Two other GWAS reports using lung cancer case-control designs, reported that rs1051730 exceeded genome-wide significance levels for association with lung cancer but having failed to measure significant associations with smoking behavior, concluded that the effect on lung cancer risk was independent of smoking behavior. Our analysis demonstrating that strong associations between CHRNA5-A3-B4 variants and nicotine dependence are seen only amongst smokers who began daily smoking relatively early in life, coupled with the detailed molecular definition of the CHRNA5-A3-B4 haplotype structures generated from resequencing, supports the hypothesis that the disease outcome effects of rs1051730, and other surrogate markers for Haplotype A, are mediated by nicotine addiction. In our opinion, the biological link between nicotinic receptor variants and smoking behavior is more plausible than a direct effect of these ion channels on lung cancer susceptibility. The association of rs1051730 with lung cancer may therefore be due to disease mortality related to long-term, persistent smoking caused by severe nicotine addiction [60],[61].
