An important open question is the degree to which the associations between chr15q25 variants and lung cancer are due to their effects on smoking. When comparing smoking and lung cancer single-SNP results, the patterns of association (odds ratios and directions of effect) were similar across the loci studied. Locus 1 is associated with lung cancer even when controlling for amount smoked per day (p = 1.99×10−21, OR = 1.31). This result suggests possible direct genetic effects of locus 1 on this cancer, at least in the presence of smoking. However, CPD is not a sufficient proxy for carcinogen exposure [34], and in never-smokers there is a lack of association between locus 1 and lung cancer [35]–[37], so it is possible that more refined adjustment for smoking will reduce or abolish this association.
