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

Amanda Farage Frade,Christophe Chevillard,Cristina Wide Pissetti,Ariana De Melo Borges,Abílio Fragata,Monique Baron,Ludmila Rodrigues Pinto Ferreira,Jorge Kalil,Paula Buck,Bruno Saba,Hui Tzu Lin-Wang,Edécio Cunha-Neto ,André Schmidt ,Fabrício C Dias ,Virmondés Rodrigues ,Eduardo Antônio Donadi ,Bárbara Maria Ianni ,L Nogueira ,Mário Hiroyuki Hirata ,Alexandre C Pereira ,Marcelo Ferraz Sampaio ,José Antônio Marin-Neto

doi:10.1186/1471-2334-13-587

Abstract

BackgroundChagas 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.MethodsOur 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.ResultsThe 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%.ConclusionsOur 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.

Highlights

Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America
Circulating CD4+IL-17+ T cells appear in low frequency in peripheral blood mononuclear cells (PBMC) from chronic Chagas cardiomyopathy (CCC) patients as compared with ASY patients and non-infected individuals [18,19]. These results suggest that proinflammatory cells and cytokines are markers associated with progression to CCC, whereas the production of IL-10, IL-17 and increased numbers of regulatory T cells are markers of protection from CCC development, indicating that failure to regulate T helper 1 (Th1) responses may be the underlying immune defect of patients who progress to CCC
All the Single nucleotide polymorphism (SNP) were in Hardy-Weinberg equilibrium on the ASY individuals considered as control subjects (p > 0,001) (Table 6)

Summary

Introduction

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. Chagas disease (American trypanosomiasis) is caused by the protozoan Trypanosoma cruzi and transmitted by the reduviid bug. It occurs exclusively in the Americas, in poor, rural areas of Mexico, Central America, and South America. Approximately 30% of infected individuals develop Chronic Chagas cardiomyopathy (CCC), one of the most important consequence of T. cruzi infection. The remaining twothirds of infected individuals remain asymptomatic (ASY) and free from heart disorders for life [2]. Heart failure due to CCC has a worse prognosis with 50% shorter survival when compared to other cardiomyopathies of different etiologies [4,5]

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Conclusion