Several factors contribute to cotinine levels: consumption of nicotine (i.e., heaviness of smoking), conversion of nicotine to cotinine (catalysed primarily by CYP2A6), and cotinine clearance (including cotinine glucuronidation). It is theoretically possible that the reduced function UGT2B10 variant identified in this GWAS function could alter consumption. Reduced clearance of nicotine through glucuronidation (a minor pathway) would theoretically result in modestly longer lasting circulating levels of nicotine, which could reduce smoking if individuals self-titrate nicotine levels. Consistent with this theory, a previous study found that ad libitum smokers with this reduced function UGT2B10 variant had lower nicotine intake14, as indexed by total nicotine equivalent levels. However, other studies (including a much larger study from the same group) have found that this variant has no effect on consumption1617. Further, a decrease in nicotine intake via ad libitum smoking is inconsistent with higher cotinine levels, thus a change in consumption does not explain the association we note with the reduced function UGT2B10 variant and higher cotinine levels. A more likely explanation for our findings is a reduction in cotinine metabolism, through decreased cotinine
