Cotinine is a relatively stable compound with a half-life of 15–20h, and is superior as a biomarker of nicotine intake compared to self-reported smoking quantity (cigarettes per day, CPD) [15]. The ratio of 3-hydroxycotinine/cotinine (i.e. nicotine metabolite ratio, NMR) is an established biomarker of CYP2A6 activity, as well as nicotine metabolism rate, and it correlates strongly with total nicotine clearance [3]. Twin studies suggest an important genetic contribution to nicotine metabolism, measured using the nicotine metabolite ratio. Swan and colleagues reported that the estimated additive genetic effects on plasma NMR were 0.67 (95% CI 0.56–0.76), dropped to 0.61 (95% CI 0.48–0.71) after adjusting for non-genetic covariates, and further reduced to 0.49 (95% CI 0.33–0.63) when CYP2A6 was adjusted for [16], suggesting that known CYP2A6 variants identified at the time accounted for approximately 15–20% of NMR heritability.
