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.

尼古丁代谢物比率（NMR；3'羟基可替宁/可替宁）是 CYP2A6 酶活性和尼古丁清除率的稳定生物标志物，在个性化戒烟治疗中具有临床实用性。 CYP2A6区域的常见遗传变异与吸烟者的 NMR 密切相关。在这里，我们更详细地调查了这个区域协会。我们通过两项戒烟临床试验评估了非洲裔美国吸烟者 (N = 953) 中CYP2A6单核苷酸多态性 (SNP) 和 * 等位基因与 NMR 的关联。进行了逐步条件分析和贝叶斯精细映射。假定的因果变异被纳入现有的 NMR 非洲血统特定遗传风险评分 (GRS) 中，并在非裔美国人 (n = 953) 和欧洲血统吸烟者 (n = 933) 中评估了更新后的 GRS 的性能。临床试验。使用逐步条件分析确定了CYP2A6区域中与 NMR 的五个独立关联，包括删除变体CYP2A6*4 (beta = -0.90, p = 1.55 × 10 ^-11 )。使用贝叶斯精细映射确定了六个假定的因果变异（后验概率，PP = 0.67），其中顶级因果配置包括CYP2A6*4 、 rs116670633 、 CYP2A6*9 、 rs28399451 、 rs8192720 和 rs10853742 （PP = 0.09）。将这些假定的因果变异纳入现有的特定血统的 GRS 中，可以对非裔美国吸烟者进行 NMR 预测，并提高欧洲吸烟者的 GRS 的跨血统可移植性。 我们的研究结果表明 * 等位基因和 SNP 都是非洲裔美国吸烟者中CYP2A6区域与 NMR 关联的基础，确定了可能影响尼古丁清除率的变异体的候选名单，并表明可以通过纳入假定的 GRS 来改善人群中 GRS 的可移植性因果变异。