Initially, Saccone et al. [14] reported associations of multiple single nucleotide polymorphisms (SNPs) in the CHRNA5/A3/B4 gene cluster with ND, with the smallest P value of 0.00064 for rs16969968 (D398N) in exon 5 of CHRNA5. However, the significance of these results did not survive correction for multiple testing. Shortly after the initial publication, rs1051730 (Y215Y) in exon 5 of CHRNA3 was reported to be significantly associated at a genome-wide level with smoking quantity (SQ) [15] and lung cancer (LC) [15], [16], [17]. Several other genome-wide and candidate gene-based association studies provided further evidence for the association of variants of the CHRNA5/A3/B4 cluster with various nicotine-related behaviors [14], [18], [19], [20], [21], [22], [23], [24], [25]. In contrast, other studies have failed to reveal a significant association of this gene cluster with ND or other smoking-related phenotypes [26], [27].
