Cytochrome P450 2D6 (CYP2D6) is a key enzyme in drug response owing to its involvement in the metabolism of ~ 25% of clinically prescribed medications. The encoding CYP2D6 gene is highly polymorphic, and many pharmacogenetics studies have been performed worldwide to investigate the distribution of CYP2D6 star alleles (haplotypes); however, African populations have been relatively understudied to date. In this study, the distributions of CYP2D6 star alleles and predicted drug metabolizer phenotypes—derived from activity scores—were examined across multiple sub-Saharan African populations based on bioinformatics analysis of 961 high-depth whole genome sequences. This was followed by characterization of novel star alleles and suballeles in a subset of the participants via targeted high-fidelity Single-Molecule Real-Time resequencing (Pacific Biosciences). This study revealed varying frequencies of known CYP2D6 alleles and predicted phenotypes across different African ethnolinguistic groups. Twenty-seven novel CYP2D6 star alleles were predicted computationally and two of them were further validated. This study highlights the importance of studying variation in key pharmacogenes such as CYP2D6 in the African context to better understand population-specific allele frequencies. This will aid in the development of better genotyping panels and star allele detection approaches with a view toward supporting effective implementation of precision medicine strategies in Africa and across the African diaspora.

中文翻译：

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撒哈拉以南非洲人群中 CYP2D6 药理学变异的表征

细胞色素 P450 2D6 (CYP2D6) 是药物反应中的关键酶，因为它参与约 25% 的临床处方药物的代谢。编码CYP2D6的基因具有高度多态性，世界范围内进行了许多药物遗传学研究以研究CYP2D6星等位基因（单倍型）的分布；然而，迄今为止，非洲人口的研究相对不足。在本研究中， CYP2D6的分布基于对 961 个高深度全基因组序列的生物信息学分析，对多个撒哈拉以南非洲人群的星等位基因和预测的药物代谢表型（源自活动评分）进行了检查。随后通过靶向高保真单分子实时重测序（Pacific Biosciences）表征一部分参与者中的新星等位基因和亚等位基因。这项研究揭示了不同非洲民族语言群体中已知CYP2D6等位基因和预测表型的不同频率。通过计算预测了27 个新的CYP2D6星等位基因，并进一步验证了其中两个。这项研究强调了研究CYP2D6等关键药物基因变异的重要性在非洲背景下更好地了解特定人群的等位基因频率。这将有助于开发更好的基因分型面板和星等位基因检测方法，以支持在非洲和整个非洲侨民中有效实施精准医学战略。