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https://www.arca.fiocruz.br/handle/icict/50141
FATOR DE TRANSFORMAÇÃO DO CRESCIMENTO BETA E POLIMORFISMOS NO GENE DO RECEPTOR 3 DO FATOR DE TRANSFORMAÇÃO DO CRESCIMENTO BETA NA DOENÇA FALCIFORME
Fator de transformação do crescimento Beta
Receptor 3 do fator de transformação crescimento Beta
Transforming growth factor beta
Transforming growth factor beta receptor 3
Santiago, Rayra Pereira | Date Issued:
2020
Author
Advisor
Comittee Member
Affilliation
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil.
Abstract in Portuguese
INTRODUÇÃO: o fator de transformação do crescimento beta (TGF-\03B2) é uma citocina com papel importante em processos biológicos, como disfunção endotelial e vascular, inflamação e homeostase hematopoiética. OBJETIVO: o presente estudo buscou investigar a associação dos níveis plasmáticos de TGF-\03B21 e de polimorfismos no gene do receptor 3 do fator de transformação do crescimento beta (TGFBR3) com biomarcadores genéticos, hematológicos, bioquímicos e imunológicos em indivíduos com doença falciforme (DF) e com as complicações clínicas da doença. MATERIAL E MÉTODOS: para tanto, foi conduzido um estudo transversal, onde foram investigados 175 indivíduos com DF (120 HbSS e 55 HbSC). Os níveis plasmáticos do TGF-\03B2, inibidor tecidual de metaloproteases-1 (TIMP-1) e da metaloproteinase da matriz 9 (MMP-9) foram determinados pela técnica de ELISA e os marcadores hematológicos, bioquímicos e imunológicos foram determinados por métodos automatizados. A genotipagem dos polimorfismos no gene TGFBR3 foi realizada utilizando TaqMan SNP Genotyping Assays. RESULTADOS: os indivíduos HbSS apresentaram concentrações elevadas de TGF-\03B21 quando comparados a indivíduos controles saudáveis e HbSC. Nos indivíduos HbSS, o TGF-\03B21 esteve positivamente correlacionado com as hemácias, plaquetas, hemoglobina, hematócrito e TIMP-1. Além desses marcadores, os indivíduos HbSS com concentrações de TGF-\03B21 \226572.29 ng/mL apresentaram contagem elevada de monócitos e níveis diminuídos de albumina. Os indivíduos HbSC apresentaram correlação positiva entre o TGF-\03B21 e leucócitos, eosinófilos, linfócitos, monócitos, plaquetas, TIMP-1, lipoproteínas de muito baixa densidade (VLDL-C), triglicérides, heme e aspartato aminotransferase (AST). Os indivíduos HbSC com concentrações de TGF-\03B21 \2265 47.80 ng/mL apresentaram contagens elevadas de leucócitos e plaquetas e concentrações elevadas de triglicérides, VLDL-C, MMP-9 e TIMP-1 e c concentrações diminuídas de lipoproteína de alta densidade (HDL-C). Nos indivíduos HbSS, o alelo variante A do polimorfismo rs1805110 no gene TGFBR3 esteve associado a concentrações elevadas de hemoglobina, hematócrito, lipoproteína de baixa densidade (LDL-C), ácido úrico e endotelina; contagem elevada de reticulócitos e platelet distribution width (PDW) diminuídos e estiveram associados à ocorrência de alterações ósseas. O alelo variante T do polimorfismo rs7526590 no gene TGFBR3 esteve associado a concentrações elevadas de red cell distribution width (RDW), PDW, fosfatase alcalina, AST, bilirrubina indireta e lactato desidrogenase e concentrações diminuídas de ferritina e a ocorrência de úlceras de pernas. Os indivíduos com DF portadores do haplótipo 9 GG no gene TGFBR3 apresentaram níveis mais elevados de colesterol total (T-CHOL), LDL-C, triglicérides, colesterol não HDL (não-HDL-C), proteínas totais e globulina que aqueles com o haplótipo não-GG. Indivíduos com o haplótipo CGG apresentaram níveis elevados de plaquetócrito, T-CHOL, LDL-C e não-HDL-C. Ambos os haplótipos GG e CGG estiveram associados à ocorrência de pneumonia e os indivíduos com haplótipo não-GG apresentaram ocorrência maior de colelitíase. CONCLUSÃO: nossos dados sugerem que o TGF-\03B21 desempenha papel importante no remodelamento vascular, vasculopatia, angiogênese, inflamação e hemólise na DF e que polimorfismos no gene TGFBR3 podem estar ligados ao estado inflamatório, hemólise e a complicações clínicas. Além disso, os indivíduos portadores dos haplótipos GG e CGG no gene TGFBR3 apresentaram alterações importantes no perfil lipídico e apresentaram ocorrência maior de pneumonia.
Abstract
INTRODUCTION: transforming growth factor beta (TGF-\03B2) is a cytokine that plays an important role in biological process, such as endothelial and vascular dysfunction, inflammation and hematopoietic homeostasis. OBJECTIVE: this study aimed to investigate associations of TGF-\03B21 levels and transforming growth factor beta receptor 3 (TGFBR3) gene polymorphisms with genetic, hematological, biochemical and immunological biomarkers in individuals with sickle cell disease (SCD), as well as clinical complications. MATERIALS AND METHODS: a cross-sectional study was conducted, which were investigated 175 individuals with SCD (120 HbSS and 55 HbSC genotype). TGF-\03B2, tissue inhibitor of metalloproteases-1 (TIMP-1) and matrix metalloproteinase 9 (MMP-9) plasma measurements were performed by ELISA technique. Hematological, biochemical and immunological markers were carried out by automated methods and TGFBR3 polymorphisms genotyping was performed using TaqMan SNP Genotyping Assays. RESULTS: TGF-\03B21 plasma levels were higher in HbSS individuals than in HbSC and health controls. In HbSS individuals, TGF-\03B21 levels were positively correlated with red blood cells (RBC), hemoglobin, hematocrit, platelets and TIMP-1. In addition, HbSS individuals with TGF-\03B21 levels above the median (\226572.29 ng/mL) also presented increased monocyte counts and decreased albumin levels. In patients with HbSC, TGF-\03B21 levels were positively correlated with leukocytes, eosinophils, lymphocytes, monocytes, platelets, TIMP-1, VLDL-C, triglycerides, heme and AST. Additionally, HbSC individuals with TGF-\03B21 levels above the median (\226547.80 ng/mL) presented increased leukocyte and platelet counts, as well as increased levels of triglycerides, VLDL-C, MMP-9 and TIMP-1, and decreased HDL-C. In HbSS individuals, the minor allele (A) of the TGFBR3 rs1805110 polymorphism was associated with increased hemoglobin, hematocrit, reticulocyte counts, low density lipoprotein, uric levels, as well as decreased platelet distribution width (PDW) and the occurrence of bone alterations. The minor allele (T) of TGFBR3 rs7526590 was associated with increased red cell distribution width, PDW, alkaline phosphatase, aspartate aminotransferase, indirect bilirubin and lactate dehydrogenase levels, as well as lower ferritin levels and the occurrence of leg ulcers. Our data suggest that the minor allele (A) of TGFBR3 rs1805110 is associated with inflammation and bone alterations, while the minor allele (T) of TGFBR3 rs7526590 is related to hemolysis and the occurrence of leg ulcers. SCD individuals carries of GG haplotype presented higher levels of total cholesterol (T-CHOL), low density lipoprotein cholesterol (LDL-C), triglycerides, non-HDL cholesterol, total proteins and globulin than individuals with non-GG haplotypes. SCD individuals with the CGG haplotype presented increased plateletcrit, T-CHOL, 11 LDL-C levels and non-HDL cholesterol. Both haplotypes were associated with a previous history of pneumonia. In addition, the GG haplotype was associated with a previous history of pneumonia. CONCLUSION: our findings suggest the importance of TGF-\03B21 in vascular remodeling, vasculopathy, angiogenesis and inflammation in pediatric patients with SCD. TGFBR3 polymorphisms were associated to inflammatory status, hemolysis as well as clinical complications, bone alterations and leg ulcers occurrence. In addition, individuals with the GG and CGG haplotypes of TGFBR3 present significant lipid profile alterations and could be associated with the occurrence of pneumonia.
Keywords in Portuguese
Doença falciformeFator de transformação do crescimento Beta
Receptor 3 do fator de transformação crescimento Beta
Keywords
Sickle cell diseaseTransforming growth factor beta
Transforming growth factor beta receptor 3
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