Abstract
AimsChagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America, and may lead to a life-threatening inflammatory dilated, chronic Chagas cardiomyopathy (CCC). One third of T. cruzi-infected individuals progress to CCC while 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. Since mutations in multiple sarcomeric genes, including alpha-cardiac actin (ACTC1) have been involved in hereditary dilated cardiomyopathy, we investigated the involvement of the ACTC1 gene in CCC pathogenesis. Methods and ResultsWe conducted a proteomic and genetic study on a Brazilian study population. The genetic study was done on a main cohort including 118 seropositive asymptomatic subjects and 315 cases and the replication was done on 36 asymptomatic and 102 CCC cases. ACTC1 protein and mRNA levels were lower in myocardial tissue from patients with end-stage CCC than those found in hearts from organ donors. Genotyping a case-control cohort of CCC and ASY subjects for all informative single nucleotide polymorphism (SNP) in the ACTC1 gene identified rs640249 SNP, located at the 5’ region, as associated to CCC. Associations are borderline after correction for multiple testing. Correlation and haplotype analysis led to the identification of a susceptibility haplotype. Functional assays have shown that the rs640249A/C polymorphism affects the binding of transcriptional factors in the promoter regions of the ACTC1 gene. Confirmation of the detected association on a larger independent replication cohort will be useful.ConclusionsGenetic variations at the ACTC1 gene may contribute to progression to chronic Chagas Cardiomyopathy among T. cruzi-infected patients, possibly by modulating transcription factor binding to ACTC1 promoter regions.
Highlights
Chagas disease is an infection caused by the protozoan Trypanosoma cruzi[1], which is transmitted by an insect vector of the Reduviidae family, blood transfusion or congenitally [1]
We investigated the involvement of the ACTC1 gene in chronic Chagas cardiomyopathy (CCC) pathogenesis, by comparing ACTC1 mRNA and protein levels in myocardial tissues from patients with CCC and normal donor hearts, and determining whether ACTC1 gene polymorphisms were associated with CCC
Alpha-cardiac actin 1 (ACTC1) protein levels in the myocardium from left ventricle free wall differed between CCC patients and normal control (NC hearts) (Table S1), after normalization against glyceraldehyde 3-phosphate dehydrogenase (GAPDH)
Summary
Chagas disease is an infection caused by the protozoan Trypanosoma cruzi[1], which is transmitted by an insect vector of the Reduviidae family, blood transfusion or congenitally [1]. 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. This condition has a fatal outcome and the only treatment is heart transplantation. Evidence from the Syrian hamster model of chronic Chagas cardiomyopathy indicates that while the intensity of inflammation correlated with ventricular dilation (i.e. disease progression), it was not associated to death among hamsters with end-stage dilated chronic Chagas cardiomyopathy [23] This may suggest that additional, noninflammatory factors could contribute to severity or progression to death from CCC. This suggests that the dilated cardiomyopathy phenotype and clinical outcome may involve an interplay between the inflammatory environment and specific gene regulation in cardiomyocytes and other myocardial cell types
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
