Caracterização do gene ESR1 em populações nativas da América do Sul

Abstract

According to the World Health Organization, breast cancer is the first or second leading cause of death among women in 95% of countries. Estrogen is considered to be one of the risk factors associated with the development of the disease; it is formed mainly through the action of the aromatase enzyme, and its action in the organism takes place, in particular, from the hormone's binding to the estrogen receptor ERα, encoded by the ESR1 gene. The gene is part of the anti-estrogen pathway, which is the target of aromatase inhibitor drugs, whose mechanism of action aims to reduce the concentration of estrogen in the body; however, it is known that the response to treatments may be affected by several factors, including the patient's genetic profile. Pharmacogenetics is the field that investigates the association between genetic polymorphisms and inter-individual variability in the response to drugs. Ancestry is also considered an important factor in this context, as the frequency of polymorphisms in genes of pharmacogenetic interest varies when comparing different populations. Nevertheless, Native American, African, and mixed populations are under-represented in genetic studies; this is extremely relevant when considering that these differences can lead to different clinical implications for different populations. Therefore, this study aims to infer the genomic subcontinental ancestry and allele frequencies of ESR1 gene variants in 2504 individuals from 26 populations worldwide from the 1000 Genomes Project and 150 Natives from Peru, whose genomes are original data not yet analyzed in the literature regarding this gene. Regression and correlation analyses between these data were carried out based on the inference of ancestry and frequencies. Our findings demonstrate a subcontinental differentiation of African, Asian, European, and Native components (W-AFR, E-AFR, W-EAS, E-EAS, SAS, N-EUR, S-EUR, NAT, and NAT2). A total of 145 associations were found (p <0.01), 73.1% of which were positive. The frequencies of 73 clinically relevant variants were associated with the nine components, particularly the African components, for which more than half of the associations were observed. In particular, subcontinental associations were observed for most of the variants associated with the native, Asian, and European components. Additionally, it was observed that nearly half the variants are in intronic regions, highlighting the importance of studying whole genomes rather than exomes. These results point to the relevance of subcontinental differences for the design of pharmacogenetic panels and reinforce the dangers of extrapolating genetic data from one population to another. In clinical practice, association results between clinically relevant ESR1 variants and subcontinental ancestry components could be used to guide clinical decisions on a patient in the absence of their own genetic data. Including neglected populations in genomic and pharmacogenomic studies is paramount if access to scientific advances is to be democratic and if pharmacogenetic implementation is to be more egalitarian and effective in the future, tailored to the specificities of each population.