In addition to the myriad of carcinogens present in tobacco smoke, nicotine and the nicotinic acetylcholine receptor pathway may be involved in the pathogenesis of lung cancer through inhibition of proapoptotic pathways and promotion of cell proliferation, invasion, and angiogenesis.19–21 Candidate genes in this 15q region include CHRNA3 and CHRNA5. The strong link between smoking amount and lung cancer makes it difficult to determine whether lung cancer risk is more directly associated with variation in this genetic region or indirectly through increased exposure because of nicotine addiction. Three of the four GWAS studies and this study did not include measures of nicotine dependence other than smoking dose and duration making nicotine addiction difficult to classify. SNPs in this region have been associated with nicotine dependence severity among subjects initiating daily smoking at or before age 16 years11 and heavy smoking. 10 These studies were conducted in healthy populations and included only whites. Most recently, Le Marchand et al.12 demonstrated that variants in CHRNA3 (rs1051730, and included in this study) and CHRNA5 (rs16969968, which is in near perfect LD with rs1051730
