A Phenome-wide association study of a genetic score for the nicotine metabolite ratio

Abstract

AbstractBackgroundFaster nicotine metabolism associates with heavier smoking and challenges in cessation. Understanding which variables and diseases associate with the rate of nicotine metabolism, defined as the nicotine metabolite ratio (NMR), the 3-hydroxycotinine-to-cotinine-ratio, is crucial for drug development and personalized interventions for nicotine addiction.MethodsWe performed a hypothesis-free phenome-wide association study (PheWAS) of over 21 000 outcome variables from UK Biobank (UKB) to explore how the NMR associates with the phenome. As the exposure variable, we used a genetic score for faster nicotine metabolism based on 10 putatively causal genetic variants, explaining 33.8 % of the variance in the NMR. We analyzed ever and never smokers separately to assess whether the association had a causal pathway through smoking. Additionally, we performed complementary PheWASs in FinnGen and MRBase.ResultsFaster nicotine metabolism was associated with a greater number of cigarettes smoked per day, increased smoking compared to ten years ago, and greater smoking in the past. We found, inconsistently with previous literature, faster nicotine metabolism to be associated with higher odds of quitting. Notably, we also found associations that did not appear to differ between ever and never smokers, suggesting the association pathway may not go through smoking: faster nicotine metabolism was associated with worse liver enzyme and lipid values with respect to associated diseases, as well as increased coffee and tea consumption.ConclusionsWe observed expected associations with several smoking and nicotine -related phenotypes, but could not replicate prior findings on cessation. Our other findings support a possibility that a future therapy converting fast metabolizers to slower ones could work without adverse side effects and potentially even provide other health-related benefits. Further research using different data and study designs is warranted to validate and extend these discoveries.