Genomic investigation on genes related to mercury metabolism in Amazonian indigenous populations.

Studies have identified elevated levels of mercury in Amazonian Indigenous individuals, highlighting them as one of the most exposed to risks. In the unique context of the Brazilian Indigenous population, it is crucial to identify genetic variants with clinical significance to better understand vulnerability to mercury and its adverse effects. Currently, there is a lack of research on the broader genomic profile of Indigenous people, particularly those from the Amazon region, concerning mercury contamination. Therefore, the aim of this study was to assess the genomic profile related to the processes of mercury absorption, distribution, metabolism, and excretion in 64 Indigenous individuals from the Brazilian Amazon. We aimed to determine whether these individuals exhibit a higher susceptibility to mercury exposure. Our study identified three high-impact variants (GSTA1 rs1051775, GSTM1 rs1183423000, and rs1241704212), with the latter two showing a higher frequency in the study population compared to global populations. Additionally, we discovered seven new variants with modifier impact and a genomic profile different from the worldwide populations. These genetic variants may predispose the study population to more harmful mercury exposure compared to global populations. As the first study to analyze broader genomics of mercury metabolism pathways in Brazilian Amazonian Amerindians, we emphasize that our research aims to contribute to public policies by utilizing genomic investigation as a method to identify populations with a heightened susceptibility to mercury exposure.

Molecular Profile of Variants in CDH1, TP53, PSCA, PRKAA1, and TTN Genes Related to Gastric Cancer Susceptibility in Amazonian Indigenous Populations.

Gastric Cancer is a disease associated with environmental and genetic changes, becoming one of the most prevalent cancers around the world and with a high incidence in Brazil. However, despite being a highly studied neoplastic type, few efforts are aimed at populations with a unique background and genetic profile, such as the indigenous peoples of the Brazilian Amazon. Our study characterized the molecular profile of five genes associated with the risk of developing gastric cancer by sequencing the complete exome of 64 indigenous individuals belonging to 12 different indigenous populations in the Amazon. The analysis of the five genes found a total of 207 variants, of which 15 are new in our indigenous population, and among these are two with predicted high impact, present in the TTN and CDH1 genes. In addition, at least 20 variants showed a significant difference in the indigenous population in comparison with other world populations, and three are already associatively related to some type of cancer. Our study reaffirms the unique genetic profile of the indigenous population of the Brazilian Amazon and allows us to contribute to the conception of early diagnosis of complex diseases such as cancer, improving the quality of life of individuals potentially suffering from the disease.

Correlation between Genomic Variants and Worldwide Epidemiology of Prostate Cancer.

Prostate cancer (PCa) incidence and mortality vary across territories and populations. This can be explained by the genetic factor of this disease. This article aims to correlate the epidemiological data, worldwide incidence, and mortality of PCa with single-nucleotide polymorphisms (SNPs) associated with the susceptibility and severity of this neoplasm in different populations. Eighty-four genetic variants associated with prostate cancer susceptibility were selected from the literature through genome association studies (GWAS). Allele frequencies were obtained from the 1000 Genomes Project, and epidemiological data were obtained from Surveillance, Epidemiology, and End Results (SEER). The PCa incidence, mortality rates, and allele frequencies of variants were evaluated by Pearson's correlation. Our study demonstrated that 12 SNPs (rs2961144, rs1048169, rs7000448, rs4430796, rs2066827, rs12500426, rs6983267, rs11649743, rs2075110, rs114798100, rs855723, and rs2075109) were correlated with epidemiological data in different ethnic groups. Ten SNPs (rs2961144, rs1048169, rs7000448, rs4430796, rs2066827, rs12500426, rs11649743, rs2075110, rs114798100, and rs2075109) were positively correlated with the mortality rate. Seven SNPs (rs1048169, rs2961144, rs7000448, rs4430796, rs2066827, rs12500426, and rs114798100) were positively correlated with incidence. Positive correlations of incidence and mortality rates were more frequent in the African population. The genetic variants investigated here are likely to predispose to PCa and could play a role in its progression and aggressiveness. This genetic study demonstrated here is promising for implementing personalized strategies to screen for prostate cancer in diverse populations.

Association of Androgenic Regulation and MicroRNAs in Acinar Adenocarcinoma of Prostate.

BACKGROUND: Prostate cancer represents 3.8% of cancer deaths worldwide. For most prostate cancer cells to grow, androgens need to bind to a cellular protein called the androgen receptor (AR). This study aims to demonstrate the expression of five microRNAs (miRs) and its influence on the AR formation in patients from the northern region of Brazil. MATERIAL AND METHODS: Eighty-four tissue samples were investigated, including nodular prostatic hyperplasia (NPH) and acinar prostatic adenocarcinoma (CaP). Five miRs (27a-3p, 124, 130a, 488-3p, and 506) were quantified using the TaqMan® Real Time PCR method and AR was measured using Western blotting. RESULTS: Levels of miRs 124, 130a, 488-3p, and 506 were higher in NPH samples. Conversely, in the CaP cases, higher levels of miR 27a-3p and AR were observed. CONCLUSION: In the future, these microRNAs may be tested as markers of CaP at the serum level. The relative expression of AR was 20% higher in patients with prostate cancer, which suggests its potential as a biomarker for prostate malignancy.

The Genomic Profile Associated with Risk of Severe Forms of COVID-19 in Amazonian Native American Populations.

Genetic factors associated with COVID-19 disease outcomes are poorly understood. This study aimed to associate genetic variants in the SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, and ABO genes with the risk of severe forms of COVID-19 in Amazonian Native Americans, and to compare the frequencies with continental populations. The study population was composed of 64 Amerindians from the Amazon region of northern Brazil. The difference in frequencies between the populations was analyzed using Fisher's exact test, and the results were significant when p ≤ 0.05. We investigated 64 polymorphisms in 7 genes; we studied 47 genetic variants that were new or had impact predictions of high, moderate, or modifier. We identified 15 polymorphisms with moderate impact prediction in 4 genes (ABO, CXCR6, FYCO1, and SLC6A20). Among the variants analyzed, 18 showed significant differences in allele frequency in the NAM population when compared to others. We reported two new genetic variants with modifier impact in the Amazonian population that could be studied to validate the possible associations with COVID-19 outcomes. The genomic profile of Amazonian Native Americans may be associated with protection from severe forms of COVID-19. This work provides genomic data that may help forthcoming studies to improve COVID-19 outcomes.

Impact of Variants in the ATIC and ARID5B Genes on Therapeutic Failure with Imatinib in Patients with Chronic Myeloid Leukemia.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm derived from the balanced reciprocal translocation of chromosomes 9 and 22 t (9q34 and 22q11), which leads to the formation of the Philadelphia chromosome and fusion of the BCR-ABL genes. The first-line treatment for CML is imatinib, a tyrosine kinase inhibitor that acts on the BCR-ABL protein. However, even though it is a target-specific drug, about 25% of patients do not respond to this treatment. The resistance mechanisms involved in this process have been investigated and studies have shown that germinal alterations can influence this mechanism. The aim of this work was to investigate 32 polymorphisms in 24 genes of carcinogenic pathway to verify the influence of these genetic variants on the response to treatment with imatinib. Our results demonstrated that individuals with the recessive GG genotype for the rs2372536 variant in the ATIC gene are approximately three times more likely to experience treatment failure with imatinib (p = 0.045, HR = 2.726, 95% CI = 0.9986-7.441), as well as individuals with the TT genotype for the rs10821936 variant in the ARID5B gene, who also have a higher risk for treatment failure with imatinib over time (p = 0.02, HR = 0.4053, IC 95% = 0.1802-0.911). In conclusion, we show that variants in the ATIC and ARIDB5 gene, never screened in previous studies, could potentially influence the therapeutic response to imatinib in patients treated for CML.

Influence of APOE locus on poor prognosis of COVID-19.

The COVID-19 pandemic has infected over 25 million of people worldwide, 5% of whom evolved to death and, among of the active cases, more than 60 thousand are classified as critical or severe. Recent studies revealed that ApoE, a protein encoded by APOE gene, may increase the risk of severe COVID-19 cases. ApoE has been involved with prevention of tissue damage and promotion of adaptative immune response in the lungs. This study investigated frequencies distribution of alleles that alter the ApoE expression in lung tissues to trace a profile of these variants and associate them to COVID-19 clinical outcomes. Data about APOE expression levels was obtained from the Genotype-Tissue Expression Project and the allele frequencies of APOE variants was acquired from the populations included in the phase 3 release of the 1000 Genomes Project. A total of 128 variants showed a significant impact on the APOE expression in lung tissues (p < 0.0001). Linkage Disequilibrium analysis revealed that 98 variants were closely grouped into seven distinct haplotype blocks, of which six were composed of variants that significantly decrease APOE gene expression in the lungs. Most of the haplotypes with higher impact on APOE expression showed greater frequencies in Europeans and lower in Africans, which implies that European populations might be more susceptible to SARS-CoV-2 infection. The present study indicates a potential genetic contribution of APOE expression-modifying variants in modulating the prognosis of COVID-19.

Influence of variants of the drosha, mir499a, and mir938 genes on susceptibility to acute lymphoblastic leukemia in an admixed population from the brazilian amazon.

Acute Lymphoblastic Leukemia (ALL) is the most common type of cancer in children. Polymorphisms that alter the normal function of the microRNAs involved in the development of ALL have been widely investigated, although published data on these polymorphisms in admixed populations are scarce. We investigated the role of 10 polymorphisms in the microRNA and protein-coding genes of the microRNA synthesis complex in susceptibility to pediatric B-cell ALL. The study includes 100 pediatric ALL patients and 180 healthy individuals. The statistical analyses were run in SPSS v.25.0. In the case of the microRNA synthesizing genes, a significant pattern was found in only gene, that is, the rs3805500 polymorphism of DROSHA, in which the homozygous mutant (AA) genotype was associated with a threefold increase in the risk of developing ALL when compared to other genotypes (P=0.004, OR=2.913, CI=1.415-5.998). In the microRNA coding genes, the homozygous mutant rs3746444 genotype of the MIR499A gene was associated with a 17-fold increase in the risk of development of ALL (P<0.001, OR=17.797, CI=5.55-57.016). A protective effect against the development of ALL was also observed in the carriers of the wild homozygous rs2505901 genotype in the MIR938 gene. Our findings highlight the potential of these polymorphisms in the genes involving in the coding of microRNAs for the evaluation of the risk of contracting ALL in the population of the Brazilian Amazon region. These findings contribute to a more complete understanding of the complex etiology of ALL.