Publications by authors named "Hui-Tzu Lin Wang"

16 Publications

  • Page 1 of 1

Serological Testing for COVID-19, Immunological Surveillance, and Exploration of Protective Antibodies.

Front Immunol 2021 19;12:635701. Epub 2021 Aug 19.

Brazilian Biosciences National Laboratory, Center for Research in Energy and Materials, Campinas, Brazil.

Serological testing is a powerful tool in epidemiological studies for understanding viral circulation and assessing the effectiveness of virus control measures, as is the case of SARS-CoV-2, the pathogenic agent of COVID-19. Immunoassays can quantitatively reveal the concentration of antiviral antibodies. The assessment of antiviral antibody titers may provide information on virus exposure, and changes in IgG levels are also indicative of a reduction in viral circulation. In this work, we describe a serological study for the evaluation of antiviral IgG and IgM antibodies and their correlation with antiviral activity. The serological assay for IgG detection used two SARS-CoV-2 proteins as antigens, the nucleocapsid N protein and the 3CL protease. Cross-reactivity tests in animals have shown high selectivity for detection of antiviral antibodies, using both the N and 3CL antigens. Using samples of human serum from individuals previously diagnosed by PCR for COVID-19, we observed high sensitivity of the ELISA assay. Serological results with human samples also suggest that the combination of higher titers of antiviral IgG antibodies to different antigen targets may be associated with greater neutralization activity, which can be enhanced in the presence of antiviral IgM antibodies.
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http://dx.doi.org/10.3389/fimmu.2021.635701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417107PMC
September 2021

COVID-19 in heart transplant patients: Case reports from Brazil.

Clin Transplant 2021 May 24:e14330. Epub 2021 May 24.

Laboratory of Molecular Investigation in Cardiology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.

Introduction: The COVID-19 pandemic continues, with a late hyperinflammatory phase. The immunosuppressive therapy used in heart transplant patients, in theory, could reduce inflammation, thus benefitting patients with COVID-19. So far, however, there is still very little literature on this subject.

Methods: This is a single-center retrospective study. We described laboratory parameters and clinical outcomes from 11 heart transplant patients with COVID-19 assisted at Dante Pazzanese Institute of Cardiology between March and July 2020.

Results: Patients with ages of between 35 and 79 years were enrolled, and heart transplantation ranged from 3 to 264 months. The main comorbidities were diabetes mellitus (9/11; 81.8%), hypertension (10/11; 90.9%), and chronic renal disease (6/11; 54.5%). Cyclosporine A was used in 10 (90.9%) patients, mycophenolate mofetil in 9 (81.8%) patients, and mTOR inhibitor in 5 (45.5%) patients. Fever and cough were observed in 8 (72.7%) patients, and dyspnea and gastrointestinal symptoms in 5 (45.5%) patients. Lymphopenia was observed in 10 (90.9%) patients and thrombocytopenia in 5 (45.5%) patients. The higher level of troponin associated with chest tomography above 50% of bilateral pulmonary infiltrates with ground-glass opacity (GGO) was observed in those with the worst outcomes. Nine patients needed intensive care, and hospital stay ranged from 4 to 21 days, with 2 (18.2%) patients requiring vasopressor drugs and mechanical ventilation, and three (27.3%) patients dying due to COVID-19 complications.

Conclusion: Heart transplant patients had similar symptoms and outcomes as the general population; immunosuppressive therapy seems not to have protected them. Patients who presented higher levels of troponin and D-dimer, associated with greater GGO pulmonary infiltrates, had worse outcomes. More studies with larger cohorts may clarify immunosuppressive effects on COVID-19 outcomes.
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http://dx.doi.org/10.1111/ctr.14330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209934PMC
May 2021

Effect of qualitative and quantitative nutritional plan on gene expression in obese patients in secondary prevention for cardiovascular disease.

Clin Nutr ESPEN 2021 02 26;41:351-359. Epub 2020 Nov 26.

Nutritional Genomics and Inflammation Laboratory, Department of Nutrition, School of Public Health, University of São Paulo, 01246-904, São Paulo, Brazil. Electronic address:

Background & Aims: Diet is a modifiable risk factor, which may influence the gene expression and the concentration of inflammatory biomarkers related to obesity and atherosclerosis. In this substudy from Brazilian Cardioprotective Nutritional (BALANCE) Program, we hypothesized that a nutritional intervention based on the usual Brazilian diet modulates the expression of genes involved with atherosclerosis and inflammatory biomarkers in male patients, in the secondary prevention for cardiovascular disease.

Methods: Six male patients, aged 45 years or older, obese, were selected to follow a qualitative-quantitative food plan for 6 months. Glycemia, insulinemia, lipid profile, plasma concentration of inflammatory biomarkers (interleukin (IL) -1β), IL-6, IL-8, IL-10, IL-12, tumor necrosis factor alpha, C-reactive protein and adiponectin, and expression of 84 atherosclerosis-related genes in total peripheral blood cells, were measured.

Results: After nutritional intervention, the participants reduced weight (p < 0.04), waist circumference (p < 0.04), Homeostasis Model Assessment index for insulin resistance (p = 0.046) and overall leukocyte count (p = 0.046) and neutrophils (p = 0.028). There was no significant modification in the plasma concentration of the inflammatory biomarkers, however, there was a significant increase in the expression of Apo A1 (p = 0.011), ELN (p = 0.017) and IL4 (p = 0.037) genes.

Conclusions: The BALANCE Program, the qualitative-quantitative food plan composed of Brazilian usual foods, did not reduce the concentration of inflammatory biomarkers, but increased in total peripheral blood cells the expression of genes involved in reducing the risk of cardiometabolic in obese patients, in secondary prevention for cardiovascular disease. The clinical trial is registered at https://clinicaltrials.gov/ and the unique identifier is NCT01620398.
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http://dx.doi.org/10.1016/j.clnesp.2020.11.002DOI Listing
February 2021

Smoking load reduction is insufficient to downregulate miR-301b, a lung cancer promoter.

Sci Rep 2020 12 3;10(1):21112. Epub 2020 Dec 3.

Department of Physiotherapy, LIM-54, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455 room 1150, São Paulo, São Paulo, 01246-930, Brazil.

Several circulating miRNAs identified in the plasma of smokers have been implicated as promoters of nasopharyngeal and lung carcinoma. To investigate the plasma profile of miRNAs in subjects who reduces the number of smoked cigarettes and who quit after six months. We accompanied 28 individuals enrolled in a Smoking Cessation Program over 6 months. At Baseline, clinical characteristics, co-morbidities, and smoking history were similar among subjects. After 6 months, two groups were defined: who successfully quitted smoking (named "quitters", n = 18, mean age 57 years, 11 male) and who reduced the number of cigarettes smoked (20-90%) but failed to quit smoking (named "smokers", n = 10, mean age 52 years, 3 male). No significant clinical changes were observed between groups at baseline and after a 6-month period, however, quitters showed significant downregulations in seven miRNAs at baseline: miR-17 (- 2.90-fold, p = 0.029), miR-20a (- 3.80-fold, p = 0.021); miR-20b (- 4.71-fold, p = 0.027); miR-30a (- 3.95-fold, p = 0.024); miR-93 (- 3.63-fold, p = 0.022); miR-125a (- 1.70-fold, p = 0.038); and miR-195 (- 5.37-fold, p = 0.002), and after a 6-month period in 6 miRNAs: miR-17 (- 5.30-fold, p = 0.012), miR-20a (- 2.04-fold, p = 0.017), miR-20b (- 5.44-fold, p = 0.017), miR-93 (- 4.00-fold, p = 0.041), miR-101 (- 4.82-fold, p = 0.047) and miR-125b (- 3.65-fold, p = 0.025). Using time comparisons, only quitters had significant downregulation in miR-301b (- 2.29-fold, p = 0.038) after 6-month. Reductions in the number of smoked cigarettes was insufficient to change the plasma profile of miRNA after 6 months. Only quitting smoking (100% reduction) significantly downregulated miR-301b related to hypoxic conditions, promotion of cell proliferation, decreases in apoptosis, cancer development, and progression as increases in radiotherapy and chemotherapy resistance.
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http://dx.doi.org/10.1038/s41598-020-78242-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713348PMC
December 2020

Genomics, epigenomics and pharmacogenomics of familial hypercholesterolemia (FHBGEP): A study protocol.

Res Social Adm Pharm 2021 07 29;17(7):1347-1355. Epub 2020 Oct 29.

Cruzeiro do Sul University, Sao Paulo, Brazil. Electronic address:

Background: Familial hypercholesterolemia (FH) is a genetic disease that affects millions of people worldwide.

Objectives: The study protocol FHBGEP was design to investigate the main genomic, epigenomic, and pharmacogenomic factors associated with FH and polygenic hypercholesterolemia (PH).

Methods: FH patients will be enrolled at six research centers in Brazil. An exon-targeted gene strategy will be used to sequence a panel of 84 genes related to FH, PH, pharmacogenomics and coronary artery disease. Variants in coding and regulatory regions will be identified using a proposed variant discovery pipeline and classified according to the American College Medical Genetics guidelines. Functional effects of variants in FH-related genes will be investigated by in vitro studies using lymphocytes and cell lines (HepG2, HUVEC and HEK293FT), CRISPR/Cas9 mutagenesis, luciferase reporter assay and other technologies. Functional studies in silico, such as molecular docking, molecular dynamics, and conformational analysis, will be used to explore the impact of novel variants on protein structure and function. DNA methylation profile and differential expression of circulating non-coding RNAs (miRNAs and lncRNAs) will be analyzed in FH patients and normolipidemic subjects (control group). The influence of genomic and epigenomic factors on metabolic and inflammatory status will be analyzed in FH patients. Pharmacogenomic studies will be conducted to investigate the influence of genomic and epigenomic factors on response to statins in FH patients.

Summary: The FHBGEP protocol has the potential to elucidate the genetic basis and molecular mechanisms involved in the pathophysiology of FH and PH, particularly in the Brazilian population. This pioneering approach includes genomic, epigenomic and functional studies, which results will contribute to the improvement of the diagnosis, prognosis and personalized therapy of FH patients.
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http://dx.doi.org/10.1016/j.sapharm.2020.10.007DOI Listing
July 2021

Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy.

Front Immunol 2020 7;11:1386. Epub 2020 Jul 7.

Heart Institute (InCor), University of São Paulo School of Medicine (FMUSP), São Paulo, Brazil.

Chagas disease, caused by the protozoan , is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of infection, while the others remain asymptomatic (ASY). IFN-γ and IFN-γ-producing Th1-type T cells are increased in peripheral blood and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN-γ-producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN-γ production by Th1-type T cells may be a key event for progression toward CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development. We studied a Brazilian population including 315 CCC cases and 118 ASY subjects. We assessed 35 Tag SNPs designed to represent all the genetic information contained in the , and genes. We found 2 SNPs (rs2546893, rs919766) and a trend of association for a SNP (rs3024496) to be significantly associated with the ASY group. these associations were confirmed by multivariate analysis and allele tests. The rs919766C, 12rs2546893G, and rs3024496C alleles were associated to an increase risk to CCC development. Our data show that novel polymorphisms affecting and , but not or genes play a role in genetic susceptibility to CCC development. This might indicate that the increased Th1 differentiation and IFN-γ production associated with CCC is genetically controlled.
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http://dx.doi.org/10.3389/fimmu.2020.01386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358543PMC
April 2021

Dysregulation of microRNAs and target genes networks in human abdominal aortic aneurysm tissues.

PLoS One 2019 20;14(9):e0222782. Epub 2019 Sep 20.

Department of Clinical Cardiology, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil.

Background: Abdominal aortic aneurysm (AAA) is a pathological enlargement of infrarenal aorta close to the aortic bifurcation, and it is an important cause of mortality in the elderly. Therefore, the biomarker identification for early diagnosis is of great interest for clinical benefit. It is known that microRNAs (miRNAs) have important roles via target genes regulation in many diseases. This study aimed to identify miRNAs and their target genes involved in the pathogenesis of AAA.

Methods: Tissue samples were obtained from patients who underwent AAA surgery and from organ donors (control group). Quantitative PCR Array was applied to assess 84 genes and 384 miRNAs aiming to identify differentially expressed targets (AAA n = 6, control n = 6), followed by validation in a new cohort (AAA n = 18, control n = 6) by regular qPCR. The functional interaction between validated miRNAs and target genes was performed by the Ingenuity Pathway Analysis (IPA) software.

Results: The screening cohort assessed by PCR array identified 10 genes and 59 miRNAs differentially expressed (≥2-fold change, p<0.05). Among these, IPA identified 5 genes and 9 miRNAs with paired interaction. ALOX5, PTGIS, CX3CL1 genes, and miR-193a-3p, 125b-5p, 150-5p maintained a statistical significance in the validation cohort. IPA analysis based on the validated genes and miRNAs revealed that eicosanoid and metalloproteinase/TIMP synthesis are potentially involved in AAA.

Conclusion: Paired interactions of differentially expressed ALOX5, PTGIS, CX3CL1 genes, and miR-193b-3p, 125b-5p, 150-5p revealed a potentially significant role of the eicosanoid synthesis and metalloproteinase/TIMP pathways in the AAA pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222782PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754147PMC
March 2020

Donor hypernatremia and smoking addiction contribute to primary graft failure in heart transplantation.

Clin Transplant 2019 10 8;33(10):e13693. Epub 2019 Sep 8.

Laboratory of Molecular Investigation in Cardiology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.

Introduction: Primary graft failure (PGF) is an important contributor to early mortality, accounting for 41% of deaths within the first 30 days after heart transplantation (HT). Donor hypernatremia has been associated with PGF development. However, controversial data exist regarding the impact of sodium deregulation in patient survival after HT. This study aimed to assess the influence of donor hypernatremia on PGF development and to determine the serum sodium level threshold to assist in decision-making for organ procurement.

Methods: The medical record from 200 HT patients and organ donors were retrospectively assessed and categorized by PGF occurrence. Donor sodium levels were compared and cut-off points obtained by receiver operating characteristic (ROC) curve. A multiple logistic regression model was applied to assess the effects of factors and covariates that influence PGF development.

Results: Sodium levels of donors were significantly higher in recipients who developed PGF than those who did not develop PGF (162 vs. 153 mmol/L, P = .001). The sodium cut-off value determined by the ROC curve was 159 mmol/L. The group who received organs from donors with a serum sodium concentration ≥159 mmol/L had a higher incidence of PGF (63.3% vs 32.4%, P < .001). Furthermore, donor sodium levels ≥159 mmol/L increased the likelihood of recipients developing PGF by 3.4 times. It is also observed that the incidence of donor smoking addiction was significantly higher in the PGF group (28.6% vs. 11.5%, P = .004) and donor smoking addiction increased the risk of developing PGF by 2.8 times.

Conclusion: Smoking addiction and the application of suboptimal organs from donors with hypernatremia contribute to primary graft failure in heart transplantation.
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http://dx.doi.org/10.1111/ctr.13693DOI Listing
October 2019

Intragraft vasculitis and gene expression analysis: Association with acute rejection and prediction of mortality in long-term heart transplantation.

Clin Transplant 2018 10 31;32(10):e13373. Epub 2018 Aug 31.

Laboratory of Molecular Investigation in Cardiology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.

Introduction: Vasculitis entails heterogeneous origins; it starts with an inflammatory process that leads to small vessels' necrosis, hemorrhage, and ischemic lesion, and may further result in occlusion of the vascular lumen. Vasculitis' contribution to allograft rejection is still unclear. This study aims to investigate the incidence of vasculitis in the early stages of heart transplantation as well as to assess the intragraft genes' expression associated with vascular function and subsequently to verify the way in which it affects the outcome of the allograft.

Methods: In this retrospective study, 300 archive paraffin-embedded endomyocardial biopsies from 63 heart allograft recipients were assessed. Cellular rejection and vasculitis were diagnosed through histological analysis, and antibody-mediated rejection was performed with immunohistochemical C4d staining. The transcripts of ICAM, VCAM, VEGF, CCL2, IFNG, TGFB, TNF, ADIPOR1, and ADIPOR2 genes were examined through quantitative polymerase chain reaction using B2M for normalization.

Results: We observed a higher prevalence of severe vasculitis in the early period of post-transplant, and recovery was observed to take place around 1 year post-transplant. Additionally, vasculitis was found to be directly associated with acute cellular rejection and antibody-mediated rejection. The intense C4d capillary positivity predicts higher long-term cardiovascular disease mortality. In comparison with the vasculitis-free group, the group with severe vasculitis displayed reduced left ventricular ejection fraction and an upregulation of VCAM and IFNG associated with the downregulation of VEGF, ADIPOR1, and ADIPOR2.

Conclusion: The vasculitis associated with the presence of C4d and the change in intragraft gene expression profile may contribute to poor allograft outcomes.
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http://dx.doi.org/10.1111/ctr.13373DOI Listing
October 2018

Down regulation of protective genes is associated with cellular and antibody-mediated rejection.

Clin Transplant 2017 Oct 21;31(10). Epub 2017 Aug 21.

Laboratory of Molecular Investigation in Cardiology, Dante Pazzanese Institute of Cardiology, São Paulo, Brazil.

Despite advances in immunosuppressive therapy, rejection still remains the main obstacle to a successful transplant. This study aims to explore the gene expression profile of the rejection process in order to decrease the number of unnecessary endomyocardial biopsies in stable patients.

Methods: A total of 300 formalin-fixed and paraffin-embedded (FFPE) endomyocardial biopsies sampled from 63 heart allograft recipients were included in this study. Acute cellular rejection (ACR) and antibody-mediated rejection (AMR) were diagnosed by histological analysis and immunohistochemical C4d staining, respectively. Analysis of gene expression was performed by quantitative real-time polymerase chain reaction. The samples were grouped according to the ISHLT rejection classification, aiming the statistical analysis.

Results: There was a significant decrease in the HMOX1, AIF1, and CCL2 transcript over the post-transplantation period in non-rejection group (P<.001). Furthermore, the ADIPOR1, ADIPOR2, BCL2L1, and VEGFA protective genes were significantly downregulated in the ACR group (P<.05). ADIPOR2, BCL2L1, IL6, and NOS2 genes were also significantly downregulated in the AMR group than in the non-rejection group (P<.05).

Conclusion: The downregulations of the protective genes contribute to the allograft rejection, and the archived FFPE samples are useful for the gene expression analysis aiming the allograft rejection surveillance.
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http://dx.doi.org/10.1111/ctr.13060DOI Listing
October 2017

Analysis of Circulating miR-1, miR-23a, and miR-26a in Atrial Fibrillation Patients Undergoing Coronary Bypass Artery Grafting Surgery.

Ann Hum Genet 2017 May;81(3):99-105

Instituto Dante Pazzanese de Cardiologia Sao Paulo, São Paulo, BR.

Atrial fibrillation (AF) is the most common arrhythmia after cardiac surgery. From a pathophysiological point of view, a myriad of factors such as trauma, atrial dilation, ischemia, mechanical myopericarditis, autonomic imbalance, loss of connexins, AF nest remodeling, inflammation, sutures, and dysfunction caused by postextracorporeal circulation can contribute to postoperative atrial fibrillation (POAF) resulting in a longer hospital stay and consequently higher cost. Recent studies showed that short fragments of RNA, called microRNA (miRNA), can contribute to the development of several cardiovascular diseases, including AF. The aim of this study was to evaluate the levels of circulating miRNAs (miR-1, -23a, and -26a) that can be involved in POAF. Patients submitted to coronary artery bypass graft surgery were grouped in POAF (24 patients) and without POAF (24 patients). Results showed older age, longer clamp-time, and more days in the intensive care unit as well as a longer total hospital stay in the POAF group. Preoperative levels of circulating miRNAs were similar. Analysis of miRNAs revealed significantly lower circulating levels of miRNA-23a (P  =  0.02) and -26a (P  =  0.01) in the POAF group during the postoperative period. Receiver operating characteristic (ROC) analysis showed the area under the ROC curve of miR-23a and miR-26a for predicting FA was 0.63 (95% confidence interval [CI]: 0.51-0.74; P  =  0.02) and 0.66 (95% CI: 0.55-0.77; P  =  0.01), respectively. Our data suggests that circulating miRNA-23a and -26a may be involved in the underlying biology of postoperative AF development.
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http://dx.doi.org/10.1111/ahg.12188DOI Listing
May 2017

WITHDRAWN: Selection of reference genes in five types of human tissues for normalization of gene expression studies in infectious diseases.

Gene 2016 Oct 12. Epub 2016 Oct 12.

Laboratório de Imunogenética, Departamento de Biologia Molecular, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, Brazil.

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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http://dx.doi.org/10.1016/j.gene.2016.10.012DOI Listing
October 2016

Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease.

Cytokine 2015 May 2;73(1):79-83. Epub 2015 Mar 2.

Laboratory of Immunology, Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil; Division of Clinical Immunology and Allergy, School of Medicine, University of São Paulo, São Paulo, Brazil; Institute for Investigation in Immunology (iii), INCT, São Paulo, Brazil. Electronic address:

Background: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the rest of the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described. IL-18 could potentially amplify the process by inducing increased expression of IFN-γ which in turn can increase the production of IL-18, thereby creating a positive feedback mechanism. In order to assess the contribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the association between a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developing Chagas cardiomyopathy.

Methods And Results: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas disease cardiomyopathy patients (n=849) and asymptomatic subjects (n=202). We found a significant difference in genotype frequencies among moderate and severe CCC patients with ventricular dysfunction.

Conclusions: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkage disequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome.
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http://dx.doi.org/10.1016/j.cyto.2015.01.037DOI Listing
May 2015

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.

BMC Infect Dis 2013 Dec 12;13:587. Epub 2013 Dec 12.

Aix-Marseille Université, INSERM, GIMP UMR_S906, Faculté de médecine, 27 bd Jean Moulin, Marseille, cedex 05 13385, France.

Background: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage.

Methods: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.

Results: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.

Conclusions: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.
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http://dx.doi.org/10.1186/1471-2334-13-587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866603PMC
December 2013

Myocardial chemokine expression and intensity of myocarditis in Chagas cardiomyopathy are controlled by polymorphisms in CXCL9 and CXCL10.

PLoS Negl Trop Dis 2012 25;6(10):e1867. Epub 2012 Oct 25.

Laboratory of Immunology, Heart Institute (InCor), School of Medicine, University of São Paulo, São Paulo, Brazil.

Background: Chronic Chagas cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi. Even though the Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis, little is known about the factors controlling inflammatory cell migration to CCC myocardium.

Methods And Results: Using confocal immunofluorescence and quantitative PCR, we studied cell surface staining and gene expression of the CXCR3, CCR4, CCR5, CCR7, CCR8 receptors and their chemokine ligands in myocardial samples from end-stage CCC patients. CCR5+, CXCR3+, CCR4+, CCL5+ and CXCL9+ mononuclear cells were observed in CCC myocardium. mRNA expression of the chemokines CCL5, CXCL9, CXCL10, CCL17, CCL19 and their receptors was upregulated in CCC myocardium. CXCL9 mRNA expression directly correlated with the intensity of myocarditis, as well as with mRNA expression of CXCR3, CCR4, CCR5, CCR7, CCR8 and their ligands. We also analyzed single-nucleotide polymorphisms for genes encoding the most highly expressed chemokines and receptors in a cohort of Chagas disease patients. CCC patients with ventricular dysfunction displayed reduced genotypic frequencies of CXCL9 rs10336 CC, CXCL10 rs3921 GG, and increased CCR5 rs1799988CC as compared to those without dysfunction. Significantly, myocardial samples from CCC patients carrying the CXCL9/CXCL10 genotypes associated to a lower risk displayed a 2-6 fold reduction in mRNA expression of CXCL9, CXCL10, and other chemokines and receptors, along with reduced intensity of myocarditis, as compared to those with other CXCL9/CXCL10 genotypes.

Conclusions: Results may indicate that genotypes associated to reduced risk in closely linked CXCL9 and CXCL10 genes may modulate local expression of the chemokines themselves, and simultaneously affect myocardial expression of other key chemokines as well as intensity of myocarditis. Taken together our results may suggest that CXCL9 and CXCL10 are master regulators of myocardial inflammatory cell migration, perhaps affecting clinical progression to the life-threatening form of CCC.
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http://dx.doi.org/10.1371/journal.pntd.0001867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493616PMC
March 2013
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