Published in:
Open Access
01-07-2021 | Cardiomyopathy | Original Article
Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease
Authors:
Maryem Ouarhache, Sandrine Marquet, Amanda Farage Frade, Ariela Mota Ferreira, Barbara Ianni, Rafael Ribeiro Almeida, Joao Paulo Silva Nunes, Ludmila Rodrigues Pinto Ferreira, Vagner Oliveira-Carvalho Rigaud, Darlan Cândido, Charles Mady, Ricardo Costa Fernandes Zaniratto, Paula Buck, Magali Torres, Frederic Gallardo, Pauline Andrieux, Sergio Bydlowsky, Debora Levy, Laurent Abel, Clareci Silva Cardoso, Omar Ribeiro Santos-Junior, Lea Campos Oliveira, Claudia Di Lorenzo Oliveira, Maria Do Carmo Nunes, Aurelie Cobat, Jorge Kalil, Antonio Luiz Ribeiro, Ester Cerdeira Sabino, Edecio Cunha-Neto, Christophe Chevillard
Published in:
Journal of Clinical Immunology
|
Issue 5/2021
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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.