TGF-? Polymorphisms Are a Risk Factor for Chagas Disease.
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ABSTRACT:
SUBMITTER: Ferreira RR
PROVIDER: S-EPMC5835243 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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TGF-<i>β</i> Polymorphisms Are a Risk Factor for Chagas Disease.
Ferreira Roberto Rodrigues RR Madeira Fabiana da Silva FDS Alves Gabriel Farias GF Chambela Mayara da Costa MDC Curvo Eduardo de Oliveira Vaz EOV Moreira Aline Dos Santos ADS Almeida de Sá Renata R Mendonça-Lima Leila L Cabello Pedro Hernan PH Bailly Sabine S Feige Jean-Jacques JJ Araujo-Jorge Tania Cremonini TC Saraiva Roberto Magalhães RM Waghabi Mariana Caldas MC
Disease markers 20180218
Transforming growth factor <i>β</i>1 (TGF-<i>β</i>1) is an important mediator in Chagas disease. Furthermore, patients with higher TGF-<i>β</i>1 serum levels show a worse clinical outcome. Gene polymorphism may account for differences in cytokine production during infectious diseases. We tested whether <i>TGFB1</i> polymorphisms could be associated with Chagas disease susceptibility and severity in a Brazilian population. We investigated five single-nucleotide polymorphisms (-800 G>A, -509 C>T, ...[more]
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Project description:The anti-inflammatory cytokine transforming growth factor beta (TGF-β) plays an important role in Chagas disease (CD), a potentially life-threatening illness caused by Trypanosoma cruzi. In this review we revisited clinical studies in CD patients combined with in vitro and in vivo experiments, presenting three main sections: an overview of epidemiological, economic, and clinical aspects of CD and the need for new biomarkers and treatment; a brief panorama of TGF-β roles and its intracellular signaling pathways, and an update of what is known about TGF-β and Chagas disease. In in vitro assays, TGF-β increases during T. cruzi infection and modulates heart cells invasion by the parasite fostering its intracellular parasite cycle. TGF-β modulates host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. TGF-β signaling inhibitors reverts these effects opening a promising therapeutic approach in pre-clinical studies. CD patients with higher TGF-β1 serum level show a worse clinical outcome, implicating a predictive value of serum TGF-β as a surrogate biomarker of clinical relevance. Moreover, pre-clinical studies in chronic T. cruzi infected mice proved that inhibition of TGF-β pathway improved several cardiac electric parameters, reversed the loss of connexin-43 enriched intercellular plaques, reduced fibrosis of the cardiac tissue, restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Finally, TGF-β polymorphisms indicate that CD immunogenetics is at the base of this phenomenon. We searched in a Brazilian population five single-nucleotide polymorphisms (-800 G>A rs1800468, -509 C>T rs1800469, +10 T>C rs1800470, +25 G>C rs1800471, and +263 C>T rs1800472), showing that CD patients frequently express the TGF-β1 gene genotypes CT and TT at position -509, as compared to noninfected persons; similar results were observed with genotypes TC and CC at codon +10 of the TGF-β1 gene, leading to the conclusion that 509 C>T and +10 T>C TGF-β1 polymorphisms are associated with Chagas disease susceptibility. Studies in genetically different populations susceptible to CD will help to gather new insights and encourage the use of TGF-β as a CD biomarker.
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Project description:ObjectivesThe aim of the present study was to compare the circulating transforming growth factor-beta (TGF-β) of clinically normal age-matched and naturally occurring chronic kidney disease (CKD) cats and to determine the correlation between the TGF-β expression and histopathological changes in cats with CKD.MethodsA total of 11 clinically normal age-matched and 27 cats with naturally occurring CKD were included in this study. Circulating TGF-β was quantified by immunoassays. Kaplan-Meier analysis was used to calculate the association between survival time and the concentration of circulating TGF-β. A general linear model was used to compare the circulating TGF-β between groups. Immunohistochemical analyses revealed TGF-β expression in renal tissues from cats with CKD that died during the study (n = 7) and in available archived renal tissue specimens taken at necropsy from cats that had previous CKD with renal lesions (n = 10). Correlations of the TGF-β expression and clinical parameters (n = 7) and histopathological changes (n = 17) were analysed using Spearman's rank correlation.ResultsThe median survival time of cats with a lower concentration of circulating TGF-β was shorter than that of cats with a higher concentration. The area under the curve of circulating TGF-β for predicting CKD was 0.781, indicating good differentiation. The study indicated a significant difference in circulating TGF-β concentrations between clinically normal cats and those with CKD and demonstrated that TGF-β expression is correlated with tubular atrophy.Conclusions and relevanceThe study findings suggest that decreased serum TGF-β and tubular atrophy with TGF-β immunoreactivity may be significant in cats with CKD.
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Project description:PurposeTransforming growth factor beta receptor 2 (TGFBR2) is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs) of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of TGFBR2 gene suggest that the TGFBR2 gene SNPs are related to the pathogenesis of Kawasaki disease (KD) and coronary artery lesion (CAL).MethodsThe subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected TGFBR2 gene SNPs from serum and performed direct sequencing.ResultsThe sequences of the eleven SNPs in the TGFBR2 gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430) were associated with development of KD (P=0.019, P=0.026, P=0.016, respectively). One SNP (rs1495592) was associated with CAL in KD group (P=0.022).ConclusionEleven SNPs in TGFBR2 gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the TGFBR2 gene. One of the six SNPs (rs6550004) was associated with development of KD. One SNP associated with CAL (rs1495592) was disassociated from the TGFBR2 gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.
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Project description:The intensity and duration of TGF-β signaling determine the cellular biological response. How this is negatively regulated is not well understood. Here, we identified a novel negative regulator of TGF-β signaling, transmembrane p24-trafficking protein 10 (TMED10). TMED10 disrupts the complex formation between TGF-β type I (also termed ALK5) and type II receptors (TβRII). Misexpression studies revealed that TMED10 attenuated TGF-β-mediated signaling. A 20-amino acid-long region from Thr91 to Glu110 within the extracellular region of TMED10 was found to be crucial for TMED10 interaction with both ALK5 and TβRII. Synthetic peptides corresponding to this region inhibit both TGF-β-induced Smad2 phosphorylation and Smad-dependent transcriptional reporter activity. In a xenograft cancer model, where previously TGF-β was shown to elicit tumor-promoting effects, gain-of-function and loss-of-function studies for TMED10 revealed a decrease and increase in the tumor size, respectively. Thus, we determined herein that TMED10 expression levels are the key determinant for efficiency of TGF-β receptor complex formation and signaling.
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Project description:PurposeOsteoporotic vertebral compression fracture (OVCF) is a common disease in the elderly, and genetic factors play a key role in its occurrence. The present study was conducted to investigate the association between interleukin-6 (IL-6) and the transforming growth factor (TGF-β) gene polymorphisms and the occurrence of thoracolumbar OVCF.Patients and methodsThis case-control study recruited 146 patients with OVCF and 144 osteoporosis patients as the control group. Genotypes of the IL-6 rs1800796 and TGF-β rs1982073 were analyzed by sequencing. Genotype distribution and allelic frequencies were investigated by the χ2 test. Odds ratios (OR) and 95% confidence intervals (CI) evaluated the relationship of IL-6 or TGF-β polymorphism and OVCF susceptibility.ResultsAllele G and genotype GG of IL-6 rs1800796 was more frequent in patients with OVCF (40.07% vs.28.47%; 19.18% vs.7.64%) compared with controls. GG genotype (OR=3.394, 95% CI=1.560-7.385, P < 0.001) and G allele (OR=1.680, 95% CI=1.187-2.376, P < 0.001) of IL-6 rs1800796 was significantly associated with increased risk of OVCF. What is more, CT and TT genotypes (41.78 vs.51.39; 19.86 vs.26.39) and allele T (40.75 vs 52.08) of TGF-β rs1982073 were less frequent in OVCFs, more common in controls and protective against OVCF risk (OR=0.436, 95% CI=0.228-0.835, P = 0.012; OR=0.615, 95% CI=0.443-0.855, P = 0.004).ConclusionOur results suggest that the G allele and GG genotype of IL-6 rs1800796 may contribute to increased susceptibility to OVCF in elderly Chinese. In contrast, CT and TT genotypes and the T allele of TGF-β rs1982073 may contribute to lower susceptibility of OVCF.
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Project description:BackgroundSchizophrenia is one of the most common devastating psychiatric disorders that negatively affects the quality of life and psychosocial functions. Its etiology involves the interplay of complex polygenic influences and environmental risk factors. Inflammatory markers are well-known etiological factors for psychiatric disorders, including schizophrenia.ObjectiveThe aim of this study was to investigate the association of proinflammatory cytokine genes, tumor necrosis factor (TNF)-α (-308G/A) and TNF-β (+252A/G) polymorphisms with schizophrenia susceptibility.Subjects and methodsTNF-α and TNF-β genes were amplified using amplification refractory mutation system primers in 180 schizophrenia patients and 200 healthy matched controls recruited from the Psychiatry Clinic of Prince Sultan Military Medical City, Riyadh. The frequencies of alleles and genotypes of TNF-α (-308G/A) and TNF-β (+252A/G) polymorphisms in patients were compared with those in controls.ResultsThe frequencies of TNF-α (-308) allele A and genotype GA were significantly higher, while those of allele G and genotype GG were lower in schizophrenia patients as compared to controls, indicating that genotype GA and allele A of TNF-α (-308G/A) may increase susceptibility to schizophrenia, while genotype GG and allele G may reduce it. On the other hand, the distribution of alleles and genotypes of TNF-β (+252A/G) polymorphism does not differ significantly in patients from controls; however, the frequency of genotype GG of TNF-β (+252A/G) was significantly higher in male patients than in female patients. The distribution of TNF-α (-308G/A) and TNF-β (+252A/G) polymorphisms was almost similar in schizophrenia patients with negative or positive symptoms.ConclusionTNF-α (-308G/A) and TNF-β (+252G/A) polymorphisms may increase the susceptibility to schizophrenia in Saudi patients and could be a potential risk factor for its etiopathogenesis. However, further studies are warranted involving a larger sample size to strengthen our findings.
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