There is no question that significant progress has been made in identifying the CHRNA5/A3/B4 cluster as a susceptibility locus for smoking and lung cancer. However, several important issues remain to be addressed. First, it is important to determine which variant(s) is responsible for the associations with ND and lung cancer. Within this region, rs1051730 has been associated with both ND (Saccone and others 2007; Thorgeirsson and others 2008; Weiss and others 2008) and lung cancer (Amos and others 2008; Hung and others 2008; Thorgeirsson and others 2008) whereas rs8034191 is associated primarily with lung cancer (Amos and others 2008; Hung and others 2008). In addition, several other SNPs, such as rs16969968, rs1317286, and rs6495308, are associated with ND. Of these, rs16969968 is most noteworthy because it represents a nonsynonymous α5 coding variant (e.g., aspartic acid to asparagine at position 398 of the polypeptide chain), resulting in a substitution of a negatively charged residue within the M3–M4 intracellular loop, a region thought to be involved in receptor trafficking. A recent function study (Bierut and others 2008) showed that the variant forms
