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1. Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy

Author

Pauline Brochet, Barbara Maria Ianni, Laurie Laugier, Amanda Farage Frade, João Paulo Silva Nunes, Priscila Camillo Teixeira, Charles Mady, Ludmila Rodrigues Pinto Ferreira, Quentin Ferré, Ronaldo Honorato Barros Santos, Andreia Kuramoto, Sandrine Cabantous, Samuel Steffen, Antonio Noedir Stolf, Pablo Pomerantzeff, Alfredo Inacio Fiorelli, Edimar Alcides Bocchi, Cristina Wide Pissetti, Bruno Saba, Darlan da Silva Cândido, Fabrício C. Dias, Marcelo Ferraz Sampaio, Fabio Antônio Gaiotto, José Antonio Marin-Neto, Abílio Fragata, Ricardo Costa Fernandes Zaniratto, Sergio Siqueira, Giselle De Lima Peixoto, Vagner Oliveira-Carvalho Rigaud, Fernando Bacal, Paula Buck, Rafael Ribeiro Almeida, Hui Tzu Lin-Wang, André Schmidt, Martino Martinelli, Mario Hiroyuki Hirata, Eduardo Antonio Donadi, Alexandre Costa Pereira, Virmondes Rodrigues Junior, Denis Puthier, Jorge Kalil, Lionel Spinelli, Edecio Cunha-Neto, Christophe Chevillard, Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade de São Paulo = University of São Paulo (USP), Génétique et immunologie des maladies parasitaires (GIMP), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal de Minas Gerais (UFMG), Universidade Federal do Triângulo Mineiro (UFTM), Instituto de Cardiologia Dante Pazzanese (IDPC), ANR-13-ISV3-0002,Br-Fr-CHAGAS,Identification de marqueurs génétiques pour les formes chroniques de la maladie Chagas(2013), and ANR-19-CE15-0010,Landscardio,Caractérisation de variations génétiques délétaires associées au cardiomyopathies(2019)

Subjects
Chagas Cardiomyopathy, [SDV]Life Sciences [q-bio], Trypanosoma cruzi, Immunology, METILAÇÃO, Epigenesis, Genetic, dilated cardiomyopathy, Th1 response, Immunology and Allergy, Humans, Chagas Disease, methylation, epigenetic, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Transcription Factors
Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS’s DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

Published
2022

2. European Association of Cardiothoracic Anesthesiology and Intensive Care Pediatric Cardiac Anesthesia Fellowship Curriculum: First Edition

Author

Ricard Navarro-Ripoll, Marc Vives, Steffen Rex, P. Matute, R. Peter Alston, Theofili Kousi, Simon J. Howell, Mona Momeni, Hossam El-Ashmawi, Fawzia Aboulfetouh, M. Granell, Aniruddha R. Janai, Gabor Erdoes, Caetano Nigro Neto, Alberto Hernandez Martinez, Sascha Treskatsch, Gianluca Paternoster, Theofani Antoniou, Anna Flo Forner, Kirstin Wilkinson, Giovanni Landoni, Joost M.A.A. van der Maaten, Joachim Erb, Philippe Gaudard, Philippe Burtin, E Schindler, Andrea Székely, Alain Vuylsteke, Laszlo L. Szegedi, Vera von Dossow, Jens Fassl, Chirojit Mukherjee, Mohamed R. El-Tahan, Fabio Guarracino, Dominique Bettex, Maria Benedetto, Dieter Van Beersel, Jan-Uwe Schreiber, Patrick Wouters, Dragana Unic-Stojanovic, Mansoura University [Egypt], University of Bern, University Medical Center Groningen [Groningen] (UMCG), University Hospital Southampton NHS Foundation Trust, Onassis Cardiac Surgery Center [Athens] (OCSC), Ruhr University Bochum (RUB), Instituto de Cardiologia Dante Pazzanese (IDPC), University Hospital Bonn, Semmelweis University [Budapest], University of Leipzig [Leipzig, Allemagne], University Department of Fundamental and Applied Medical Sciences and Clinical Department of Anesthesiology and Perioperative Medicine, Ghent, Belgium, Azienda Ospedaliera Universitaria Pisana, Clinique du Millénaire - Oc Santé [Montpellier], Oc Santé [Montpellier], University of Belgrade [Belgrade], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Hospital Clinic [Barcelona, Spain], Misr University for Science & Technology (MUST), Technische Universität Dresden = Dresden University of Technology (TU Dresden), University hospital of Zurich [Zurich], Sant'Orsola-Malpighi Hospital [Bologna, Italy], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Royal Infirmary of Edinburgh, IRCCS San Raffaele Scientific Institute [Milan, Italie], University General Hospital of Valencia, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Charité Campus Benjamin Franklin, University Hospitals Leuven [Leuven], Royal Papworth Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom., University of Leeds, Hospital Universitario de Bellvitge, University Hospital Basel [Basel], Hospital Dr Josep Trueta, Cairo University, Department of Anesthesia & Intensive Care, Helios Clinic for Cardiac Surgery, Karlsruhe, Germany., Hospital Clinico San Carlos, Hospital Clínico San Carlos, Cliniques Universitaires Saint-Luc [Bruxelles], Université Catholique de Louvain = Catholic University of Louvain (UCL), UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'anesthésiologie, El-Tahan, M. R., Erdoes, G., van der Maaten, J., Wilkinson, K., Kousi, T., Antoniou, T., von Dossow, V., Neto, C. N., Schindler, E., Szekely, A., Forner, A. F., Wouters, P. F., Guarracino, F., Burtin, P., Unic-Stojanovic, D., Schreiber, J. -U., Matute, P., Aboulfetouh, F., Navarro-Ripoll, R., Fassl, J., Bettex, D., Benedetto, M., Szegedi, L., Alston, R. P., Landoni, G., Granell, M., Gaudard, P., Treskatsch, S., Van Beersel, D., Vuylsteke, A., Howell, S., Janai, A. R., Martinez, A. H., Erb, J. M., Vives, M., El-Ashmawi, H., Rex, S., Mukherjee, C., Paternoster, G., Momeni, M., MUMC+: MA Anesthesiologie (9), and RS: MHeNs - R3 - Neuroscience

Subjects
medicine.medical_specialty, Critical Care, [SDV]Life Sciences [q-bio], education, MEDLINE, Subspecialty, 03 medical and health sciences, 0302 clinical medicine, 030202 anesthesiology, Pediatric anesthesiology, Anesthesiology, Intensive care, Anesthesia, Cardiac Procedures, Medicine, Humans, Fellowships and Scholarships, 610 Medicine & health, Child, Curriculum, Cardiothoracic anesthesiology, business.industry, General surgery, 030208 emergency & critical care medicine, 3. Good health, Cardiac Anesthesia, Anesthesiology and Pain Medicine, Perioperative care, cardiovascular system, Cardiology and Cardiovascular Medicine, business
Abstract

International audience; Pediatric cardiac anesthesia is a subspecialty of cardiac and pediatric anesthesiology dedicated to the perioperative care of patients with congenital heart disease. Members of the Congenital and Education Subcommittees of the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) agreed on the necessity to develop an EACTAIC pediatric cardiac anesthesia fellowship curriculum. This manuscript represents a consensus on the composition and the design of the EACTAIC Pediatric Cardiac Anesthesia Fellowship program. This curriculum provides a basis for the training of future pediatric cardiac anesthesiologists by clearly defining the theoretical and practical requirements for fellows and host centers.

Published
2021

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

Author

Amanda Farage Frade-Barros, Barbara Maria Ianni, Sandrine Cabantous, Cristina Wide Pissetti, Bruno Saba, Hui Tzu Lin-Wang, Paula Buck, José Antonio Marin-Neto, André Schmidt, Fabrício Dias, Mario Hiroyuki Hirata, Marcelo Sampaio, Abílio Fragata, Alexandre Costa Pereira, Eduardo Donadi, Virmondes Rodrigues, Jorge Kalil, Christophe Chevillard, Edecio Cunha-Neto, University of São Paulo School of Medicine, Génétique et immunologie des maladies parasitaires (GIMP), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade Federal do Triângulo Mineiro (UFTM), Instituto de Cardiologia Dante Pazzanese (IDPC), University of São Paulo (USP), Theories and Approaches of Genomic Complexity (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade de São Paulo = University of São Paulo (USP), and Spinelli, Lionel

Subjects
lcsh:Immunologic diseases. Allergy, 0303 health sciences, Chagas disease, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, [SDV]Life Sciences [q-bio], Immunology, IL 10, IFN, IL4, susceptibility, 3. Good health, [SDV] Life Sciences [q-bio], DOENÇAS CARDIOVASCULARES, 03 medical and health sciences, 0302 clinical medicine, Immunology and Allergy, IL12, lcsh:RC581-607, cardiomyopathy, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology, 030215 immunology
Abstract

International audience

Published
2020

4. Bleeding-Related Deaths in Relation to the Duration of Dual-Antiplatelet Therapy After Coronary Stenting

Author

Abdourahmane Diallo, Bo Xu, Giuseppe Biondi-Zoccai, Seung-Jung Park, Jung-Min Ahn, Philippe Généreux, Gregg W. Stone, Yaling Han, Gilles Montalescot, Hyo-Soo Kim, Stefanie Schüpke, Diego Della Riva, Alexandre Abizaid, Deepak L. Bhatt, Adnan Kastrati, Philippe Gabriel Steg, Martine Gilard, Letizia Bacchi Reggiani, Marco Valgimigli, Yangsoo Jang, Marie Claude Morice, Tullio Palmerini, Myeong Ki Hong, Mattia Romanello, Eric Vicaut, Alaide Chieffo, Gérard Helft, Antonio Colombo, Byeong Keuk Kim, Kyung Woo Park, Fausto Feres, Palmerini, Tullio, Bacchi Reggiani, Letizia, Della Riva, Diego, Romanello, Mattia, Feres, Fausto, Abizaid, Alexandre, Gilard, Martine, Morice, Marie-Claude, Valgimigli, Marco, Hong, Myeong-Ki, Kim, Byeong-Keuk, Jang, Yangsoo, Kim, Hyo-Soo, Park, Kyung Woo, Colombo, Antonio, Chieffo, Alaide, Ahn, Jung-Min, Park, Seung-Jung, Schüpke, Stefanie, Kastrati, Adnan, Montalescot, Gille, Steg, Philippe Gabriel, Diallo, Abdourahmane, Vicaut, Eric, Helft, Gerard, Biondi-Zoccai, Giuseppe, Xu, Bo, Han, Yaling, Genereux, Philippe, Bhatt, Deepak L., Stone, Gregg W, Morice, Marie claude, Hong, Myeong ki, Kim, Byeong keuk, Kim, Hyo soo, Ahn, Jung min, Park, Seung jung, Schã¼pke, Stefanie, Biondi zoccai, Giuseppe, Stone, Gregg W., University of Bologna/Università di Bologna, Instituto de Cardiologia Dante Pazzanese (IDPC), Université de Brest (UBO), Institut Cardiovasculaire Paris Sud [Massy] (ICPS), Inselspital Bern, Yonsei University, Seoul National University [Seoul] (SNU), IRCCS San Raffaele Scientific Institute [Milan, Italie], University of Ulsan, Deutsches Zentrum für Herz-Kreislauf-Forschung partner site, Munich Heart Alliance, German Heart Center = Deutsches Herzzentrum München [Munich, Germany] (GHC), Institut de cardiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cardiologie [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot, Sorbonne Paris Cité, Unité de Recherche Clinique (Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [APHP]), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Fuwai Hospital of Chinese Academy of Medical Sciences [Beijing, China] (FH-CAMS), General Hospital of Shenyang Military Region [Shenyang, China] (GH-SMR), New York Presbyterian Hospital, Columbia University Medical Center (CUMC), Columbia University [New York], Brigham and Women’s Hospital [Boston, MA], Harvard Medical School [Boston] (HMS), and Lesnik, Philippe

Subjects
medicine.medical_specialty, Multivariate analysis, animal structures, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Population, MEDLINE, Hemorrhage, 030204 cardiovascular system & hematology, Lower risk, law.invention, 03 medical and health sciences, 0302 clinical medicine, Percutaneous Coronary Intervention, Randomized controlled trial, law, Internal medicine, medicine, Drug-Eluting Stent, drug-eluting stent, dual antiplatelet therapy, 030212 general & internal medicine, dual antiplatelet therapy, mortality, drug-eluting stents, hemorrhage, humans, percutaneous coronary intervention, platelet aggregation inhibitors, postoperative complications, randomized controlled trials as topic, cardiology and cardiovascular medicine, education, Randomized Controlled Trials as Topic, education.field_of_study, business.industry, Platelet Aggregation Inhibitor, Hazard ratio, Confidence interval, Surgery, [SDV] Life Sciences [q-bio], Drug-eluting stent, Postoperative Complication, business, Cardiology and Cardiovascular Medicine, Human
Abstract

Background Although some randomized controlled trials (RCTs) and meta-analyses have suggested that prolonged dual-antiplatelet therapy (DAPT) may be associated with increased mortality, the mechanistic underpinnings of this association remain unclear. Objectives The aim of this study was to analyze the associations among bleeding, mortality, and DAPT duration after drug-eluting stent implantation in a meta-analysis of RCTs. Methods RCTs comparing different DAPT durations after drug-eluting stent placement were sought through the MEDLINE, Embase, and Cochrane databases and the proceedings of international meetings. Deaths were considered possibly bleeding related if occurring within 1 year of the episodes of bleeding. Primary analysis was by intention-to-treat. Secondary analysis was performed in a modified intention-to-treat population in which events occurring when all patients were on DAPT were excluded. Results Individual patient data were obtained for 6 RCTs, and aggregate data were available for 12 RCTs. Patients with bleeding had significantly higher rates of mortality compared with those without, and in a time-adjusted multivariate analysis, bleeding was an independent predictor of mortality occurring within 1 year of the bleeding episode (hazard ratio: 6.93; 95% confidence interval: 4.53 to 10.60; p< 0.0001). Shorter DAPT was associated with lower rates of all-cause death compared with longer DAPT (hazard ratio: 0.85; 95% confidence interval: 0.73 to 1.00; p= 0.05), which was driven by lower rates of bleeding-related deaths with shorter DAPT compared with prolonged DAPT (hazard ratio: 0.65; 95% confidence interval: 0.43 to 0.99; p= 0.04). Mortality unrelated to bleeding was comparable between the 2groups. Similar results were apparent in the modified intention-to-treat population. Conclusions Bleeding was strongly associated with the occurrence of mortality within 1 year after the bleeding event. Shorter compared with longer DAPT was associated with lower risk for bleeding-related death, a finding that mayunderlie the lower all-cause mortality with shorter DAPT in the RCTs of different DAPT durations after DES.

Published
2017

5. Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease

Author

Ariana de Melo Borges, Virmondes Rodrigues, Monique Andrade Baron, Cristina Wide Pissetti, Christophe Chevillard, Hui-Tzu Lin Wang, Mario Hiroyuki Hirata, Abílio Fragata, Jorge Kalil, Mariana M Lensi, Charles Mady, Marcelo Ferraz Sampaio, Bruno Saba, Eduardo Antônio Donadi, Gisele de Lima Peixoto, Luciana Gabriel Nogueira, Sandrine Cabantous, José Antonio Marin-Neto, Martino Martinelli, André Schmidt, Paula Buck, Sérgio Siqueira, Laurie Laugier, Amanda Farage Frade, Alexandre C. Pereira, Fabrício Moura Dias, Edecio Cunha-Neto, Barbara Maria Ianni, Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Heart Institute (InCor), Universidade de São Paulo = University of São Paulo (USP)-Faculdade de Medicina FMUSP, School of Medicine of Ribeirão Preto (FMRP), Universidade de São Paulo = University of São Paulo (USP), Cardiologia, Instituto de Cardiologia Dante Pazzanese (IDPC), Laboratory of Immunology, Heart Institute (InCor), University of São Paulo School of Medicine, Division of Clinical Immunology and Allergy, Institute for Investigation in Immunology, iii-INCT, Génétique et immunologie des maladies parasitaires (GIMP), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de São Paulo (USP)-Faculdade de Medicina FMUSP, University of São Paulo (USP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
Chagas Cardiomyopathy, Male, Linkage disequilibrium, medicine.medical_specialty, Myocarditis, Immunology, Single-nucleotide polymorphism, Biology, POLIMORFISMO, Biochemistry, Asymptomatic, Polymorphism, Single Nucleotide, Pathogenesis, Cohort Studies, Internal medicine, medicine, Immunology and Allergy, SNP, Humans, Genetic Predisposition to Disease, Molecular Biology, Genetic Association Studies, ComputingMilieux_MISCELLANEOUS, Interleukin-18, Dilated cardiomyopathy, Stroke Volume, Hematology, medicine.disease, 3. Good health, Genotype frequency, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Case-Control Studies, Chronic Disease, Cardiology, Female, medicine.symptom
Abstract

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.

Published
2015

6. Blood DNA methylation marks discriminate Chagas cardiomyopathy disease clinical forms.

Author

Brochet P, Ianni B, Nunes JPS, Frade AF, Teixeira PC, Mady C, Ferreira LRP, Kuramoto A, Pissetti CW, Saba B, Cândido DDS, Dias F, Sampaio M, Marin-Neto JA, Fragata A, Zaniratto RCF, Siqueira S, Peixoto GDL, Rigaud VOC, Buck P, Almeida RR, Lin-Wang HT, Schmidt A, Martinelli M, Hirata MH, Donadi E, Rodrigues Junior V, Pereira AC, Kalil J, Spinelli L, Cunha-Neto E, and Chevillard C

Subjects
Adenosine Triphosphate metabolism, Biomarkers metabolism, DNA Methylation, Humans, Chagas Cardiomyopathy diagnosis, Chagas Cardiomyopathy genetics, Chagas Disease genetics
Abstract

Chagas disease is a parasitic disease from South America, affecting around 7 million people worldwide. Decades after the infection, 30% of people develop chronic forms, including Chronic Chagas Cardiomyopathy (CCC), for which no treatment exists. Two stages characterized this form: the moderate form, characterized by a heart ejection fraction (EF) ≥ 0.4, and the severe form, associated to an EF < 0.4. We propose two sets of DNA methylation biomarkers which can predict in blood CCC occurrence, and CCC stage. This analysis, based on machine learning algorithms, makes predictions with more than 95% accuracy in a test cohort. Beyond their predictive capacity, these CpGs are located near genes involved in the immune response, the nervous system, ion transport or ATP synthesis, pathways known to be deregulated in CCCs. Among these genes, some are also differentially expressed in heart tissues. Interestingly, the CpGs of interest are tagged to genes mainly involved in nervous and ionic processes. Given the close link between methylation and gene expression, these lists of CpGs promise to be not only good biomarkers, but also good indicators of key elements in the development of this pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brochet, Ianni, Nunes, Frade, Teixeira, Mady, Ferreira, Kuramoto, Pissetti, Saba, Cândido, Dias, Sampaio, Marin-Neto, Fragata, Zaniratto, Siqueira, Peixoto, Rigaud, Buck, Almeida, Lin-Wang, Schmidt, Martinelli, Hirata, Donadi, Rodrigues Junior, Pereira, Kalil, Spinelli, Cunha-Neto and Chevillard.)

Published
2022
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7. Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Author

Brochet P, Ianni BM, Laugier L, Frade AF, Silva Nunes JP, Teixeira PC, Mady C, Ferreira LRP, Ferré Q, Santos RHB, Kuramoto A, Cabantous S, Steffen S, Stolf AN, Pomerantzeff P, Fiorelli AI, Bocchi EA, Pissetti CW, Saba B, Cândido DDS, Dias FC, Sampaio MF, Gaiotto FA, Marin-Neto JA, Fragata A, Zaniratto RCF, Siqueira S, Peixoto GL, Rigaud VO, Bacal F, Buck P, Almeida RR, Lin-Wang HT, Schmidt A, Martinelli M, Hirata MH, Donadi EA, Costa Pereira A, Rodrigues Junior V, Puthier D, Kalil J, Spinelli L, Cunha-Neto E, and Chevillard C

Subjects
Epigenesis, Genetic, Humans, Transcription Factors genetics, Chagas Cardiomyopathy, Chagas Disease genetics, Trypanosoma cruzi
Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi , is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Brochet, Ianni, Laugier, Frade, Silva Nunes, Teixeira, Mady, Ferreira, Ferré, Santos, Kuramoto, Cabantous, Steffen, Stolf, Pomerantzeff, Fiorelli, Bocchi, Pissetti, Saba, Cândido, Dias, Sampaio, Gaiotto, Marin-Neto, Fragata, Zaniratto, Siqueira, Peixoto, Rigaud, Bacal, Buck, Almeida, Lin-Wang, Schmidt, Martinelli, Hirata, Donadi, Costa Pereira, Rodrigues Junior, Puthier, Kalil, Spinelli, Cunha-Neto and Chevillard.)

Published
2022
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8. Corrigendum: Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy.

Author

Farage Frade-Barros A, Ianni BM, Cabantous S, Pissetti CW, Saba B, Lin-Wang HT, Buck P, Marin-Neto JA, Schmidt A, Dias F, Hirata MH, Sampaio M, Fragata A, Pereira AC, Donadi E, Rodrigues V, Kalil J, Chevillard C, and Cunha-Neto E

Abstract

[This corrects the article DOI: 10.3389/fimmu.2020.01386.]., (Copyright © 2020 Farage Frade-Barros, Ianni, Cabantous, Pissetti, Saba, Lin-Wang, Buck, Marin-Neto, Schmidt, Dias, Hirata, Sampaio, Fragata, Pereira, Donadi, Rodrigues, Kalil, Chevillard and Cunha-Neto.)

Published
2020
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9. Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy.

Author

Frade-Barros AF, Ianni BM, Cabantous S, Pissetti CW, Saba B, Lin-Wang HT, Buck P, Marin-Neto JA, Schmidt A, Dias F, Hirata MH, Sampaio M, Fragata A, Pereira AC, Donadi E, Rodrigues V, Kalil J, Chevillard C, and Cunha-Neto E

Subjects
Cell Differentiation, Chagas Cardiomyopathy immunology, Chronic Disease, Disease Progression, Genetic Predisposition to Disease, Interferon-gamma biosynthesis, Interferon-gamma genetics, Interleukin-4 genetics, Polymorphism, Single Nucleotide, Th1 Cells immunology, Chagas Cardiomyopathy genetics, Interleukin-10 genetics, Interleukin-12 Subunit p40 genetics
Abstract

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 the most important clinical consequence of T. cruzi 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. Methods: 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 IL12B, IL10, IFNG , and IL4 genes. Results: We found 2 IL12 SNPs (rs2546893, rs919766) and a trend of association for a IL10 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. Conclusions: Our data show that novel polymorphisms affecting IL12B and IL10 , but not IFNG or IL4 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., (Copyright © 2020 Frade-Barros, Ianni, Cabantous, Pissetti, Saba, Lin-Wang, Buck, Marin-Neto, Schmidt, Dias, Hirata, Sampaio, Fragata, Pereira, Donadi, Rodrigues, Kalil, Chevillard and Cunha-Neto.)

Published
2020
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