Fine-mapping the CYP2A6 regional association with nicotine metabolism among African American smokers.

Autor: Pouget JG; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada., Giratallah H; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada., Langlois AWR; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada., El-Boraie A; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada., Lerman C; Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA., Knight J; Data Science Institute and Medical School, Lancaster University, Lancaster, UK., Cox LS; Department of Population Health, University of Kansas School of Medicine, Kansas City, KS, USA., Nollen NL; Department of Population Health, University of Kansas School of Medicine, Kansas City, KS, USA., Ahluwalia JS; Departments of Behavioral and Social Sciences and Medicine, Brown University, Providence, RI, USA., Benner C; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Chenoweth MJ; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada., Tyndale RF; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada. r.tyndale@utoronto.ca.; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. r.tyndale@utoronto.ca.; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada. r.tyndale@utoronto.ca.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Aug 31. Date of Electronic Publication: 2024 Aug 31.
DOI: 10.1038/s41380-024-02703-5
Abstrakt: The nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine) is a stable biomarker for CYP2A6 enzyme activity and nicotine clearance, with demonstrated clinical utility in personalizing smoking cessation treatment. Common genetic variation in the CYP2A6 region is strongly associated with NMR in smokers. Here, we investigated this regional association in more detail. We evaluated the association of CYP2A6 single-nucleotide polymorphisms (SNPs) and * alleles with NMR among African American smokers (N = 953) from two clinical trials of smoking cessation. Stepwise conditional analysis and Bayesian fine-mapping were undertaken. Putative causal variants were incorporated into an existing African ancestry-specific genetic risk score (GRS) for NMR, and the performance of the updated GRS was evaluated in both African American (n = 953) and European ancestry smokers (n = 933) from these clinical trials. Five independent associations with NMR in the CYP2A6 region were identified using stepwise conditional analysis, including the deletion variant CYP2A6*4 (beta = -0.90, p = 1.55 × 10 -11 ). Six putative causal variants were identified using Bayesian fine-mapping (posterior probability, PP = 0.67), with the top causal configuration including CYP2A6*4, rs116670633, CYP2A6*9, rs28399451, rs8192720, and rs10853742 (PP = 0.09). Incorporating these putative causal variants into an existing ancestry-specific GRS resulted in comparable prediction of NMR within African American smokers, and improved trans-ancestry portability of the GRS to European smokers. Our findings suggest that both * alleles and SNPs underlie the association of the CYP2A6 region with NMR among African American smokers, identify a shortlist of variants that may causally influence nicotine clearance, and suggest that portability of GRSs across populations can be improved through inclusion of putative causal variants.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: