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Non-small cell lung cancer (NSCLC) accounts for the vast majority of cases of lung neoplasms. It is formed in multiple stages, with interactions between environmental risk factors and individual genetic susceptibility and with genes involved in the immune and inflammatory response paths, cell or genome stability, and metabolism, among others. Our objective was to evaluate the association between five genetic variants (IL-1A, NFKB1, PAR1, TP53, and UCP2) and the development of NSCLC in the Brazilian Amazon. The study included 263 individuals with and without lung cancer. The samples were analyzed for the genetic variants of NFKB1 (rs28362491), PAR1 (rs11267092), TP53 (rs17878362), IL-1A (rs3783553), and UCP2 (INDEL 45-bp), which were genotyped in PCR, followed by an analysis of the fragments, in which we applied a previously developed set of informative ancestral markers. We used a logistic regression model to identify differences in the allele and the genotypic frequencies among individuals and their association with NSCLC. The variables of gender, age, and smoking were controlled in the multivariate analysis to prevent confusion by association. The individuals that were homozygous for the Del/Del of polymorphism NFKB1 (rs28362491) (p = 0.018; OR = 0.332) demonstrate a significant association with NSCLC, which was similar to that observed in the variants of PAR1 (rs11267092) (p = 0.023; OR = 0.471) and TP53 (rs17878362) (p = 0.041; OR = 0.510). Moreover, the individuals with the Ins/Ins genotype of polymorphism IL-1A (rs3783553) demonstrated greater risk for NSCLC (p = 0.033; OR = 2.002), as did the volunteers with the Del/Del of UCP2 (INDEL 45-bp) (p = 0.031; OR = 2.031). The five polymorphisms investigated can contribute towards NSCLC susceptibility in the population of the Brazilian Amazon.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Subunidade p50 de NF-kappa B , Receptor PAR-1 , Proteína Supressora de Tumor p53 , Proteína Desacopladora 2 , Humanos , Brasil/epidemiologia , Subunidade p50 de NF-kappa B/genética , Polimorfismo Genético , Receptor PAR-1/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
A number of genomic variants related to native American ancestry may be associated with an increased risk of developing Acute Lymphoblastic Leukemia (ALL), which means that Latin American and hispanic populations from the New World may be relatively susceptible to this disease. However, there has not yet been any comprehensive investigation of the variants associated with susceptibility to ALL in traditional Amerindian populations from Brazilian Amazonia. We investigated the exomes of the 18 principal genes associated with susceptibility to ALL in samples of 64 Amerindians from this region, including cancer-free individuals and patients with ALL. We compared the findings with the data on populations representing five continents available in the 1000 Genomes database. The variation in the allele frequencies found between the different groups was evaluated using Fisher's exact test. The analyses of the exomes of the Brazilian Amerindians identified 125 variants, seven of which were new. The comparison of the allele frequencies between the two Amerindian groups analyzed in the present study (ALL patients vs. cancer-free individuals) identified six variants (rs11515, rs2765997, rs1053454, rs8068981, rs3764342, and rs2304465) that may be associated with susceptibility to ALL. These findings contribute to the identification of genetic variants that represent a potential risk for ALL in Amazonian Amerindian populations and might favor precision oncology measures.
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Background: Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis and represents an important global public health issue. Single-nucleotide polymorphisms and INDELs are common genetic variations that can be located in genes associated with immune response and, therefore, they may have direct implications over the phenotype of susceptibility to infections like tuberculosis. This study aimed to investigate the association between the 17 genetic polymorphisms and susceptibility to tuberculosis in a Brazilian population. Methods: This case-control study enrolled 283 individuals with active tuberculosis and 145 health care workers. Four INDELs and 13 single nucleotide polymorphisms and were genotyped using Multiplex PCR method and TaqMan SNP Genotyping Assays. Group comparisons for categorical variables were performed using the chi-squared test, whilst the t-Student test was used to analyze the continuous variables. Multiple logistic regression analyses were performed to estimate the odds ratio (OR) with 95% confidence intervals (CI). Deviation from Hardy-Weinberg equilibrium was assessed using chi-squared tests with Bonferroni correction. The results were analyzed comparing the genotypic distributions adopting the dominant model and the estimated values ââof p corrected for multiple tests through FDR (False Discovery Rate) test. Results: The HWE test confirmed that the genotypic frequencies for polymorphisms were balanced. The frequency of Del allele was 73 and 75%, in cases and controls respectively. Frequency of Del allele was significantly higher in the control group than TB group. The homozygous Del/Del genotype was present in 51.6% of cases and 58.6% of controls. The rare Ins/Ins genotype was present in only 7.6% of controls and 6% of cases. The ACE Del/Del genotype was significantly higher in the cases than in controls revealing significant protection for TB in the domain model (OR = 0.465; p < 0.005). Conclusions: The Del/Del genotype of the rs4646994 in ACE gene was associated with susceptibility to tuberculosis. The identification of genetic variants responsible for susceptibility to tuberculosis will allow the development of new diagnostic tools for tuberculosis infection. These studies will help improve control and the future eradication of this disease.
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In Brazil, Acute lymphoid leukemia (ALL) is the leading cause of cancer deaths in children and adolescents. Treatment toxicity is one of the reasons for stopping chemotherapy. Amerindian genomic ancestry is an important factor for this event due to fluctuations in frequencies of genetic variants, as in the NUDT15 and SLC22A1 genes, which make up the pharmacokinetic and pharmacodynamic pathways of chemotherapy. This study aimed to investigate possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphism and genomic ancestry as a risk of treatment toxicities in patients with childhood ALL in the Amazon region of Brazil. The studied population consisted of 51 patients with a recent diagnosis of ALL when experiencing induction therapy relative to the BFM 2009 protocol. Our results evidenced a significant association of risk of severe infectious toxicity for the variant of the SLC22A1 gene (OR: 3.18, p = 0.031). Genetic ancestry analyses demonstrated that patients who had a high contribution of African ancestry had a significant protective effect for the development of toxicity (OR: 0.174; p = 0.010), possibly due to risk effects of the Amerindian contribution. Our results indicate that mixed populations with a high degree of African ancestry have a lower risk of developing general toxicity during induction therapy for ALL. In addition, individuals with the SLC22A1 variant have a higher risk of developing severe infectious toxicity while undergoing the same therapy.
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Transportador 1 de Cátions Orgânicos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , População Negra , Criança , Humanos , Transportador 1 de Cátions Orgânicos/genética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pirofosfatases/genéticaRESUMO
Lung cancer is one of the most frequent neoplasms in the world. Because it is a complex disease, its formation occurs in several stages, stemming from interactions between environmental risk factors, such as smoking, and individual genetic susceptibility. Our objective was to investigate associations between a UGT1A1 gene polymorphism (rs8175347) and lung cancer risk in an Amazonian population. This is a pilot study, case-controlled study, which included 276 individuals with cancer and without cancer. The samples were analyzed for polymorphisms of the UGT1A1 gene (rs8175347) and genotyped in PCR, followed by fragment analysis in which we applied a previously developed set of informative ancestral markers. We used logistic regression to identify differences in allelic and genotypic frequencies between individuals. Individuals with the TA7 allele have an increased chance of developing lung adenocarcinoma (p = 0.035; OR: 2.57), as well as those with related genotypes of reduced or low enzymatic activity: TA6/7, TA5/7, and TA7/7 (p = 0.048; OR: 8.41). Individuals with homozygous TA7/7 have an increased chance of developing squamous cell carcinoma of the lung (p = 0.015; OR: 4.08). Polymorphism in the UGT1A1 gene (rs8175347) may contribute as a risk factor for adenocarcinoma and lung squamous cell carcinoma in the population of the Amazon region.
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Carcinoma de Células Escamosas , Glucuronosiltransferase , Neoplasias Pulmonares , Glucuronosiltransferase/genética , Humanos , Neoplasias Pulmonares/genética , Projetos Piloto , Polimorfismo Genético , Fatores de RiscoRESUMO
Autism spectrum disorder is a neurodevelopmental disorder, affecting one in 160 children worldwide. The causes of autism are still poorly understood, but research shows the relevance of genetic factors in its pathophysiology, including the CHD8, SCN2A, FOXP1 and SYNGAP1 genes. Information about the genetic influence on various diseases, including autism, in the Amerindian population from Amazon, is still scarce. We investigated 35 variants of the CHD8, SCN2A, FOXP1, and SYNGAP1 gene in Amazonian Amerindians in comparison with publicly available population frequencies from the 1000 Genomes Project database. Our study identified 16 variants in the Amerindian population of the Amazon with frequencies significantly different from the other populations. Among them, the SCN2A (rs17183814, rs75109281, and rs150453735), FOXP1 (rs56850311 and rs939845), and SYNGAP1 (rs9394145 and rs115441992) variants presented higher frequency than all other populations analyzed. In addition, nine variants were found with lower frequency among the Amerindians: CHD8 (rs35057134 and rs10467770), SCN2A (rs3769951, rs2304014, rs1838846, and rs7593568), FOXP1 (rs112773801 and rs56850311), and SYNGAP1 (rs453590). These data show the unique genetic profile of the indigenous population of the Brazilian Amazon. Knowledge of these variants can help to understand the pathophysiology and diagnosis of autism among Amerindians, Brazilians, and in admixed populations that have contributions from this ethnic group.
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Transtorno do Espectro Autista , Transtorno Autístico , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Criança , Exoma , Fatores de Transcrição Forkhead/genética , Frequência do Gene , Humanos , Proteínas Repressoras/genética , Fatores de Transcrição/genéticaRESUMO
Gastric cancer (GC) is a multifactorial, complex, and aggressive disease with a prevalence of one million new cases and high global mortality. Factors such as genetic, epigenetic, and environmental changes contribute to the onset and progression of the disease. Identification of INDELs in miRNA and its target sites in current studies showed an important role in the development of cancer. In GC, miRNAs act as oncogenes or tumor suppressors, favoring important cancer pathways, such as cell proliferation and migration. This work aims to investigate INDELs in the coding region of miRNAs (hsa-miR-302c, hsa-miR-548AJ-2, hsa-miR-4274, hsa-miR-630, hsa-miR-516B-2, hsa-miR-4463, hsa-miR-3945, hsa-miR-548H_4, hsa-miR-920, has-mir-3171, and hsa-miR-3652) that may be associated with susceptibility and clinical variants of gastric cancer. For this study, 301 patients with GC and 145 individuals from the control group were selected from an admixed population in the Brazilian Amazon. The results showed the hsa-miR-4463, hsa-miR-3945, hsa-miR-548H_4, hsa-miR-920 and hsa-miR-3652 variants were associated with gastric cancer susceptibility. The hsa-miR-4463 was significantly associated with clinical features of GC such as diffuse gastric tumor histological type, "non-cardia" localization region, and early onset. Our findings indicated that INDELs could be potentially functional genetic variants for gastric cancer risk.
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MicroRNAs , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , MicroRNAs/metabolismo , Oncogenes , Biomarcadores Tumorais/genéticaRESUMO
BACKGROUND: Sarcopenia is a disease characterized by progressive reduction in muscle mass and strength or function. Although it is known that sarcopenia may be associated with environmental factors, studies suggest the identification of genes related to skeletal muscle maintenance that explain the susceptibility to the disease. OBJECTIVE: To analyze the influence of NFkB1 gene polymorphism on susceptibility to sarcopenia in the elderly. METHODS: This is a case-control study, which included 219 elderly people, 74 elderly people with sarcopenia, and 145 without sarcopenia. Samples were analyzed for NFkB1 gene polymorphism (rs28362491), genotyped in PCR, and followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between elderly people with and without sarcopenia. RESULTS: It was observed that the NFkB1 gene polymorphism presented frequencies of 24%, 50%, and 26% for the genotype DEL/DEL, DEL/INS, and INS/INS, respectively. Furthermore, elderly individuals with the INS/INS genotype had increased chances (p = 0.010; OR:2.943; 95%CI:1.301-6.654) for the development of sarcopenia. CONCLUSION: The INDEL polymorphism of the NFkB1 gene (rs28362491) may influence the susceptibility to sarcopenia in the elderly in elderly people in the Amazon.
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BACKGROUND: Susceptibility to Chronic Myeloid Leukemia (CML) may be modulated by genetic variables. However, the majority of previous investigations have focused on genetically homogeneous populations, resulting in a lack of evidence on how genetic factors may influence the development of CML in miscegenated populations. We analyzed 30 polymorphisms in genes related to DNA repair, folate metabolism, transmembrane transport, xenobiotic metabolism, and pyrimidine synthesis in relation to their potential role in the susceptibility of the individual to CML. METHODS: This case-control study included 126 healthy individuals and 143 patients diagnosed with CML from the admixed population of the Brazilian Amazon. The samples were genotyped by real-time PCR and the genetic ancestry analysis was based on a panel of 61 ancestry informative markers. RESULTS: The results indicated a protective effect against the development of CML in carriers of the C allele of the rs28399433 (CYP2A6) gene and the CC genotype of the rs3742106 (ABCC4) gene. CONCLUSION: Our findings suggest that the rs3742106 (ABCC4) and rs28399433 (CYP2A6) polymorphisms may modulate susceptibility to CML in a population of the Brazilian Amazon region.
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Citocromo P-450 CYP2A6/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Circulating tumor DNA (ctDNA) has recently emerged as a minimally invasive "liquid biopsy" tool in precision medicine. ctDNA-genomic DNA fragments that are released into the bloodstream after the active secretion of microvesicles or tumor cell lysis reflects tumor evolution and the genomic alterations present in primary and/or metastatic tumors. Notably, ctDNA analysis might allow the stratification of patients, the monitoring of the therapeutic response, and the establishment of an opportunity for early intervention independent of detection by imaging modalities or clinical symptoms. As oncology moves towards precision medicine, the information in ctDNA provides a means for the individual management of the patient based on their tumor's genetic profile. This review presents current evidence on the potential role for ctDNA in helping to guide individualized clinical treatment decisions for patients with melanoma, castration-resistant prostate cancer, breast cancer, metastatic colorectal cancer, and non-small cell lung cancer.
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DNA Tumoral Circulante/genética , Neoplasias/terapia , Medicina de Precisão/métodos , HumanosRESUMO
Frozen shoulder is a condition of loss of active and passive motion as result of inflammatory contracture and fibrosis of the joint capsule. We hypothesize that genetic variants in genes involved in these processes such as genes that play a role in extracellular matrix homeostasis (collagens, glycoproteins, genes involved in TGFß signaling, and metalloproteinases and its inhibitors) may contribute to the susceptibility to frozen shoulder. We evaluated eighteen SNPs of genes involved in extracellular matrix homeostasis in 186 cases (Nfemales = 114; Nmales = 72) of frozen shoulder and 600 age-matched controls (Nfemales = 308; Nmales = 292). Multivariate logistic regressions were carried out with age, gender, genetic ancestry, and common comorbidities as covariates. Carriers of the C allele of MMP13 rs2252070 and G/G MMP9 (rs17576 A>G/rs17577 G>A) haplotype may have an increased risk of frozen shoulder (p = 0.002, OR = 1.64, 95%CI = 1.20-2.26, and p = 0.046, OR = 1.40, 95%CI = 1.01-1.95, respectively), especially in females (p = 0.005, OR = 1.91, 95%CI = 1.22-2.99, and p = 0.046, OR = 1.59, 95%CI = 1.01-2.51, respectively). In females, the G allele of MMP9 rs17576 tended to contribute to the susceptibility to the studied disease (p = 0.05, OR = 1.51, 95%CI = 0.97-2.33). In contrast, the presence of the C allele of TGFB1 rs1800470 seems to be associated with a reduced risk (p = 0.04, OR = 0.47, 95%CI = 0.23-0.96) while the GG-genotype of TGFBR1 rs1590 was associated with increased risk (p = 0.027, OR = 4.11, 95%CI = 1.17-14.38) to frozen shoulder development in males. Thus, we identified genetic variants that were independent risk factors that can aid in the risk assessment of frozen shoulder reinforcing the involvement of MMP and TGFß signaling in disease development. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
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Bursite/genética , Matriz Extracelular/genética , Metaloproteinases da Matriz/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Hb E-Saskatoon [ß22(B4)GluâLys, HBB: c.67G > A] is a rare, nonpathological ß-globin variant that was first described in a Canadian woman of Scottish and Dutch ancestry and has since then been detected in several populations. The aim of the present study was to identify the origin of Hb E-Saskatoon in Brazil using ß-globin haplotypes and genetic ancestry in carriers of this hemoglobin (Hb) variant. Blood samples were investigated by isoelectric focusing (IEF) and high performance liquid chromatography (HPLC) using commercial kits. Hb E-Saskatoon was confirmed by amplification of the HBB gene, followed by sequence analysis. Haplotypes of the ß-globin gene were determined by polymerase chain reaction (PCR), followed by digestion with specific restriction enzymes. Individual ancestry was estimated with 48 biallelic insertion/deletions using three 16-plex PCR amplifications. The IEF pattern was similar to Hbs C (HBB: c.19G > A) and Hb E (HBB: c.79G > A) [isoelectric point (pI): 7.59-7.65], and HPLC results showed an elution in the Hb S (HBB: c.20A > T) window [retention time (RT): 4.26-4.38]. DNA sequencing of the amplified ß-globin gene showed a mutation at codon 22 (GAA>AAA) corresponding to Hb E-Saskatoon. A total of 11 cases of this variant were identified. In nine unrelated individuals, Hb E-Saskatoon was in linkage disequilibrium with haplotype 2 [+ - - - -]. All subjects showed a high degree of European contribution (mean = 0.85). Hb E-Saskatoon occurred on the ß-globin gene of haplotype 2 in all Brazilian carriers. These findings suggest a different genetic origin for this Hb variant from that previously described.
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Frequência do Gene , Hemoglobina E/genética , Epidemiologia Molecular/métodos , Brasil , Variação Genética , Haplótipos , Hemoglobinopatias/genética , Hemoglobinas Anormais/genéticaRESUMO
Circular RNAs are a class of long noncoding RNA that were recently rediscovered as diverse, highly abundant, conserved and naturally occurring RNAs in eukaryotes. They are characterized by their 5' and 3' covalently joined ends. Some studies have attributed functions for circular RNAs, such as miRNAs sponges and transcriptional regulators, indicating that they may be largely biomarkers of both physiological and pathological processes. Circular RNAs have the potential to play important roles in transcription and post-transcription, giving rise to a whole complexity level to gene expression regulation. In this review, we discuss the biogenesis of circular RNAs, their properties and functions as well as different methods for their identification and their role in some diseases.
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Regulação da Expressão Gênica , RNA/genética , Pesquisa Translacional Biomédica , Humanos , Splicing de RNA , RNA Circular , RNA Longo não Codificante/genéticaRESUMO
The spectrum of ß-thalassemia (ß-thal) mutations was investigated for the first time in a cohort of 33 unrelated patients from the Brazilian Amazon attending the Center for Hemotherapy and Hematology of the Pará Foundation (HEMOPA), in Belém, the state capital of Pará, Northern Brazil. Identification of the ß-thal mutations was made by direct genomic sequencing of the ß-globin gene. Mutations were identified in all patients, corresponding to a spectrum of 10 different point mutations and a total of 37 alleles studied. HBB: c.92 + 5G > A [IVS-I-5 (G > A)], was the most common ß-thal mutation, followed by HBB: c.118C > T [codon 39 (C > T)], HBB: c.-138C > T [-88 (C>T)], HBB: c.92 + 1G > A [IVS-I-1 (G > A)] and HBB: c.92 + 6T > C [IVS-I-6 (T > C)] mutations. These five mutations (four Mediterranean origin and one African origin) accounted for 86.5% of the ß-thal alleles. The profile of ß-thal mutations found in northern Brazil is different from those described in other regions of the country. In the southeast and south, the nonsense mutation HBB: c.118C > T is the most prevalent, followed by HBB: c.93-21G > A [IVS-I-110 (G > A)], whereas in the northeast, HBB: c.92 + 6T > C has been identified as the most common mutation, followed by HBB: c.92 + 1G > A. This heterogeneous geographical distribution is certainly related to the ancestry of Brazilian populations because they have similar genetic backgrounds (European, African and Amerindian), although with slightly different admixture proportions. Furthermore, the European contribution in the southeast and south was largely made up of immigrants of other nationalities, such as Italian and Spanish, in addition to Portuguese.
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Mutação Puntual , Globinas beta/genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Adulto , Brasil/epidemiologia , Estudos de Coortes , Feminino , Frequência do Gene , Humanos , Masculino , Adulto JovemRESUMO
The higher proportion of smokers among Black people in Brazil has been attributed to socioeconomic disparities, but genetic factors could also contribute for this finding. This study aimed at investigating associations between smoking status with genetically defined ethnic ancestry and socioeconomic features in Brazilians. Blood samples were collected from 448 volunteers (66.7% male; age: 37.1 ± 11.4 years) classified as current smokers (CS: 60.9%), former smokers (FS: 8.9%) and never smokers (NS: 30.1%). Individual interethnic admixtures were determined using a 48 insertion-deletion polymorphisms ancestry-informative-marker panel. CS showed a lower amount of European ancestry than NS (0.837 ± 0.243 X 0.883 ± 0.194, p ≤ 0.05) and FS (0.837 ± 0.243 X 0.864 ± 0.230, p ≤ 0.05), and a higher proportion of African Sub-Saharan ancestry than FS (0.128 ± 0.222 X 0.07 ± 0.174, p ≤ 0.05) and NS (0.128 ± 0.222 X 0.085 ± 0.178, p ≤ 0.05). NS reported a higher number of years in school than CS (11.2 ± 3.7 X 8.9 ± 3.8, p ≤ 0.001). CS were less common in economic Class A (30%) and more common in Class B (56.8%). In multivariate analysis, only lower number of school years and lower economic class were associated with higher chances for CS. The use of genetic molecular markers for characterizing ethnic background confirmed that socioeconomic disparities are the main determinants of higher smoking rates among Blacks in Brazil.
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Citocromo P-450 CYP2A6/genética , Polimorfismo Genético/genética , Fumar/etnologia , Adulto , Indígena Americano ou Nativo do Alasca , População Negra , Brasil/etnologia , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Fatores de Risco , Fumar/genética , Fatores Socioeconômicos , População BrancaRESUMO
OBJECTIVE: To investigate the influence of IL6, IL12B and VDR single nucleotide polymorphisms (SNPs) in uncomplicated Plasmodium vivax infection symptoms intensity, parasitemia and gametocytemia levels in a Brazilian Amazonian population. METHODS: A total of 167 malaria patients infected by P. vivax have parasitemia and gametocytemia levels estimated before treatment. Fourteen clinical symptoms were evaluated and included in a principal component analysis to derive a clinical symptom index. Patients were genotyped for IL6-174C>G, IL12B 735T>C, 458A>G, 159A>C, and VDR FokI, TaqI, BsmI SNPs by Taqman 5' nuclease assays. A General Linear Model analysis of covariance with age, gender, exposure period and infection history and genetic ancestry was performed to investigate the association of genotypes with parasitemia and gametocytemia levels and with a clinical symptom index. RESULTS: Higher parasitemia levels were observed in IL6-174C carriers (p=0.02) whereas IL12B CGT haplotype carriers presented lower parasitemia levels (p=0.008). VDR TaqIC/BsmIA haplotype carriers showed higher gametocyte levels than non-carriers (p=0.013). Based on the clinical index values the IL6-174C>G polymorphism was associated with malaria severity. The IL6-174C carriers presented a more severe clinical index when compared to GG homozygotes (p=0.001). CONCLUSION: The present study suggests that IL6, IL12 and VDR influence severity, parasitemia and gametocytemia clearance in P. vivax infections, and highlights their potential role in malaria immune response in an Amazonian population.
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Subunidade p40 da Interleucina-12/genética , Interleucina-6/genética , Malária Vivax/genética , Parasitemia/genética , Plasmodium vivax , Receptores de Calcitriol/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Criança , Feminino , Genótipo , Humanos , Subunidade p40 da Interleucina-12/imunologia , Interleucina-6/imunologia , Malária Vivax/epidemiologia , Malária Vivax/imunologia , Masculino , Pessoa de Meia-Idade , Parasitemia/parasitologia , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/imunologia , Adulto JovemRESUMO
Ionizing radiation, such as that emitted by uranium, may cause mutations and consequently lead to neoplasia in human cells. The TP53 gene acts to maintain genomic integrity and constitutes an important biomarker of susceptibility. The present study investigated the main alterations observed in exons 4, 5, 6, 7, and 8 of the TP53 gene and adjacent introns in Amazonian populations exposed to radioactivity. Samples were collected from 163 individuals. Occurrence of the following alterations was observed: (i) a missense exchange in exon 4 (Arg72Pro); (ii) 2 synonymous exchanges, 1 in exon 5 (His179His), and another in exon 6 (Arg213Arg); (iii) 4 intronic exchanges, 3 in intron 7 (C â T at position 13.436; C â T at position 13.491; T â G at position 13.511) and 1 in intron 8 (T â G at position 13.958). Alteration of codon 72 was found to be an important risk factor for cancer development (P = 0.024; OR = 6.48; CI: 1.29-32.64) when adjusted for age and smoking. Thus, TP53 gene may be an important biomarker for carcinogenesis susceptibility in human populations exposed to ionizing radiation.
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Éxons/efeitos da radiação , Instabilidade Genômica/efeitos da radiação , Radiação Ionizante , Proteína Supressora de Tumor p53/genética , Adulto , Alelos , Transformação Celular Neoplásica , Exposição Ambiental , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/patologia , Doses de Radiação , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/efeitos da radiação , Urânio/toxicidadeRESUMO
BACKGROUND: Malaria is among the most prevalent parasitic diseases worldwide. In Brazil, malaria is concentrated in the northern region, where Plasmodium vivax accounts for 85% disease incidence. The role of genetic factors in host immune system conferring resistance/susceptibility against P. vivax infections is still poorly understood. METHODS: The present study investigates the influence of polymorphisms in 18 genes related to the immune system in patients with malaria caused by P. vivax. A total of 263 healthy individuals (control group) and 216 individuals infected by P. vivax (malaria group) were genotyped for 33 single nucleotide polymorphisms (SNPs) in IL1B, IL2, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, IL12RB1, SP110, TNF, TNFRSF1A, IFNG, IFNGR1, VDR, PTPN22 and P2X7 genes. All subjects were genotyped with 48 ancestry informative insertion-deletion polymorphisms to determine the proportion of African, European and Amerindian ancestry. Only 13 SNPs in 10 genes with differences lower than 20% between cases and controls in a Poisson Regression model with age as covariate were further investigated with a structured population association test. RESULTS: The IL1B gene -5839C > T and IL4R 1902A > G polymorphisms and IL12RB1 -1094A/-641C and TNF -1031 T/-863A/-857 T/-308 G/-238 G haplotypes were associated with malaria susceptibility after population structure correction (p = 0.04, p = 0.02, p = 0.01 and p = 0.01, respectively). CONCLUSION: Plasmodium vivax malaria pathophysiology is still poorly understood. The present findings reinforce and increase our understanding about the role of the immune system in malaria susceptibility.
Assuntos
Interleucina-1beta/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Malária Vivax/genética , Malária Vivax/imunologia , Receptores de Interleucina-12/genética , Fator de Necrose Tumoral alfa/genética , Adolescente , Adulto , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Interações Hospedeiro-Parasita/genética , Interações Hospedeiro-Parasita/imunologia , Humanos , Malária Vivax/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Adult-type hypolactasia is a common phenotype caused by the lactase enzyme deficiency. The -13910 C>T polymorphism, located 14 Kb upstream of the lactase gene (LCT) in the MCM6 gene was associated with lactase persistence (LP) in Europeans. This polymorphism is rare in Africa but several other variants associated with lactase persistence were observed in Africans. The aims of this study were to identify polymorphisms in the MCM6 region associated with the lactase persistence phenotype and to determine the distribution of LCT gene haplotypes in 981 individuals from North, Northeast and South Brazil. These polymorphisms were genotyped by PCR based methods and sequencing. The -13779*C,-13910*T, -13937*A, -14010*C, -14011*T LP alleles previously described in the MCM6 gene region that acts as an enhancer for the LCT gene were identified in Brazilians. The most common LP allele was -13910*T. Its frequency was highly correlated with European ancestry in the Brazilian populations investigated. The -13910*T was higher (0.295) in southern Brazilians of European ancestry and lower (0.175) in the Northern admixed population. LCT haplotypes were derived from the 10 LCT SNPs genotyped. Overall twenty six haplotypes previously described were identified in the four Brazilian populations studied. The Multidimensional Scaling analysis showed that Belém, in the north, was closer to Amerindians. Northeastern and southern Afro-descendants were more related with Bantu-speaking South Africans whereas the Southern population with European ancestry grouped with Southern and Northern Europeans. This study shows a high variability considering the number of LCT haplotypes observed. Due to the highly admixed nature of the Brazilian populations, the diagnosis of hypolactasia in Brazil, based only in the investigation of the -13910*T allele is an oversimplification.
Assuntos
Intolerância à Lactose/genética , Polimorfismo de Nucleotídeo Único , Adolescente , População Negra , Brasil , Estudos de Casos e Controles , Frequência do Gene , Estudos de Associação Genética , Haplótipos , Humanos , Lactase/deficiência , Lactase/genética , Intolerância à Lactose/etnologia , Desequilíbrio de Ligação , População BrancaRESUMO
Information on one Ecuadorian and three Peruvian Amerindian populations for 11 autosomal short tandem repeat (STR) loci is presented and incorporated in analyses that includes 26 other Native groups spread all over South America. Although in comparison with other studies we used a reduced number of markers, the number of populations included in our analyses is currently unmatched by any genome-wide dataset. The genetic polymorphisms indicate a clear division of the populations into three broad geographical areas: Andes, Amazonia, and the Southeast, which includes the Chaco and southern Brazil. The data also show good agreement with proposed hypotheses of splitting and dispersion of major language groups over the last 3,000 years. Therefore, relevant aspects of Native American history can be traced using as few as 11 STR autosomal markers coupled with a broad geographic distribution of sampled populations.