Open Access Research article

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

Amanda Farage Frade127, Cristina Wide Pissetti3, Barbara Maria Ianni1, Bruno Saba4, Hui Tzu Lin-Wang4, Luciana Gabriel Nogueira12, Ariana de Melo Borges3, Paula Buck1, Fabrício Dias5, Monique Baron1, Ludmila Rodrigues Pinto Ferreira1, Andre Schmidt5, José Antonio Marin-Neto5, Mario Hirata4, Marcelo Sampaio4, Abílio Fragata4, Alexandre Costa Pereira1, Eduardo Donadi5, Jorge Kalil126, Virmondes Rodrigues3, Edecio Cunha-Neto126 and Christophe Chevillard7*

Author Affiliations

1 Heart Institute (InCor), University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar, 44 Bloco 2 9º andar, São Paulo, SP 06504-000, Brazil

2 Institute for Investigation in Immunology (iii), INCT, São Paulo, SP, Brazil

3 Laboratory of Immunology, Universidade Federal do Triângulo Mineiro (UFTM), 40 Frei Paulino, Uberaba, MG 48036-180, Brazil

4 Instituto de Cardiologia Dante Pazzanese (IDPC), Avenida Dante Pazzanese 500 - Ibirapuera, Sâo Paulo, SP 04012-909, Brazil

5 School of Medicine of Ribeirão Preto (FMRP), University of São Paulo, Av. Bandeirantes, 4900 - Monte Alegre 15059-900, Ribeirão Preto, SP, Brazil

6 Division of Clinical Immunology and Allergy, University of São Paulo School of Medicine, São Paulo, SP 06504-000, Brazil

7 Aix-Marseille Université, INSERM, GIMP UMR_S906, Faculté de médecine, 27 bd Jean Moulin, Marseille, cedex 05 13385, France

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BMC Infectious Diseases 2013, 13:587  doi:10.1186/1471-2334-13-587

Published: 12 December 2013

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