Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.

Amanda Frade; Cristina Pissetti; Barbara Ianni; Bruno Saba; Hui Lin-Wang; Luciana Nogueira; Ariana de Melo Borges; Paula Buck; Fabrício Dias; Monique Baron; Ludmila Rodrigues Ferreira; Andre Schmidt; José Marin-Neto; Mario Hirata; Marcelo Sampaio; Abílio Fragata; Alexandre Pereira; Eduardo Donadi; Jorge Kalil; Virmondes Rodrigues; Edecio Cunha-Neto; Christophe Chevillard

Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.

Amanda Frade ^{1, 2, 3} Cristina Pissetti ⁴ Barbara Ianni ¹ Bruno Saba ⁵ Hui Lin-Wang ⁵ Luciana Nogueira ^{1, 2} Ariana de Melo Borges ⁴ Paula Buck ¹ Fabrício Dias ⁶ Monique Baron ¹ Ludmila Rodrigues Ferreira ¹ Andre Schmidt ⁶ José Marin-Neto ⁶ Mario Hirata ⁵ Marcelo Sampaio ⁵ Abílio Fragata ⁵ Alexandre Pereira ¹ Eduardo Donadi ⁶ Jorge Kalil ^{1, 2, 7} Virmondes Rodrigues ⁴ Edecio Cunha-Neto ^{1, 2, 7} Christophe Chevillard ^{3, *}

* Corresponding author

1 InCor - Heart Institute

2 III - Institute for Investigation in Immunology

3 GIMP - Génétique et immunologie des maladies parasitaires

4 Laboratory of Immunology

5 Cardiologia

6 FMRP - School of Medicine of Ribeirão Preto

7 Division of Clinical Immunology and Allergy

Abstract : BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. The others remain asymptomatic (ASY). A possible genetic component to disease progression was suggested by familial aggregation of cases and the association of markers of innate and adaptive immunity genes with CCC development. Migration of Th1-type T cells play a major role in myocardial damage. METHODS: Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects. RESULTS: The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%. CONCLUSIONS: Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.

Keywords : Chagas disease Susceptibility CCR5 CCL2 TIRAP

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Human health and pathology / Infectious diseases

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Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.

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Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.

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