title: Polymorphic sites at the immunoregulatory CTLA-4 gene are associated with chronic chagas disease and its clinical manifestations.
abstract: BACKGROUND
  Chagas disease affects approximately 10 million people mainly in Latin America. The immune regulation by the host seems to be an essential factor for disease evolution, and immune system inhibitory molecules such as CTLA-4 and PD-1 favor the maintenance of peripheral tolerance. Considering that polymorphisms at the immunoregulatory CTLA-4 and PDCD1 genes may alter their inhibitory function, we investigated the association of alleles, genotypes and haplotypes of polymorphic sites observed at the CTLA-4 and PDCD1 genes with different clinical manifestations of chronic Chagas disease (indeterminate, cardiac, digestive and mixed).
  
  
  METHODS
  The polymorphisms at the CTLA-4 (-1722T/C, -318C/T and +49A/G) and PDCD1 (PD-1.3G/A) genes were typed using TaqMan methodology in 277 chronic Chagas disease patients classified into four groups, according to clinical characteristics, and 326 non-infected controls.
  
  
  RESULTS
  Our results showed that CTLA-4 -1722CC genotype (22%), -1722C allele (27%) and CTLA-4 TCG (8.6%), TCA (26%) and CCA (15%) haplotypes were strongly associated with the indeterminate form, while the CTLA-4-318CT genotype (82%) and CTLA-4-318T allele (47%) were found mainly in patients with the mixed form of the disease. The CTLA-4 TCG haplotype (10.2%) was associated with the digestive form. On the other hand, the PD-1.3G/A polymorphism was not associated with chronic Chagas disease and its clinical manifestations.
  
  
  CONCLUSIONS
  Here, we showed that alleles, genotypes and haplotypes reported to increase the expression of the regulatory molecule CTLA-4 were associated with the indeterminate form of the disease. Taken together, our data support the idea that polymorphic sites at immunoregulatory genes may influence the development of Chagas disease variants.
authors.affiliation: Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil ; CEA, Institute of Emerging Diseases and Innovative Therapies, Research Division in Hematology and Immunology, Saint-Louis Hospital, Paris, France.
authors.forename: Fabrício C
authors.initials: FC
authors.lastname: Dias
authors.forename: Tiago da S
authors.initials: Tda S
authors.lastname: Medina
authors.forename: Celso T
authors.initials: CT
authors.lastname: Mendes-Junior
authors.forename: Roberto O
authors.initials: RO
authors.lastname: Dantas
authors.forename: Cristina W
authors.initials: CW
authors.lastname: Pissetti
authors.forename: Virmondes
authors.initials: V
authors.lastname: Rodrigues Junior
authors.forename: Renata
authors.initials: R
authors.lastname: Dellalibera-Joviliano
authors.forename: José A
authors.initials: JA
authors.lastname: Marin-Neto
authors.forename: Fredy R S
authors.initials: FR
authors.lastname: Gutierrez
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.forename: João S
authors.initials: JS
authors.lastname: Silva
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Donadi
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D014355:Chagas Disease / Q000235:genetics*; D002908:Chronic Disease; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics
chemical_list: D026901:Membrane Transport Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C583905:SLC44A4 protein, human