Malinga Thandeka V B, Othman Houcemeddine, Paximadis Maria, Tiemessen Caroline T, Ramsay Michèle, Hazelhurst Scott, Twesigomwe David
Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Division of Human Genetics, National Health Laboratory Service, and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Clin Pharmacol Ther. 2025 May;117(5):1338-1357. doi: 10.1002/cpt.3557. Epub 2025 Jan 20.
Tuberculosis (TB) is a major health burden in Africa. Although TB is treatable, anti-TB drugs are associated with adverse drug reactions (ADRs), which are partly attributed to pharmacogenetic variation. The distribution of star alleles (haplotypes) influencing anti-TB drug metabolism is unknown in many African populations. This presents challenges in implementing genotype-guided therapy in Africa to decrease the occurrence of ADRs and enhance the efficacy of anti-TB drugs. In this study, we used StellarPGx to call variants and star alleles in NAT1, NAT2, GSTM1, GSTT1, GSTP1, and CYP2E1, from 1079 high-depth African whole genomes. We present the distribution of common, rare, and potential novel star alleles across various Sub-Saharan African (SSA) populations, in comparison with other global populations. NAT110 (53.6%), GSTT10 (65%), GSTM10 (48%), and NAT25 (17.5%) were among the predominant functionally relevant star alleles. Additionally, we predicted varying phenotype distributions for NAT1 and NAT2 (acetylation) and the glutathione-S-transferase (GST) enzymes (detoxification activity) between SSA and other global populations. Forty-seven potentially novel haplotypes were identified computationally across the genes. This study provides insight into the distribution of key variants and star alleles potentially relevant to anti-TB drug metabolism and other drugs prescribed across various African populations. The high number of potentially novel star alleles exemplifies the need for pharmacogenomics studies in the African context. Overall, our study provides a foundation for functional pharmacogenetic studies and potential implementation of pharmacogenetic testing in Africa to reduce the risk of ADRs related to treatment of TB and other diseases.
结核病（TB）是非洲的一项重大健康负担。尽管结核病是可治疗的，但抗结核药物会引发药物不良反应（ADR），部分原因可归因于药物遗传学变异。在许多非洲人群中，影响抗结核药物代谢的星型等位基因（单倍型）分布情况尚不清楚。这给在非洲实施基因型指导疗法带来了挑战，该疗法旨在减少药物不良反应的发生并提高抗结核药物的疗效。在本研究中，我们使用StellarPGx软件，从1079个深度测序的非洲全基因组中，对NAT1、NAT2、GSTM1、GSTT1、GSTP1和CYP2E1基因中的变异和星型等位基因进行分型。我们展示了撒哈拉以南非洲（SSA）不同人群中常见、罕见和潜在新型星型等位基因的分布情况，并与其他全球人群进行了比较。NAT110（53.6%）、GSTT10（65%）、GSTM10（48%）和NAT25（17.5%）是主要的功能相关星型等位基因。此外，我们预测了SSA人群与其他全球人群之间，NAT1和NAT2（乙酰化）以及谷胱甘肽-S-转移酶（GST）酶（解毒活性）的不同表型分布。通过计算在这些基因中鉴定出了47种潜在的新型单倍型。本研究深入了解了与抗结核药物代谢以及非洲不同人群所使用的其他药物可能相关的关键变异和星型等位基因的分布情况。大量潜在的新型星型等位基因表明在非洲开展药物基因组学研究的必要性。总体而言，我们的研究为功能药物遗传学研究以及在非洲潜在开展药物遗传学检测奠定了基础，以降低与结核病及其他疾病治疗相关的药物不良反应风险。
