title: Genetic susceptibility to Chagas disease cardiomyopathy: involvement of several genes of the innate immunity and chemokine-dependent migration pathways.
abstract: BACKGROUND
  Chagas disease, caused by the protozoan Trypanosoma cruzi is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is, by far, the most important clinical consequence of T. cruzi infection. 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. Migration of Th1-type T cells play a major role in myocardial damage.
  
  
  METHODS
  Our genetic analysis focused on CCR5, CCL2 and MAL/TIRAP genes. We used the Tag SNPs based approach, defined to catch all the genetic information from each gene. The study was conducted on a large Brazilian population including 315 CCC cases and 118 ASY subjects.
  
  
  RESULTS
  The CCL2rs2530797A/A and TIRAPrs8177376A/A were associated to an increase susceptibility whereas the CCR5rs3176763C/C genotype is associated to protection to CCC. These associations were confirmed when we restricted the analysis to severe CCC, characterized by a left ventricular ejection fraction under 40%.
  
  
  CONCLUSIONS
  Our data show that polymorphisms affecting key molecules involved in several immune parameters (innate immunity signal transduction and T cell/monocyte migration) play a role in genetic susceptibility to CCC development. This also points out to the multigenic character of CCC, each polymorphism imparting a small contribution. The identification of genetic markers for CCC will provide information for pathogenesis as well as therapeutic targets.
authors: Amanda Farage
authors: AF
authors: Frade
authors: Cristina Wide
authors: CW
authors: Pissetti
authors: Barbara Maria
authors: BM
authors: Ianni
authors: Bruno
authors: B
authors: Saba
authors: Hui Tzu
authors: HT
authors: Lin-Wang
authors: Luciana Gabriel
authors: LG
authors: Nogueira
authors: Ariana
authors: A
authors: de Melo Borges
authors: Paula
authors: P
authors: Buck
authors: Fabrício
authors: F
authors: Dias
authors: Monique
authors: M
authors: Baron
authors: Ludmila Rodrigues Pinto
authors: LR
authors: Ferreira
authors: Andre
authors: A
authors: Schmidt
authors: José Antonio
authors: JA
authors: Marin-Neto
authors: Mario
authors: M
authors: Hirata
authors: Marcelo
authors: M
authors: Sampaio
authors: Abílio
authors: A
authors: Fragata
authors: Alexandre Costa
authors: AC
authors: Pereira
authors: Eduardo
authors: E
authors: Donadi
authors: Jorge
authors: J
authors: Kalil
authors: Virmondes
authors: V
authors: Rodrigues
authors: Edecio
authors: E
authors: Cunha-Neto
authors: Aix-Marseille Université, INSERM, GIMP UMR_S906, Faculté de médecine, 27 bd Jean Moulin, Marseille, cedex 05 13385, France. christophe.chevillard@univ-amu.fr.
authors: Christophe
authors: C
authors: Chevillard
mesh_terms: D000328:Adult; D000368:Aged; D001938:Brazil; D002598:Chagas Cardiomyopathy / Q000235:genetics* / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control; D018932:Chemokine CCL2 / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019713:Receptors, CCR5 / Q000235:genetics* / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000276:immunology; D014349:Trypanosoma cruzi / Q000502:physiology*
chemical_list: C111835:CCL2 protein, human; C584933:CCR5 protein, human; D018932:Chemokine CCL2; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human