The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans.
The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans.
复制标题
DOI：
10.1097/fpc.0b013e328346e8c0
复制
发表时间：
2011-07
影响因子：
2.6
通讯作者：
Murphy SE
中科院分区：
文献类型：
--
作者：
Bloom J;Hinrichs AL;Wang JC;von Weymarn LB;Kharasch ED;Bierut LJ;Goate A;Murphy SE
细胞色素 P450 2A6 (CYP2A6) 是尼古丁代谢的主要催化剂。为了开发尼古丁代谢的预测遗传模型，对 189 名欧洲裔美国人中氘代 (D2)-尼古丁向 D2-可替宁的转化进行了量化，并评估了 CYP2A6 基因型对首过尼古丁代谢变异性的贡献。具体来说，1)口服给药后D2-可替宁/(D2-可替宁+D2-尼古丁)的单时间点测量被用作CYP2A6活性的指标； 2) CYP2A6单倍型的影响被视为乘法作用； 3) 计算受试者池中所有单倍型的参数估计值，由一组先前报道的影响功能的多态性定义，包括基因拷贝数； 4) 基于单倍型之间差异的统计证据，模型中应包含最少数量的预测多态性。最终模型包含 7 个多态性，并且符合 D2-尼古丁口服给药 30 分钟后的表型，R2=0.719。该模型的预测能力很强：男性 (n=89) 计算的参数估计值可预测女性 (n=100) 的表型，R2=0.758，反之亦然，R2=0.617；当前吸烟者 (n=102) 计算的估计值可预测以前吸烟者 (n=86) 的表型，R2=0.690，反之亦然，R2=0.703。单倍型比较还表明，CYP2A6*12 是功能丧失等位基因，与 CYP2A6*4 和 CYP2A6*2 无法区分，并且 CYP2A6*1B 5' UTR 转换对代谢的影响可以忽略不计。在控制 CYP2A6 基因型后，发现新陈代谢增加与女性性别 (p= 4.8×10−4) 和当前吸烟 (p=0.02) 之间存在适度关联。
Cytochrome P450 2A6 (CYP2A6) is the primary catalyst of nicotine metabolism. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, 1) single time-point measures of D2-cotinine/(D2-cotinine + D2-nicotine) following oral administration were used as a metric of CYP2A6 activity; 2) the impact of CYP2A6 haplotype was treated as acting multiplicatively; 3) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and 4) a minimum number of predictive polymorphisms are justified to be included in the model based on statistical evidence of differences between haplotypes. The final model includes seven polymorphisms and fits the phenotype, 30 minutes following D2-nicotine oral administration, with R2=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R2=0.758 and vice versa with R2=0.617; estimates calculated in current smokers (n=102) predict phenotype in former smokers (n=86) with R2=0.690 and vice versa with R2=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss of function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′ UTR conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype modest associations were found between increased metabolism and both female gender (p= 4.8×10−4) and current smoking (p=0.02).