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

• Published in: Journal of clinical immunology Vol. 41; no. 5; pp. 1048 - 1063
• Main Authors: 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, Edecio, Chevillard, Christophe
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.07.2021; Springer Nature B.V; Springer Verlag
• Subjects: Adult; Aged; Aged, 80 and over; Biomedical and Life Sciences; Biomedicine; Cardiology and cardiovascular system; Cardiomyocytes; Cardiomyopathy; Chagas Cardiomyopathy - genetics; Chagas disease; Congestive heart failure; Coronary artery disease; Cytokines; Dihydroorotate dehydrogenase; Female; Genetic diversity; Genetic Predisposition to Disease; Genetic Variation; Human health and pathology; Humans; Immunology; Infectious Diseases; Inflammation; Inflammation - genetics; Internal Medicine; Life Sciences; Male; Medical Microbiology; Membrane potential; Middle Aged; Mitochondria; Mitochondria - genetics; Myocardium; Original; Original Article; Phenotypes; Protozoa; Trypanosoma cruzi; Whole Exome Sequencing; γ-Interferon; Variants; chagas; pathogenic; cardiomyopathy; inflammation; mitochondria
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-021-01000-y

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.