Mitochondrial DNA Haplogroups and Variants Predispose to Chagas Disease Cardiomyopathy

Frédéric Gallardo; Pauline Brochet Brochet P; David Goudenège; João Paulo Silva Nunes; Pauline Andrieux; Barbara Maria Ianni; Amanda Farage Frade; Charles Mady; Ronaldo Honorato Barros Santos; Andreia Kuramoto; Samuel Steffen; Antonio Noedir Stolf; Pablo Pomerantzeff; Alfredo Inacio Fiorelli; Edimar Alcides Bocchi; Cristina Wide Pissetti; Bruno Saba; Fabrício Dias; Marcelo Ferraz Sampaio; Fabio Antônio Gaiotto; José Antonio Marin-Neto; Abílio Fragata; Ricardo Costa Fernandes Zaniratto; Sergio Siqueira; Giselle De Lima Peixoto; Fernando Bacal; Paula Buck; Rafael Ribeiro Almeida; Hui Tzu Lin-Wang; André Schmidt; Mario Hiroyuki Hirata; Eduardo Antonio Donadi; Alexandre Costa Pereira; Virmondes Rodrigues Junior; Martino Martinelli; Michel Naslavsky; Jorge Kalil; Vincent Procaccio; Edecio Cunha-Neto; Christophe Chevillard

doi:10.20944/preprints202310.0829.v1

A peer-reviewed article of this Preprint also exists.

Gallardo, F.; Brochet, P.; Goudenège, D.; Nunes, J.P.S.; Andrieux, P.; Ianni, B.M.; Frade, A.F.; Mady, C.; Santos, R.H.B.; Kuramoto, A.; Steffen, S.; Stolf, A.N.; Pomerantzeff, P.; Fiorelli, A.I.; Bocchi, E.A.; Pissetti, C.W.; Saba, B.; Dias, F.C.; Sampaio, M.F.; Gaiotto, F.A.; Marin-Neto, J.A.; Fragata, A.; Zaniratto, R.C.F.; Siqueira, S.; Peixoto, G.D.L.; Bacal, F.; Buck, P.; Almeida, R.R.; Lin-Wang, H.T.; Schmidt, A.; Hirata, M.H.; Donadi, E.A.; Pereira, A.C.; Rodrigues Junior, V.; Martinelli, M.; Naslavsky, M.; Kalil, J.; Procaccio, V.; Cunha-Neto, E.; Chevillard, C. Mitochondrial DNA Haplogroups and Variants Predispose to Chagas Disease Cardiomyopathy. Hearts 2023, 4, 97-117. Gallardo, F.; Brochet, P.; Goudenège, D.; Nunes, J.P.S.; Andrieux, P.; Ianni, B.M.; Frade, A.F.; Mady, C.; Santos, R.H.B.; Kuramoto, A.; Steffen, S.; Stolf, A.N.; Pomerantzeff, P.; Fiorelli, A.I.; Bocchi, E.A.; Pissetti, C.W.; Saba, B.; Dias, F.C.; Sampaio, M.F.; Gaiotto, F.A.; Marin-Neto, J.A.; Fragata, A.; Zaniratto, R.C.F.; Siqueira, S.; Peixoto, G.D.L.; Bacal, F.; Buck, P.; Almeida, R.R.; Lin-Wang, H.T.; Schmidt, A.; Hirata, M.H.; Donadi, E.A.; Pereira, A.C.; Rodrigues Junior, V.; Martinelli, M.; Naslavsky, M.; Kalil, J.; Procaccio, V.; Cunha-Neto, E.; Chevillard, C. Mitochondrial DNA Haplogroups and Variants Predispose to Chagas Disease Cardiomyopathy. Hearts 2023, 4, 97-117.

Abstract

Cardiomyopathies are major causes of heart failure. Chagas disease (CD) is caused by the parasite Trypanosoma cruzi, and it is endemic in Central, South America. Thirty percent of the cases evolve into chronic cardiomyopathy (CCC) with worse prognosis as compared with other cardiomyopathies. In vivo bioenergetic analysis and ex vivo proteomic analysis of myocardial tissues highlighted worse mitochondrial dysfunction in CCC, and previous studies identified nuclear-encoded mitochondrial gene variants segregating with CCC. Here, we assessed the role of the mitochondrial genome through mtDNA copy number variations and mtDNA haplotyping and sequencing from heart or blood tissues of severe, moderate CCC and asymptomatic/indeterminate Chagas disease as well as healthy controls as an attempt to help decipher mitochondrial-intrinsic genetic involvement in Chagas disease development. We have found that mtDNA copy number was significantly lower in CCC than in heart tissue from healthy individuals, while blood mtDNA content was similar among asymptomatic Chagas disease, moderate and severe CCC patients. MtDNA haplogrouping study has indicated that African haplogroups were over represented in the Chagas subject groups in comparison with Brazilian healthy individuals. The European lineage is associated to protection against cardiomyopathy and the macro haplogroup H is associated with increased risk towards CCC. By mitochondria DNA sequencing, 84 mtDNA-encoded protein sequence pathogenic variants were associated with CCC. Among them, two variants were associated to left ventricular non-compaction and two to hypertrophic cardiomyopathy. The finding that mitochondrial protein-coding SNPs and mitochondrial haplogroups associate with risk of evolving to CCC is consistent with a key role of mitochondrial DNA in the development of Chronic Chagas disease Cardiomyopathy.

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Mitochondrial DNA Haplogroups and Variants Predispose to Chagas Disease Cardiomyopathy

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