Identification of CYP2D6 impaired functional alleles in Mexican Americans.
Identification of CYP2D6 impaired functional alleles in Mexican Americans.
复制标题
墨西哥裔美国人中 CYP2D6 功能受损等位基因的鉴定。
DOI：
10.1007/s00228-005-0044-4
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发表时间：
2005
影响因子：
2.9
通讯作者：
Wan,Yu-JuiYvonne
中科院分区：
文献类型：
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作者：
Luo,Huai-Rong;Gaedigk,Andrea;Aloumanis,Vasileios;Wan,Yu-JuiYvonne
目的扩大细胞色素P450磷酸酶D6基因的基因分型分析，进一步从遗传因素上解释美国墨西哥人细胞色素P450 2D6活性的变异。方法对264例美国墨西哥人进行了与*6、*7、*8、*9、*11、*14、*29、*41、*45和*46等位基因相关的基因序列变异以及2988G>；A SNP的检测；236例已用右美沙芬进行了表型分析。所有受试者先前都进行了CYP2D6*2、*3、*4、*5、*10、*17的基因分型，并存在基因重复。结果墨西哥裔美国人存在较高频率的功能性等位基因(CYP2D6*1和*2；73.1%)，其次是非功能性等位基因*4(10.0%)和功能减退等位基因*41(9.5%)。基因频率分别为1.7%、0.4%、1.1%、2.8%、0.8%和5.7%，只有1个个体(*2/*3、*1/*17和*4/*29)存在CYP2D6*3、*17、*4/*29，而在本研究人群中缺失。与存在*41[2988A]相比，存在*41[−1584C]可以更准确地预测细胞色素P450 2D6活性降低。1例基因型/表型不一致的受试者通过存在CYP2D6*6等位基因(*4/*6)而得到解决，而另外两例仍存在不一致的病例(*41/*41和*1/*1)。结论功能等位基因*9、*10和*41上的CYP2D6*4、*5和*6空等位基因是导致墨西哥裔美国人右美沙芬氧化能力降低的主要原因。这些发现可能对墨西哥裔美国人服用的CYP2D6底物的安全性和有效性有影响。
ObjectivesTo extend the genotyping analysis of theCYP2D6gene and further explain variability of CYP2D6 activity in Mexican Americans by genetic factors.MethodsCYP2D6gene sequence variations associated with*6,*7,*8,*9,*11,*14,*29,*41,*45, and*46alleles as well as the 2988G>A SNP were examined in 264 Mexican Americans; 236 had previously been phenotyped with dextromethorphan. All subjects were previously genotyped forCYP2D6*2,*3,*4,*5,*10,*17, and the presence of a gene duplication. Associations between genotype and CYP2D6 activity were determined.ResultsMexican Americans revealed a high frequency of functional alleles (CYP2D6*1and*2; 73.1%), followed byCYP2D6*4(non-functional, 10.0%) and the reduced-function allele*41(9.5%). The frequencies ofCYP2D6*5,*6,*9,*10, duplication, and 2988A were 1.7%, 0.4%, 1.1%, 2.8%, 0.8%, and 5.7%, respectively.CYP2D6*3,*17, and*29were found only in one individual (CYP2D6*2/*3,*1/*17, and*4/*29), whileCYP2D6*7,*8,*11,*14,*45, and*46were absent in this study population. Decreased CYP2D6 activity was more accurately predicted by the presence*41[−1584C] compared to*41[2988A]. One genotype/phenotype discordant subject was resolved by the presence of aCYP2D6*6allele (*4/*6), while two other cases remained discordant (*41/*41and*1/*1).ConclusionsTheCYP2D6*4,*5, and*6null alleles along the reduced function alleles*9,*10, and*41are the major cause for diminished dextromethorphan oxidative capacity in Mexican Americans. These findings may have implications for the safety and efficacy of CYP2D6 substrates taken by Mexican Americans.