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首页> 外文期刊>Pharmacogenetics >Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population.
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Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population.

机译：CYP2D6基因突变及其对西非人群酶功能的影响的分析。

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摘要

The data on differences in the metabolic handling of the CYP2D6 probe drugs sparteine and debrisoquine, and the relationship between phenotype and genotype and gene frequencies for several mutant CYP2D6 alleles in African populations are limited and sometimes controversial. Therefore, in a West African population (Ghana), we investigated (i) the phenotype for sparteine debrisoquine by phenotyping 201 individuals with both drugs and (iii) the genotype for CYP2D6 (n = 326) and debrisoquine (n = 201) oxidation, (ii) the coregulatory control of sparteine and alleles *3 and *4 in 133 individuals and for the alleles *1, *2, *3, *4, *5, *6, *7, *8, *9, *10, *14, *16, *17, *2b, *2xN, *2bxN in 193 individuals. Of the 326 individuals phenotyped with sparteine, eight had a metabolic ratio (MR)sp > 20 corresponding to a poor metabolizer frequency of 2.5% [95% (confidence interval) CI = 1.06-4.77]. The prevalence of the poor metabolizer phenotype for debrisoquine oxidation was 3% (95% CI = 1.1-6.39) with six of the 201 individuals having a MR greater than 12.6. The distribution of the MR of sparteine was trimodal whereas MR of debrisoquine was unimodally distributed with a pronounced kurtosis. In individuals phenotyped with both drugs, there was a significant correlation between the MRs (r(s) = 0.63, P < 0.001). The CYP2D6 alleles *1, *2 and *17 were the most common functional alleles occurring with frequencies of 43.7, 10.6 and 27.7%, respectively. The three other observed functional alleles *2xN, *10 and *20 had much lower frequencies (1.6%, 3.1% and 0.3%, respectively). Of the eight non-functional alleles, only *4 (6.3%) and *5 (6.0%) could be found. The allele *5 occurred with the same frequency as in Caucasian populations (4.1%) but the *4 allele had a much lower frequency (Caucasians 19.5%). One individual with *1/*1 was a poor metabolizer for sparteine and debrisoquine indicating the existence of as yet unknown non-functional alleles in this West African population. Although the prevalence of poor metabolizers and the number of heterozygotes for non-functional alleles was much lower in Ghanaians, the median MRsp of 0.7 was significantly higher in this population compared with a median MRsp of 0.4 in Caucasians, indicating a lower metabolic clearance for CYP2D6 substrates in the West Africans. The lower metabolic activity in Ghanaians could not be explained solely by the high frequency of the *17 allele, which is associated with an impairment of CYP2D6 enzyme function. In addition, a higher median MRsp of 0.5 corresponding to metabolic clearance of 346 ml/min was observed among extensive metabolizers with the genotype *1/*1. Thus, compared with the median of MRsp = 0.28 (CLmet 573 ml/min) in Caucasians homozygous for *1, the metabolic clearance of sparteine was 40% lower on average in respective Ghanaians.
机译：关于CYP2D6探针药物sparteine和debrisoquine在代谢处理上的差异以及非洲人群中几个突变CYP2D6等位基因的表型与基因型和基因频率之间的关系的数据有限，有时会引起争议。因此，在西非人群（加纳）中，我们调查了（i）对201种药物同时使用这两种药物进行表型鉴定的斯巴地丁debrisoquine的表型，以及（iii）CYP2D6（n = 326）和debrisoquine（n = 201）的基因型， （ii）在133个个体中对斯巴丁氨酸和等位基因* 3和* 4的共调节控制，以及等位基因* 1，* 2，* 3，* 4，* 5，* 6，* 7，* 8，* 9，* 193个个体中的10，* 14，* 16，* 17，* 2b，* 2xN，* 2bxN。在326名用斯巴丹定型的个体中，有8名的代谢率（MR）sp> 20，对应于2.5％的不良代谢频率[95％（置信区间）CI = 1.06-4.77]。代谢不良的表型对地溴异喹的患病率为3％（95％CI = 1.1-6.39），在201名个体中有6名的MR大于12.6。 Sparteine的MR分布是三峰分布的，而debrisoquine的MR是单峰分布的，具有明显的峰度。在两种药物表型的个体中，MR之间存在显着相关性（r（s）= 0.63，P <0.001）。 CYP2D6等位基因* 1，* 2和* 17是最常见的功能等位基因，频率分别为43.7、10.6和27.7％。观察到的其他三个功能等位基因* 2xN，* 10和* 20的频率要低得多（分别为1.6％，3.1％和0.3％）。在八个非功能性等位基因中，仅发现* 4（6.3％）和* 5（6.0％）。 * 5等位基因的发生频率与高加索人群相同（4.1％），但* 4等位基因的发生频率要低得多（高加索人为19.5％）。一个具有* 1 / * 1的个体代谢较弱的半胱氨酸和debrisoquine，表明该西非人群中尚存在未知的非功能性等位基因。尽管加纳尼亚人的不良代谢者患病率和非功能性等位基因杂合子的数量要低得多，但该人群的中位MRsp为0.7，而高加索人的中位MRsp为0.4，这表明CYP2D6的代谢清除率较低西非人的底物。加纳人较低的代谢活性不能仅通过* 17等位基因的高频率来解释，这与CYP2D6酶功能的损害有关。此外，在基因型为* 1 / * 1的广泛代谢者中，观察到更高的中值MRsp为0.5，对应于346 ml / min的代谢清除率。因此，与纯合子* 1的高加索人纯种的MRsp = 0.28（CLmet 573 ml / min）的中位数相比，加纳人的斯巴汀的代谢清除率平均低40％。

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