Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease
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Published:2021-03-03
Issue:5
Volume:41
Page:1048-1063
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ISSN:0271-9142
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Container-title:Journal of Clinical Immunology
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language:en
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Short-container-title:J Clin Immunol
Author:
Ouarhache Maryem, Marquet Sandrine, Frade Amanda Farage, Ferreira Ariela Mota, Ianni Barbara, Almeida Rafael Ribeiro, Nunes Joao Paulo Silva, Ferreira Ludmila Rodrigues Pinto, Rigaud Vagner Oliveira-Carvalho, Cândido Darlan, Mady Charles, Zaniratto Ricardo Costa Fernandes, Buck Paula, Torres Magali, Gallardo Frederic, Andrieux Pauline, Bydlowsky Sergio, Levy Debora, Abel Laurent, Cardoso Clareci Silva, Santos-Junior Omar Ribeiro, Oliveira Lea Campos, Oliveira Claudia Di Lorenzo, Nunes Maria Do Carmo, Cobat Aurelie, Kalil Jorge, Ribeiro Antonio Luiz, Sabino Ester Cerdeira, Cunha-Neto EdecioORCID, Chevillard ChristopheORCID
Abstract
Abstract
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-γ 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-γ 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 (ΔψM), 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-γ-induced damage in the myocardium, leading to the cardiomyopathy phenotype in Chagas disease. This mechanism may also be operative in other inflammatory cardiomyopathies.
Funder
Inserm Aix-Marseille Université the French Agency for Research the CNPq the FAPESP (São Paulo State Research Funding Agency Foundation for the National Institutes of Health A*Midex a French “Investissements d’Avenir programme”
Publisher
Springer Science and Business Media LLC
Subject
Immunology,Immunology and Allergy
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