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

Amanda Farage Frade (1) , Priscila Camilo Teixeira (1) , Barbara Maria Ianni (1) , Cristina Wide Pissetti (2) , Bruno Saba (3) , Lin Hui Tzu Wang (3) , Andreia Kuramoto (1) , Luciana Gabriel Nogueira (1) , Paula Buck (4) , Fabrício Dias (5) , Helene Giniaux (6) , Agnes Llored (6) , Sthefanny Alves (4) , Andre Schmidt (5) , Eduardo Donadi (5) , Jose Antonio Marin-Neto (5) , Mario Hirata (3) , Marcelo Sampaio (3) , Abílio Fragata (3) , Edimar Alcides Bocchi (7) , Antonio Noedir Stolf (4) , Alfredo Inacio Fiorelli (4) , Ronaldo Honorato Barros Santos (4) , Virmondes Rodrigues (8) , Alexandre Costa Pereira (4) , Jorge Kalil (4, 9, 10) , Edecio Cunha-Neto (4, 9, 10) , Christophe Chevillard (11)

1 SAO PAULO - Heart Institute - Heart Institute
2 Universidade Federal do Triângulo Mineiro Uberaba
3 IDPC - Instituto de Cardiologia Dante Pazzanese
4 InCor - Heart Institute
5 FMRP - School of Medicine of Ribeirão Preto
6 AMU - Aix Marseille Université
7 Department of Allergy and Clinical Immunology [São Paulo, Brazil]
8 Laboratory of Immunology
9 III - Institute for Investigation in Immunology
10 Division of Clinical Immunology and Allergy
11 GIMP - Génétique et immunologie des maladies parasitaires

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.

Keywords: Haplotypes; Cardiomyopathies; Variant genotypes; Chagas disease; Apoptosis; Heart; Inflammatory diseases; Actins

Domains: Life Sciences [q-bio]; Microbiology and Parasitology

Amanda Farage Frade, Priscila Camilo Teixeira, Barbara Maria Ianni, Cristina Wide Pissetti, Bruno Saba, et al.. Polymorphism in the Alpha Cardiac Muscle Actin 1 Gene Is Associated to Susceptibility to Chronic Inflammatory Cardiomyopathy. PLoS ONE, 2013, 8 (12), ⟨10.1371/journal.pone.0083446⟩. ⟨hal-01592696⟩