GWAS using metabolites measured from serum have been highly successful in identifying underlying genes [23, 24], highlighting the power of informative phenotypes. Our objective was to utilize NMR, a genetically informed biomarker of nicotine metabolism, in a GWAS meta-analysis of cotinine-verified (≥10ng/ml) current smokers from three Finnish cohorts to identify novel genetic variants influencing nicotine metabolism rate. In Caucasians, with up to 90% of individuals being normal metabolizers, a minor fraction of variance in inter-individual differences in nicotine metabolism is accounted for by known reduced activity CYP2A6 variants. Thus, we expected that other contributing factors, such as other genes, but also novel regulators of CYP2A6 action or expression, including epigenetic mechanisms, are bound to exist. Our data highlighted novel genetic and epigenetic influences on NMR, deepening our understanding on factors influencing nicotine metabolism and providing valuable guidelines for further focused studies.
