A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

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Nicotine metabolism rate significantly varies between individuals and affects smoking behavior. Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on nicotine metabolism rate. Twin and family studies have shown that genes influence nicotine metabolism; however, only a minor fraction of variance in inter-individual differences in nicotine metabolism is accounted for by known reduced activity variants in CYP2A6, the main metabolic enzyme for nicotine. Here we utilized a biomarker of nicotine metabolism (nicotine metabolite ratio, NMR) in a genome-wide association study of three Finnish cohorts to identify novel genetic variants influencing nicotine metabolism rate. Our results enclose three independent novel signals in CYP2A6. The detected variants explain a strikingly large fraction of variance (up to 31%) in NMR in the study samples. A genetic risk score constructed using the independent signals predicts smoking quantity in two independent Finnish samples. Further, we enclose evidence for plausible epigenetic mechanisms influencing NMR. With the advent of other nicotine delivery devices than tobacco, such as e-cigarettes, the need to understand the long-term consequences and action mechanisms of nicotine and its metabolism are of high public health relevance.

Vyšlo v časopise: A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005498
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005498

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