Polymorphism in the alpha cardiac muscle actin 1 gene is associated to susceptibility to chronic inflammatory cardiomyopathy.

Autor:	Frade AF; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil ; Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil ; Aix-Marseille Université, Marseille, France., Teixeira PC; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil ; Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil., Ianni BM; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Pissetti CW; Laboratory of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil., Saba B; Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil., Wang LH; Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil., Kuramoto A; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil ; Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil., Nogueira LG; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil ; Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil., Buck P; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Dias F; School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Giniaux H; Aix-Marseille Université, Marseille, France., Llored A; Aix-Marseille Université, Marseille, France., Alves S; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Schmidt A; School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Donadi E; School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Marin-Neto JA; School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Hirata M; Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil., Sampaio M; Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil., Fragata A; Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil., Bocchi EA; Division of Clinical Immunology and Allergy, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Stolf AN; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Fiorelli AI; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Santos RH; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Rodrigues V; Laboratory of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil., Pereira AC; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Kalil J; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil ; Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil ; Division of Clinical Immunology and Allergy, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Cunha-Neto E; Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil ; Institute for Investigation in Immunology (iii), Instituto Nacional de ciencias e tecnologia, São Paulo, São Paulo, Brazil ; Division of Clinical Immunology and Allergy, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil., Chevillard C; Aix-Marseille Université, Marseille, France.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2013 Dec 19; Vol. 8 (12), pp. e83446. Date of Electronic Publication: 2013 Dec 19 (Print Publication: 2013).
DOI:	10.1371/journal.pone.0083446
Abstrakt:	Aims: Chagas 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 Results: We 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. Conclusions: Genetic 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.
Databáze:	MEDLINE
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