Guevara Mariela, de la Cruz Carla González, Rodrigues-Soares Fernanda, Rodríguez Ernesto, Manóchio Caíque, Peñas-Lledó Eva, Dorado Pedro, LLerena Adrián
Research and Development Department, Universidad Nacional Pedro Henríquez Ureña, Santo Domingo 10203, Dominican Republic.
Personalized Medicine and Mental Health Unit, University Institute for Bio-Sanitary Research of Extremadura, 06080 Badajoz, Spain.
Pharmaceutics. 2024 Dec 24;17(1):8. doi: 10.3390/pharmaceutics17010008.
Genetic polymorphism of the dihydropyrimidine dehydrogenase gene () is responsible for the variability found in the metabolism of fluoropyrimidines such as 5-fluorouracil (5-FU), capecitabine, or tegafur. The genotype is linked to variability in enzyme activity, 5-FU elimination, and toxicity. Approximately 10-40% of patients treated with fluoropyrimidines develop severe toxicity. The interethnic variability of gene variants in Afro-Latin Americans is poorly studied, thereby establishing a barrier to the implementation of personalized medicine in these populations. Therefore, the present study aims to analyze the frequency of variants with clinical relevance in the Dominican population and their association with genomic ancestry components. For this study, 196 healthy volunteers from the Dominican Republic were genotyped for variants by qPCR, and individual genomic ancestry analysis was performed in 178 individuals using 90 informative ancestry markers. Data from the 1000 Genomes project were also retrieved for comparison and increased statistical power. : The c.557A>G variant (decreased dihydropyrimidine dehydrogenase function) presented a frequency of 2.6% in the Dominican population. Moreover, the frequency of this variant is positively associated with African ancestry (r = 0.67, = 1 × 10), which implies that individuals with high levels of African ancestry are more likely to present this variant. HapB3 is completely absent in Dominican, Mexican, Peruvian, Bangladeshi, and all East Asian and African populations, which probably makes its analysis dispensable in these populations. The implementation of pharmacogenetics in oncology, specifically , in populations of Afro-Latin American ancestry should include c.557A>G, to be able to carry out the safe and effective treatment of patients treated with fluoropyrimidines.
二氢嘧啶脱氢酶基因（）的遗传多态性导致了氟嘧啶（如5-氟尿嘧啶（5-FU）、卡培他滨或替加氟）代谢中的变异性。基因型与酶活性、5-FU消除及毒性的变异性相关。接受氟嘧啶治疗的患者中约10%-40%会出现严重毒性。非洲裔拉丁美洲人中基因变异的种族间变异性研究较少，这为在这些人群中实施个性化医疗设置了障碍。因此，本研究旨在分析多米尼加人群中具有临床相关性的变异频率及其与基因组祖先成分的关联。在本研究中，对来自多米尼加共和国的196名健康志愿者进行qPCR基因分型以检测变异，并使用90个信息丰富的祖先标记对178名个体进行个体基因组祖先分析。还检索了千人基因组计划的数据用于比较并提高统计效力。结果：c.557A>G变异（二氢嘧啶脱氢酶功能降低）在多米尼加人群中的频率为2.6%。此外，该变异的频率与非洲祖先成分呈正相关（r = 0.67， = 1 × 10），这意味着非洲祖先成分比例高的个体更有可能出现该变异。HapB3在多米尼加、墨西哥、秘鲁、孟加拉国以及所有东亚和非洲人群中完全不存在，这可能使得在这些人群中对其进行分析没有必要。在肿瘤学中，特别是在非洲裔拉丁美洲血统人群中实施药物遗传学应纳入c.557A>G，以便能够对接受氟嘧啶治疗的患者进行安全有效的治疗。
