Estudo da influência dos polimorfismos genéticos das citocinas IL-8, IL-17 e TGF beta e dos receptores DC-SIGN e CTLA-4 na susceptibilidade à infecção por dengue.

Abstract

Dengue is the most common disease in humans caused by arboviruses and represents a serious public health problem in tropical and subtropical regions. The viral infection leads to a variety of symptoms that range from an asymptomatic infection to serious forms of the disease. It exacerbates the inflammatory response, which seems to be related to the genetic background of the host. Thus, polymorphisms in genes involved in the inflammatory response are potential targets in susceptibility studies to DENV infection. The aim of this study was to evaluate the influence of polymorphisms in genes of cytokines IL8 (-251 A/T), IL17 (7488 A/G) and TGFβ (-509 C/T) and receptors CTLA-4 (+49 A/G) and DC-SIGN (-336 A/G) in the susceptibility to the infection by DENV in 196 patients with dengue symptoms, received in hospitals in Fortaleza, Ceará. Confirmation of dengue was performed by IgM serology, NS1 antigen detection and viral isolation through RT-PCR. Genotypic determination of the studied SNPs was performed by PCR-RFLP and real time PCR. The results of the risk analyses, considering the genes IL8, IL17 and TGFβ, showed that the allele A from IL17 is associated with the risk of dengue (p=0.029), while the polymorphic homozygote IL17 (GG) is associated with the protection against the disease (p=0.0076). On the contrary, when the genes were associated a protection against dengue was observed in the combinations DC-SIGN (AG) + CTLA-4 (AA) and DC-SIGN (AA) + IL17 (GG). In the haplotype analysis, a protection by the haplotypes [AGCAA e AGTAG] in the sequence of the respective genes IL8, IL17, TGFβ, DC-SIGN e CTLA-4 was observed the relation between the polymorphisms and the clinical findings showed a protection against hemorrhagic manifestations by the with G allele from IL17 in the presence of the TGFβ heterozygote (CT) in the overdominant model. Additionally, we observed an association between DC-SIGN (AA) with absence of hemorrhagic manifestations and the CTLA-4 (AA) genotype associated with normal platelet count. These data reveal the relevance of CTLA-4 (AG) associated with the risk of dengue, since its polymorphism would change its regulatory function and a protective role for the G allele of IL17, which was also observed with IL8 (AA). These data suggest IL17F as a potential target for the development of therapies against dengue and other flavivirus.