Scudeler Mariana M, Manóchio Caíque, Miwa Bruno, Belfort-Almeida Guilherme, Faria-Costa Lucas, Sanchez Cesar, Padilla Carlos, Caceres Omar, Tarazona-Santos Eduardo, Guio Heinner, O'Connor Timothy D, Rodrigues-Soares Fernanda
Pathology, Genetics and Evolution Department, Biological and Natural Sciences Institute, Federal University of Triângulo Mineiro, Uberaba, Brazil.
Genetics, Ecology and Evolution Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil.
Clin Pharmacol Ther. 2025 Jul;118(1):232-241. doi: 10.1002/cpt.3681. Epub 2025 Apr 17.
The ESR1 gene is relevant in breast cancer treatments in the pharmacogenetics context. However, Native, African, and mixed populations are known to be underrepresented in genomic studies. This is particularly important given that the difference in variants' frequencies among different populations can lead to population-specific clinical implications. Therefore, this study aims to infer the genomic subcontinental ancestry and allele frequencies of the ESR1 gene variants in 2,427 individuals from 26 populations worldwide from the 1000 Genomes Project and 125 Natives from Peru, whose genomes have not yet been analyzed in the literature regarding this gene. Linear regression with Bonferroni correction analyses was conducted based on ancestry inference and frequencies. Our findings demonstrate subcontinental differentiation of African, Asian, European, and Native populations. Overall, 102 associations (P < 0.01) were found for 68 clinically relevant variants. Particularly, subcontinental associations were observed for variants associated with the Native, Asian, European, and African components. We highlight the findings for the rs9349799 and rs2234693 variants, previously associated with altered responses to breast cancer treatments. rs9349799 was positively associated with the South-Asian component, while rs2234693 was negatively associated with the Coast/Amazonian Native and positively associated with the East-African component. Nearly half of the variants are intronic, highlighting the importance of studying whole genomes rather than just exomes. These results emphasize subcontinental differences' relevance for designing pharmacogenetic panels. Including neglected populations in genomic and pharmacogenomic studies is essential for democratic access to scientific advances and for more egalitarian and effective pharmacogenetic implementation, tailored to each population's specificities.
在药物遗传学背景下，ESR1基因与乳腺癌治疗相关。然而，在基因组研究中，原住民、非洲裔和混血人群的代表性不足。鉴于不同人群中基因变异频率的差异可能导致特定人群的临床意义，这一点尤为重要。因此，本研究旨在推断来自千人基因组计划的全球26个群体的2427名个体以及125名秘鲁原住民中ESR1基因变异的基因组次大陆血统和等位基因频率，关于该基因，其基因组尚未在文献中得到分析。基于血统推断和频率进行了带有Bonferroni校正分析的线性回归。我们的研究结果表明了非洲、亚洲、欧洲和原住民群体的次大陆分化。总体而言，对于68个临床相关变异，共发现102个关联（P < 0.01）。特别是，观察到与原住民、亚洲、欧洲和非洲成分相关的变异存在次大陆关联。我们强调了rs9349799和rs2234693变异的研究结果，它们之前与乳腺癌治疗反应的改变有关。rs9349799与南亚成分呈正相关，而rs2234693与海岸/亚马逊原住民呈负相关，与东非成分呈正相关。近一半的变异是内含子变异，突出了研究全基因组而非仅外显子组的重要性。这些结果强调了次大陆差异在设计药物遗传学面板方面的相关性。将被忽视的人群纳入基因组和药物基因组学研究对于平等获取科学进展以及根据每个群体的特异性进行更平等和有效的药物遗传学应用至关重要。
