title: Polymorphism in the alpha cardiac muscle actin 1 gene is associated to susceptibility to chronic inflammatory cardiomyopathy.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 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.
authors.forename: Amanda Farage
authors.initials: AF
authors.lastname: Frade
authors.affiliation: 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.
authors.forename: Priscila Camilo
authors.initials: PC
authors.lastname: Teixeira
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Barbara Maria
authors.initials: BM
authors.lastname: Ianni
authors.affiliation: Laboratory of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil.
authors.forename: Cristina Wide
authors.initials: CW
authors.lastname: Pissetti
authors.affiliation: Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil.
authors.forename: Bruno
authors.initials: B
authors.lastname: Saba
authors.affiliation: Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil.
authors.forename: Lin Hui Tzu
authors.initials: LH
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Andréia
authors.initials: A
authors.lastname: Kuramoto
authors.affiliation: 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.
authors.forename: Luciana Gabriel
authors.initials: LG
authors.lastname: Nogueira
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Paula
authors.initials: P
authors.lastname: Buck
authors.affiliation: School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Fabrício
authors.initials: F
authors.lastname: Dias
authors.affiliation: Aix-Marseille Université, Marseille, France.
authors.forename: Helene
authors.initials: H
authors.lastname: Giniaux
authors.affiliation: Aix-Marseille Université, Marseille, France.
authors.forename: Agnes
authors.initials: A
authors.lastname: Llored
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Sthefanny
authors.initials: S
authors.lastname: Alves
authors.affiliation: School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Andre
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Donadi
authors.affiliation: School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Marin-Neto
authors.affiliation: Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil.
authors.forename: Mario
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Sampaio
authors.affiliation: Instituto de Cardiologia Dante Pazzanese, São Paulo, São Paulo, Brazil.
authors.forename: Abílio
authors.initials: A
authors.lastname: Fragata
authors.affiliation: Division of Clinical Immunology and Allergy, University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Edimar Alcides
authors.initials: EA
authors.lastname: Bocchi
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Antonio Noedir
authors.initials: AN
authors.lastname: Stolf
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Alfredo Inacio
authors.initials: AI
authors.lastname: Fiorelli
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Ronaldo Honorato Barros
authors.initials: RH
authors.lastname: Santos
authors.affiliation: Laboratory of Immunology, Universidade Federal do Triângulo Mineiro, Uberaba, Minas Gerais, Brazil.
authors.forename: Virmondes
authors.initials: V
authors.lastname: Rodrigues
authors.affiliation: Heart Institute (InCor), University of São Paulo School of Medicine, São Paulo, São Paulo, Brazil.
authors.forename: Alexandre Costa
authors.initials: AC
authors.lastname: Pereira
authors.affiliation: 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.
authors.forename: Jorge
authors.initials: J
authors.lastname: Kalil
authors.affiliation: 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.
authors.forename: Edecio
authors.initials: E
authors.lastname: Cunha-Neto
authors.affiliation: Aix-Marseille Université, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Chevillard
mesh_terms: D000199:Actins / Q000235:genetics* / Q000378:metabolism; D002598:Chagas Cardiomyopathy / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C526913:ACTC1 protein, human; D000199:Actins; D012333:RNA, Messenger