TGF-? Polymorphisms Are a Risk Factor for Chagas Disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Ferreira RR
PROVIDER: S-EPMC5835243 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
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]
Similar Datasets
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.
| S-EPMC8847772 | biostudies-literature
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.
| S-EPMC10811765 | biostudies-literature
Project description:Chagas disease, caused by Trypanosoma cruzi, remains a serious public health concern in many areas of Latin America, including México. It is also endemic in Texas with an autochthonous canine cycle, abundant vectors (Triatoma species) in many counties, and established domestic and peridomestic cycles which make competent reservoirs available throughout the state. Yet, Chagas disease is not reportable in Texas, blood donor screening is not mandatory, and the serological profiles of human and canine populations remain unknown. The purpose of this analysis was to provide a formal risk assessment, including risk maps, which recommends the removal of these lacunae. The spatial relative risk of the establishment of autochthonous Chagas disease cycles in Texas was assessed using a five-stage analysis. 1. Ecological risk for Chagas disease was established at a fine spatial resolution using a maximum entropy algorithm that takes as input occurrence points of vectors and environmental layers. The analysis was restricted to triatomine vector species for which new data were generated through field collection and through collation of post-1960 museum records in both México and the United States with sufficiently low georeferenced error to be admissible given the spatial resolution of the analysis (1 arc-minute). The new data extended the distribution of vector species to 10 new Texas counties. The models predicted that Triatoma gerstaeckeri has a large region of contiguous suitable habitat in the southern United States and México, T. lecticularia has a diffuse suitable habitat distribution along both coasts of the same region, and T. sanguisuga has a disjoint suitable habitat distribution along the coasts of the United States. The ecological risk is highest in south Texas. 2. Incidence-based relative risk was computed at the county level using the Bayesian Besag-York-Mollié model and post-1960 T. cruzi incidence data. This risk is concentrated in south Texas. 3. The ecological and incidence-based risks were analyzed together in a multi-criteria dominance analysis of all counties and those counties in which there were as yet no reports of parasite incidence. Both analyses picked out counties in south Texas as those at highest risk. 4. As an alternative to the multi-criteria analysis, the ecological and incidence-based risks were compounded in a multiplicative composite risk model. Counties in south Texas emerged as those with the highest risk. 5. Risk as the relative expected exposure rate was computed using a multiplicative model for the composite risk and a scaled population county map for Texas. Counties with highest risk were those in south Texas and a few counties with high human populations in north, east, and central Texas showing that, though Chagas disease risk is concentrated in south Texas, it is not restricted to it. For all of Texas, Chagas disease should be designated as reportable, as it is in Arizona and Massachusetts. At least for south Texas, lower than N, blood donor screening should be mandatory, and the serological profiles of human and canine populations should be established. It is also recommended that a joint initiative be undertaken by the United States and México to combat Chagas disease in the trans-border region. The methodology developed for this analysis can be easily exported to other geographical and disease contexts in which risk assessment is of potential value.
| S-EPMC2950149 | biostudies-literature
Project description:Coronary artery disease (CAD) is one of the leading causes of mortality globally and has long been known to be heritable; however, the specific genetic factors involved have yet to be identified. Recent advances have started to unravel the genetic architecture of this disease and set high expectations about the future use of novel susceptibility variants for its prevention, diagnosis, and treatment. In the past decade, there has been major progress in this area. New tools, like common variant association studies, genome-wide association studies, meta-analyses, and genetic risk scores, allow a better understanding of the genetic risk factors driving CAD. In recent years, researchers have conducted further studies that confirmed the role of numerous genetic factors in the development of CAD. These include genes that affect lipid and carbohydrate metabolism, regulate the function of the endothelium and vascular smooth muscles, influence the coagulation system, or affect the immune system. Many CAD-associated single-nucleotide polymorphisms have been identified, although many of their functions are largely unknown. The inflammatory process that occurs in the coronary vessels is very important in the development of CAD. One important mediator of inflammation is TGFβ1. TGFβ1 plays an important role in the processes leading to CAD, such as by stimulating macrophage and fibroblast chemotaxis, as well as increasing extracellular matrix synthesis. This review discusses the genetic risk factors related to the development of CAD, with a particular focus on polymorphisms of the transforming growth factor β (TGFβ) gene and its receptor.
| S-EPMC10379139 | biostudies-literature
Project description:A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-? are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibrosis upon infection with Trypanosoma cruzi. Thus, considering that the heart is one of the main target organs in Chagas disease, knowledge regarding the mechanisms of action of these molecules is essential to understand how they interact and trigger local and systemic reactions and, consequently, determine whether they contribute to the development of Chagas' heart disease. In this sense, it is believed that the inflammatory microenvironment caused by the infection alters the expression of these proteins favoring progression of the host-parasite cycle and thereby stimulating cardiac tissue remodeling mechanisms and fibrosis. The aim of this review was to gather information on metalloproteinases and their tissue inhibitors, galectins, and TGF-? and discuss how these molecules and their different interrelationships contribute to the development of Chagas' heart disease.
| S-EPMC6899287 | biostudies-literature
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.
| S-EPMC3282214 | biostudies-literature
Project description:BackgroundChronic fatigue syndrome (CFS) is a prevalent and disabling condition among adolescent. The disease mechanisms are unknown. Previous studies have suggested elevated plasma levels of several cytokines, but a recent meta-analysis of 38 articles found that of 77 different cytokines measured in plasma, transforming growth factor beta (TGF-β) was the only one that was elevated in patients compared to controls in a sufficient number of articles. In the present study we therefore compared the plasma levels of the three TGF-β isoforms in adolescent CFS patients and healthy controls. In addition, the study explored associations between TGF-β levels, neuroendocrine markers, clinical markers and differentially expressed genes within the CFS group.MethodsCFS patients aged 12-18 years (n = 120) were recruited nation-wide to a single referral center as part of the NorCAPITAL project (ClinicalTrials ID: NCT01040429). A broad case definition of CFS was applied, requiring 3 months of unexplained, disabling chronic/relapsing fatigue of new onset, whereas no accompanying symptoms were necessary. Healthy controls (n = 68) were recruited from local schools. The three isoforms of TGF-β (TGF-β1, TGF-β2, TGF-β3) were assayed using multiplex technology. Neuroendocrine markers encompassed plasma and urine levels of catecholamines and cortisol, as well as heart rate variability indices. Clinical markers consisted of questionnaire scores for symptoms of post-exertional malaise, inflammation, fatigue, depression and trait anxiety, as well as activity recordings. Whole blood gene expression was assessed by RNA sequencing in a subgroup of patients (n = 29) and controls (n = 18).ResultsPlasma levels of all three isoforms of TGF-β were equal in the CFS patients and the healthy controls. Subgrouping according to the Fukuda and Canada 2003 criteria of CFS did not reveal differential results. Within the CFS group, all isoforms of TGF-β were associated with plasma cortisol, urine norepinephrine and urine epinephrine, and this association pattern was related to fatigue score. Also, TGF-β3 was related to expression of the B cell annotated genes TNFRSF13C and CXCR5.ConclusionsPlasma levels of all TGF-β isoforms were not altered in adolescent CFS. However, the TGF-β isoforms were associated with neuroendocrine markers, an association related to fatigue score. Furthermore, TGF-β3 might partly mediate an association between plasma cortisol and B cell gene expression. Trial registration Clinical Trials NCT01040429.
| S-EPMC5716371 | biostudies-literature
Project description:BackgroundChagas disease induced by Trypanosoma cruzi (T. cruzi) infection is a major cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. Transforming Growth Factor beta (TGFß) has been involved in several regulatory steps of T. cruzi invasion and in host tissue fibrosis. GW788388 is a new TGFß type I and type II receptor kinase inhibitor that can be orally administered. In the present work, we studied its effects in vivo during the acute phase of experimental Chagas disease.Methodology/principal findingsMale Swiss mice were infected intraperitoneally with 10(4) trypomastigotes of T. cruzi (Y strain) and evaluated clinically. We found that this compound given once 3 days post infection (dpi) significantly decreased parasitemia, increased survival, improved cardiac electrical conduction as measured by PR interval in electrocardiography, and restored connexin43 expression. We could further show that cardiac fibrosis development, evaluated by collagen type I and fibronectin expression, could be inhibited by this compound. Interestingly, we further demonstrated that administration of GW788388 at the end of the acute phase (20 dpi) still significantly increased survival and decreased cardiac fibrosis (evaluated by Masson's trichrome staining and collagen type I expression), in a stage when parasite growth is no more central to this event.Conclusion/significanceThis work confirms that inhibition of TGFß signaling pathway can be considered as a potential alternative strategy for the treatment of the symptomatic cardiomyopathy found in the acute and chronic phases of Chagas disease.
| S-EPMC3373641 | biostudies-literature
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.
| S-EPMC5354491 | biostudies-literature
Project description:The transforming growth factor β isoforms, TGF-β1, -β2, and -β3, are small secreted homodimeric signaling proteins with essential roles in regulating the adaptive immune system and maintaining the extracellular matrix. However, dysregulation of the TGF-β pathway is responsible for promoting the progression of several human diseases, including cancer and fibrosis. Despite the known importance of TGF-βs in promoting disease progression, no inhibitors have been approved for use in humans. Herein, we describe an engineered TGF-β monomer, lacking the heel helix, a structural motif essential for binding the TGF-β type I receptor (TβRI) but dispensable for binding the other receptor required for TGF-β signaling, the TGF-β type II receptor (TβRII), as an alternative therapeutic modality for blocking TGF-β signaling in humans. As shown through binding studies and crystallography, the engineered monomer retained the same overall structure of native TGF-β monomers and bound TβRII in an identical manner. Cell-based luciferase assays showed that the engineered monomer functioned as a dominant negative to inhibit TGF-β signaling with a Ki of 20-70 nm Investigation of the mechanism showed that the high affinity of the engineered monomer for TβRII, coupled with its reduced ability to non-covalently dimerize and its inability to bind and recruit TβRI, enabled it to bind endogenous TβRII but prevented it from binding and recruiting TβRI to form a signaling complex. Such engineered monomers provide a new avenue to probe and manipulate TGF-β signaling and may inform similar modifications of other TGF-β family members.
| S-EPMC5409485 | biostudies-literature