies that genetic factors contribute to the etiology of cigarette smoking, playing an important role in smoking initiation, progression to heavy use, and persistence (Fowler et al., 2007; Kendler et al., 1999; Lessov et al., 2004; Munafo & Johnstone, 2008; Sullivan & Kendler, 1999). A meta-analysis (Li, Cheng, Ma, & Swan, 2003) reported that genetic factors were responsible for approximately 50% of the variation noted in both initiation and persistence. However, despite a large number of candidate gene studies (focusing primarily on targets in relevant neurotransmitter pathways and enzymes associated with nicotine metabolism), few reported associations between gene variants and smoking-related phenotypes have proven to replicate reliably.

Recently, however, variation in the 15q24 nicotinic acetylcholine receptor (nAChR) gene cluster CHRNA5-A3-B4 (responsible for encoding ��5, ��3, and ��4 nAChR subunits) has shown promise as a candidate region for smoking behavior. Polymorphisms in this cluster have been linked to multiple smoking-related phenotypes, such as nicotine dependence (Bierut et al., 2008; L. S. Chen, Johnson, et al., 2009; Grucza et al., 2008; S. F. Saccone et al., 2007; Spitz, Amos, Dong, Lin, & Wu, 2008; Thorgeirsson et al., 2008), smoking quantity (Amos et al., 2008; Berrettini et al., 2008; Keskitalo et al., 2009; Lips et al., 2009; Stevens et al., 2008; Thorgeirsson et al., 2008), and smoking cessation (Freathy et al., 2009) as well as smoking-related diseases, such as lung cancer (Amos et al.

, 2008; Hung et al., 2008; Lips et al., 2009; P. Liu et al., 2008; Spitz et al., 2008; Thorgeirsson et al., 2008), chronic obstructive pulmonary disease (Pillai et al., 2009; Young et al., 2008), peripheral arterial disease (Thorgeirsson et al., 2008), and upper aerodigestive tract cancers (Lips et al., 2009). Whether the associations noted between these variants and diseases are direct or mediated via the variants�� association with smoking-related behaviors, or both, remains a topic of debate (see Thorgeirsson & Stefansson, 2010). Two single nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 region, rs16969968 in CHRNA5 and rs1051730 in CHRNA3, have generated particular interest with respect to smoking-related behaviors.

The SNP rs16969968 is notable as a missense mutation, resulting in an amino acid change (aspartate to asparagine) at position 398 in the GSK-3 ��-5 subunit protein (Bierut, 2010). This polymorphism appears to be of functional significance��in vitro studies have demonstrated that ��4��2��5 receptors with the aspartic acid variant exhibit a greater response to a nicotine agonist than ��4��2��5 receptors containing the asparagine substitution (Bierut et al., 2008). Reduced nAChR function may therefore predispose to nicotine dependence.