The impact of CYP2A6 and CYP2B6 genetic variation on nicotine metabolism, tobacco use behaviours, and nicotine biomarkers was investigated in a group of Alaska Natives (n = 400). CYP2A6 and CYP2B6 allele frequencies were unique and associations of CYP2A6 genotype and CYP2A6 activity (plasma and urine trans 3’-hydroxycotinine/cotinine (3HC/COT) ratios) were robust. Notably, this population possessed a more rapid rate of CYP2A6 activity (higher plasma 3HC/COT) when compared to CYP2A6 wild-type individuals in other ethnic groups (ANOVA P < 0.001). Also demonstrated was a significant difference in urine total nicotine equivalents by CYP2A6 activity median split (t-test P < 0.01), the first evidence of nicotine titration by CYP2A6 activity within a light smoking population. Overall, this population possessed a distinctive pattern of CYP2A6 and CYP2B6 variant frequencies and a faster rate of nicotine metabolism, which may in part explain higher levels of tobacco use prevalence and tobacco-related disease risk.

The impact of CYP2A6 and CYP2B6 genetic variation on nicotine metabolism, tobacco use behaviours, and nicotine biomarkers was investigated in a group of Alaska Natives (n = 400). CYP2A6 and CYP2B6 allele frequencies were unique and associations of CYP2A6 genotype and CYP2A6 activity (plasma and urine trans 3’-hydroxycotinine/cotinine (3HC/COT) ratios) were robust. Notably, this population possessed a more rapid rate of CYP2A6 activity (higher plasma 3HC/COT) when compared to CYP2A6 wild-type individuals in other ethnic groups (ANOVA P < 0.001). Also demonstrated was a significant difference in urine total nicotine equivalents by CYP2A6 activity median split (t-test P < 0.01), the first evidence of nicotine titration by CYP2A6 activity within a light smoking population. Overall, this population possessed a distinctive pattern of CYP2A6 and CYP2B6 variant frequencies and a faster rate of nicotine metabolism, which may in part explain higher levels of tobacco use prevalence and tobacco-related disease risk.