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

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.

Interferon-γ and other inflammatory mediators in cardiomyocyte signaling during Chagas disease cardiomyopathy

“…aggressive inflammatory dilated cardiomyopathy that occurs decades after the initial infection with the obligate intracellular parasite Trypanosoma cruzi (T.cruzi) in 30% of infected individuals [1] . T. cruzi infection affects 10 million subjects in endemic areas of South and Central America and migratory waves have taken patients to the United States, Europe and Japan [2][3][4] .…”

Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease

“…Sex was considered as a binary covariate as shown previously [50,52]. [50,52]. The genotype distribution is summarized in Table 2.…”

“…We performed binary logistic regression analysis on the whole population, to analyze the relationship between the probability of an individual to develop chronic Chagas cardiomyopathy and the main covariates (sex and polymorphisms). Sex was considered as a binary covariate as shown previously [50,52]. [50,52].…”

“…Patients with CCC presented with abnormal electrocardiography findings that ranged from typical conduction abnormalities to severe arrhythmia [51]. The CCC patients presented with typical ECG findings (right bundle branch block and/or left anterior division hemiblock and were classified as having moderate (LVEF > 40%) or severe (LVEF 6 40%)) CCC [52]. All asymptomatic (ASY) subjects had normal echocardiograph and echocardiogram findings, chest radiographs with no evidence of cardiac enlargement, and normal findings of radiographs of the esophagus and colon.…”

Neglected Tropical Diseases in the Post-Genomic Era

“…Other studies that highlight the role that protozoan parasites had in shaping the genetics of human populations were recently reviewed [129]. These studies suggest that quantitative trait loci and/or human polymorphisms play a role in genetic susceptibility to parasite burden and/or associated pathology for different pathogens of human [130][131][132][133] and livestock [134,135]. These types of investigations, however, require large cohorts of individuals (patients or animals), generate large sequence data sets, and usually lack causal conclusions.…”