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

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 genet...

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Published in:	PloS one Vol. 8; no. 12; p. e83446
Main Authors:	Frade, Amanda Farage, Teixeira, Priscila Camilo, Ianni, Barbara Maria, Pissetti, Cristina Wide, Saba, Bruno, Wang, Lin Hui Tzu, Kuramoto, Andréia, Nogueira, Luciana Gabriel, Buck, Paula, Dias, Fabrício, Giniaux, Helene, Llored, Agnes, Alves, Sthefanny, Schmidt, Andre, Donadi, Eduardo, Marin-Neto, José Antonio, Hirata, Mario, Sampaio, Marcelo, Fragata, Abílio, Bocchi, Edimar Alcides, Stolf, Antonio Noedir, Fiorelli, Alfredo Inacio, Santos, Ronaldo Honorato Barros, Rodrigues, Virmondes, Pereira, Alexandre Costa, Kalil, Jorge, Cunha-Neto, Edecio, Chevillard, Christophe
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 19-12-2013 Public Library of Science (PLoS)
Subjects:	Actin Actins - genetics Actins - metabolism Adaptive immunity Analysis Apoptosis Binding Cardiac muscle Cardiomyocytes Cardiomyopathy Cardiovascular disease Chagas Cardiomyopathy - genetics Chagas disease Correlation analysis Development and progression Dilated cardiomyopathy Disease susceptibility Drosophila Female Gene expression Gene Expression Regulation Gene polymorphism Genes Genetic aspects Genetic diversity Genetic Predisposition to Disease - genetics Genotyping Haplotypes Heart Heart diseases Heart failure Humans Immunity Immunology Infections Insects Kinases Laboratories Life Sciences Male Medical prognosis Medicine Microbiology and Parasitology Muscle proteins Muscles Mutation Myocardial diseases Myocardium - metabolism Organ donors Organ transplantation Pathogenesis Patients Polymorphism Polymorphism, Single Nucleotide Population genetics Population studies Proteomics Protozoa Replication RNA RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Single nucleotide polymorphisms Single-nucleotide polymorphism Transcription (Genetics) Transcription factors Trypanosoma cruzi Vector-borne diseases Brazil Haplotypes Heart Variant genotypes Chagas disease Actins Cardiomyopathies Inflammatory diseases Apoptosis
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Summary:	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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: JK ACP ECN CC. Performed the experiments: AFF PCT AK HG AL. Analyzed the data: AFF PCT ECN CC. Contributed reagents/materials/analysis tools: BMI CWP BS LHTW LGN PB FD SA AS ED JAMN MH MS AF EAB ANS AIF RHBS VR ACP. Wrote the manuscript: ECN CC.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0083446