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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease

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Author(s):
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Ouarhache, Maryem [1] ; Marquet, Sandrine [1, 2] ; Frade, Amanda Farage [3, 4, 5] ; Ferreira, Ariela Mota [6] ; Ianni, Barbara [7] ; Almeida, Rafael Ribeiro [3, 4, 5] ; Silva Nunes, Joao Paulo [3, 4, 5] ; Pinto Ferreira, Ludmila Rodrigues [8, 3, 4, 5] ; Rigaud, Vagner Oliveira-Carvalho [3, 4] ; Candido, Darlan [3, 4] ; Mady, Charles [7] ; Fernandes Zaniratto, Ricardo Costa [3, 4] ; Buck, Paula [7] ; Torres, Magali ; Gallardo, Frederic ; Andrieux, Pauline ; Bydlowsky, Sergio [3, 4, 5] ; Levy, Debora [3, 4, 5] ; Abel, Laurent [9, 10] ; Cardoso, Clareci Silva [11] ; Santos-Junior, Omar Ribeiro [12, 13] ; Oliveira, Lea Campos ; Oliveira, Claudia Di Lorenzo [11] ; Nunes, Maria Do Carmo [12, 13] ; Cobat, Aurelie [9, 10] ; Kalil, Jorge [3, 4, 5] ; Ribeiro, Antonio Luiz [12, 13] ; Sabino, Ester Cerdeira [14, 15, 16] ; Cunha-Neto, Edecio [3, 4, 5, 17] ; Chevillard, Christophe [1, 2]
Total Authors: 30
Affiliation:
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[1] Aix Marseille Univ, INSERM, UMR 906, Marseille - France
[2] Aix Marseille Univ, Theories & Approaches Genom Complex TAGC, INSERM, UMR 1090, Parc Sci Luminy, Case 928, 163 Ave Luminy, F-13288 Marseille - France
[3] Univ Sao Paulo, Heart Inst InCor Clin, Hosp Clin, Immunol Lab, Fac Med, FMUSP, Sao Paulo - Brazil
[4] Univ Sao Paulo, Dept Med, Fac Med, FMUSP, Sao Paulo - Brazil
[5] Inst Nacl Ciencia & Tecnol, Inst Invest Immunol, Iii INCT, Sao Paulo - Brazil
[6] Univ Estadual Montes, State Univ Montes Claros, Montes Claros, MG - Brazil
[7] Univ Sao Paulo, Fac Med FMUSP, Unidade Clin Miocardiopatias, Heart Inst Incor, Sao Paulo - Brazil
[8] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Morfol, Belo Horizonte, MG - Brazil
[9] Paris Descartes Univ, Imagine Inst, Paris - France
[10] Necker Hosp Sick Children, Necker Branch, Lab Human Genet Infect Dis, Paris - France
[11] Univ Fed Sao Joao del Rei, Sch Med, Divinopolis - Brazil
[12] Univ Fed Minas Gerais, Sch Med, Belo Horizonte, MG - Brazil
[13] Univ Fed Minas Gerais, Hosp Clin, Belo Horizonte, MG - Brazil
[14] Fac Med FMUSP, Dept Infect Dis, Sao Paulo - Brazil
[15] Fac Med FMUSP, Div Lab Med LIM03, Sao Paulo - Brazil
[16] Fac Med FMUSP, Inst Trop Med, Sao Paulo - Brazil
[17] Univ Sao Paulo, Inst Heart, Lab Clin Immunol & Allergy LIM60, Sch Med, Sao Paulo, SP - Brazil
Total Affiliations: 17
Document type: Journal article
Source: JOURNAL OF CLINICAL IMMUNOLOGY; v. 41, n. 5, p. 1048-1063, JUL 2021.
Web of Science Citations: 0
Abstract

Cardiomyopathies are an important cause of heart failure and sudden cardiac death. Little is known about the role of rare genetic variants in inflammatory cardiomyopathy. Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory cardiomyopathy prevalent in Latin America, developing in 30% of the 6 million patients chronically infected by the protozoan Trypanosoma cruzi, while 60% remain free of heart disease (asymptomatic (ASY)). The cytokine interferon-gamma and mitochondrial dysfunction are known to play a major pathogenetic role. Chagas disease provides a unique model to probe for genetic variants involved in inflammatory cardiomyopathy. Methods We used whole exome sequencing to study nuclear families containing multiple cases of Chagas disease. We searched for rare pathogenic variants shared by all family members with CCC but absent in infected ASY siblings and in unrelated ASY. Results We identified heterozygous, pathogenic variants linked to CCC in all tested families on 22 distinct genes, from which 20 were mitochondrial or inflammation-related - most of the latter involved in proinflammatory cytokine production. Significantly, incubation with IFN-gamma on a human cardiomyocyte line treated with an inhibitor of dihydroorotate dehydrogenase brequinar (enzyme showing a loss-of-function variant in one family) markedly reduced mitochondrial membrane potential (Delta psi M), indicating mitochondrial dysfunction. Conclusion Mitochondrial dysfunction and inflammation may be genetically determined in CCC, driven by rare genetic variants. We hypothesize that CCC-linked genetic variants increase mitochondrial susceptibility to IFN-gamma-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies. (AU)

FAPESP's process: 14/50890-5 - INCT of Investigation in Immunology
Grantee:Jorge Elias Kalil Filho
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 13/50302-3 - Identification of predictive / prognostic genetic signature in Chagas cardiomyopathy: a systems biology approach
Grantee:Edecio Cunha Neto
Support Opportunities: Regular Research Grants