Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy

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dc.contributor Sistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.author FRADE, Amanda Farage FMUSP-HC
TEIXEIRA, Priscila Camilo
IANNI, Barbara Maria FMUSP-HC
PISSETTI, Cristina Wide
SABA, Bruno
WANG, Lin Hui Tzu
NOGUEIRA, Luciana Gabriel FMUSP-HC
DIAS, Fabricio
ALVES, Sthefanny
DONADI, Eduardo
MARIN-NETO, Jose Antonio
SAMPAIO, Marcelo
BOCCHI, Edimar Alcides FMUSP-HC
STOLF, Antonio Noedir FMUSP-HC
SANTOS, Ronaldo Honorato Barros FMUSP-HC
RODRIGUES, Virmondes
PEREIRA, Alexandre Costa FMUSP-HC
CHEVILLARD, Christophe
dc.date.issued 2013
dc.identifier.citation PLOS ONE, v.8, n.12, 2013
dc.identifier.issn 1932-6203
dc.identifier.uri http://observatorio.fm.usp.br/handle/OPI/5090
dc.description.abstract 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.
dc.description.sponsorship · Institut National de la Sante et de la Recherche Medicale (INSERM), Aix-Marseille University (Direction des Relations Internationales)
· USP-COFECUB program
· ARCUS II PACA Brasil program
· CNPq (the Brazilian National Research Council)
· FAPESP (Sao Paulo State Research Funding Agency-Brazil)
· French ANR agency
· Brazilian FAPESP agency
dc.language.iso eng
dc.relation.ispartof Plos One
dc.rights openAccess
dc.subject.other chagas-disease cardiomyopathy; trypanosoma-cruzi infection; necrosis-factor-alpha; myosin heavy-chain; heart-failure; dilated cardiomyopathy; ejection fraction; expression; myocarditis; activation
dc.title Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy
dc.type article
dc.rights.holder Copyright PUBLIC LIBRARY SCIENCE
dc.description.group LIM/19
dc.description.group LIM/13
dc.description.group LIM/11
dc.identifier.doi 10.1371/journal.pone.0083446
dc.identifier.pmid 24367596
dc.type.category original article
dc.type.version publishedVersion
hcfmusp.author FRADE, Amanda Farage:FM:
hcfmusp.author IANNI, Barbara Maria:HC:INCOR
hcfmusp.author KURAMOTO, Andreia:HC:LIM/19
hcfmusp.author NOGUEIRA, Luciana Gabriel:FM:
hcfmusp.author BUCK, Paula:HC:INCOR
hcfmusp.author BOCCHI, Edimar Alcides:FM:MCP
hcfmusp.author STOLF, Antonio Noedir:FM:MCP
hcfmusp.author FIORELLI, Alfredo Inacio:HC:INCOR
hcfmusp.author SANTOS, Ronaldo Honorato Barros:HC:INCOR
hcfmusp.author PEREIRA, Alexandre Costa:HC:LIM/13
hcfmusp.author KALIL, Jorge:FM:MCM
hcfmusp.author CUNHA-NETO, Edecio:FM:MCM
hcfmusp.author.external · TEIXEIRA, Priscila Camilo:Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, Brazil; Inst Nacl Ciencias & Tecnol, Inst Invest Immunol 3, Sao Paulo, Brazil
· PISSETTI, Cristina Wide:Univ Fed Triangulo Mineiro, Immunol Lab, Uberaba, MG, Brazil
· SABA, Bruno:Inst Cardiol Dante Pazzanese, Sao Paulo, Brazil
· WANG, Lin Hui Tzu:Inst Cardiol Dante Pazzanese, Sao Paulo, Brazil
· DIAS, Fabricio:Univ Sao Paulo, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil
· GINIAUX, Helene:Aix Marseille Univ, Marseille, France
· LLORED, Agnes:Aix Marseille Univ, Marseille, France
· ALVES, Sthefanny:Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, Brazil
· SCHMIDT, Andre:Univ Sao Paulo, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil
· DONADI, Eduardo:Univ Sao Paulo, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil
· MARIN-NETO, Jose Antonio:Univ Sao Paulo, Sch Med Ribeirao Preto, BR-14049 Ribeirao Preto, SP, Brazil
· HIRATA, Mario:Inst Cardiol Dante Pazzanese, Sao Paulo, Brazil
· SAMPAIO, Marcelo:Inst Cardiol Dante Pazzanese, Sao Paulo, Brazil
· FRAGATA, Abilio:Inst Cardiol Dante Pazzanese, Sao Paulo, Brazil
· CHEVILLARD, Christophe:Aix Marseille Univ, Marseille, France
hcfmusp.origem.id 2-s2.0-84893170926
hcfmusp.origem.id WOS:000328741900018
hcfmusp.publisher.city SAN FRANCISCO
hcfmusp.publisher.country USA
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dc.description.index MEDLINE
hcfmusp.citation.scopus 15
hcfmusp.citation.wos 16
hcfmusp.affiliation.country Brasil
hcfmusp.affiliation.country França

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