da Rocha Jorge E B, Lombard Zané, Ramsay Michèle
Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, 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.
Front Genet. 2021 Mar 9;12:626954. doi: 10.3389/fgene.2021.626954. eCollection 2021.
Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are expensive and often cause adverse drug reactions (ADRs). Fluoropyrimidine treatments can lead to severe toxicity events which have been linked to variants within the dihydropyrimidine dehydrogenase () gene. There are clinical guidelines to improve safety outcomes of treatment, but these are primarily based on variants assessed in non-African populations. Whole genome sequencing data from the 1000 Genomes Project and the African Genome Variation Project were mined to assess variation in in eight sub-Saharan African populations. Variant functional annotation was performed with a series of bioinformatics tools to assess potential likelihood of deleterious impact. There were 29 coding variants identified in the datasets assessed, of which 25 are rare, and some of which are known to be deleterious. One African-specific variant (rs115232898-C), is common in sub-Saharan Africans (1-4%) and known to reduce the function of the dihydropyrimidine dehydrogenase enzyme (DPD), having been linked to cases of severe toxicity. This variant, once validated in clinical trials, should be considered for inclusion in clinical guidelines for use in sub-Saharan African populations. The rs2297595-C variant is less well-characterized in terms of effect, but shows significant allele frequency differences between sub-Saharan African populations (0.5-11.5%; = 1.5 × 10), and is more common in East African populations. This study highlights the relevance of African-data informed guidelines for fluorouracil drug safety in sub-Saharan Africans, and the need for region-specific data to ensure that Africans may benefit optimally from a precision medicine approach.
癌症是非洲严重的健康负担，且死亡率正在迅速上升。治疗费用高昂，还常常引发药物不良反应（ADR）。氟嘧啶治疗可导致严重毒性事件，这些事件与二氢嘧啶脱氢酶（）基因内的变异有关。有改善治疗安全结果的临床指南，但这些指南主要基于在非非洲人群中评估的变异。对来自千人基因组计划和非洲基因组变异计划的全基因组测序数据进行挖掘，以评估撒哈拉以南非洲八个群体中的变异情况。使用一系列生物信息学工具进行变异功能注释，以评估有害影响的潜在可能性。在所评估的数据集中鉴定出29个编码变异，其中25个是罕见的，有些已知具有有害性。一种非洲特异性变异（rs115232898 - C）在撒哈拉以南非洲人中很常见（1 - 4%），已知会降低二氢嘧啶脱氢酶（DPD）的功能，与严重毒性病例有关。该变异一旦在临床试验中得到验证，应考虑纳入撒哈拉以南非洲人群的临床指南。rs2297595 - C变异在效应方面的特征不太明确，但在撒哈拉以南非洲人群之间显示出显著的等位基因频率差异（0.5 - 11.5%； = 1.5 × 10），在东非人群中更为常见。这项研究强调了基于非洲数据的指南对于撒哈拉以南非洲人氟尿嘧啶药物安全性的相关性，以及获取特定区域数据以确保非洲人能从精准医学方法中获得最大益处的必要性。
