Cotinine is a strong biomarker of cigarette consumption in daily smokers518192021. The confirmation of the CHRNA5-A3-B4 locus by our meta-analysis, and the conditional analyses results which parallel those of much larger GWAS of self-reported cigarette consumption3 demonstrate the utility of cotinine to identify genetic variants responsible for smoking quantity with greater statistical power (see also Table S5). However, since cotinine is an intermediate metabolite, its concentration is influenced by multiple contributing pathways. Individual differences in nicotine and cotinine metabolism, both via glucuronidation, as suggested here, and by oxidative metabolism as previously observed18 have confounding effects. While substantially more accurate than self-report smoking levels, future studies seeking an even more comprehensive assessment of tobacco exposure may consider using total nicotine equivalents (i.e., sum of nicotine and all its metabolites), a robust measure of nicotine exposure which intrinsically controls for variation in genes influencing both nicotine and cotinine metabolism (including variation in UGT2B10 and CYP2A6)1222.
