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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 . 3 G/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 . 3 G/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.

Polymorphic Sites at the Immunoregulatory CTLA-4 Gene Are Associated with Chronic Chagas Disease and Its Clinical Manifestations