Associação de polimorfismos em genes de citocinas com a proteção e susceptibilidade à infecção e progressão da dengue

Abstract

Dengue is the most prevalent arboviruses in the world. Several factors have been associated with susceptibility to dengue, highlighting the genetics of the host immune system that may predispose to clinical severity. Polymorphisms in immune response genes have been associated with both protection and susceptibility to the development of dengue cases in different populations. In this context, the objective of this research was to investigate the role of genetic factors of the innate immune system in the infection and evolution of the dengue pathogenesis. We conducted a study of the case-control which included 127 patients diagnosed with dengue laboratory (78 with dengue fever and 49 with dengue hemorrhagic fever) and 135 healthy controls. SNPs in the TNFA (-308), IL-10 (-819) and IFNG (+874) genes were genotyped by real-time polymerase chain reaction (qPCR) and by ARMS-PCR. For statistical analysis, the free online software SNPStats and the BioEstat version 5.0 software were used. The genotypic frequencies were tested for the Hardy-Weinberg equilibrium and this was framed within the equilibrium standards as determined by the same. There was no statistically significant difference in the allelic frequencies of the SNPs in the TNFA (-308) and IFNG (+874) genes. However, the C allele of IL-10 (-819) was associated with protection against the development of dengue hemorrhagic fever when compared to the control group (OR with 95% CI = 0.56 [0.34 - 0.9]; p = 0.028). Statistically significant difference was found between the genotypic distributions of the TNFA gene (-308) in the dominant model (GA + AA vs GG) for protection against dengue fever, when compared to the dengue fever group (OR with 95% CI = 0.45 [0.20 - 1.00], p = 0.043) with the control group. The T/T genotype was significantly associated with dengue fever in the codominant model (OR with 95% CI = 4.21 [1.45-12.25], p = 0.027) and recessive (OR with 95% CI = 3.82 [1.38-10.59], p = 0.0089). Interestingly, the C/T genotype in the overdominant model (OR with 95% CI = 2.10 [1.01-4.38]; p = 0.047) was associated with progression to dengue hemorrhagic fever. As for the IFNG gene (+874), a significant association was identified between the T / A genotype with dengue protection when compared to the control group and DEN in the codominant model (AA; TA; TT) (OR with 95% CI = 0.45 [ (OR = 95% CI = 0.54 [0.30-0.96], p = 0.033) and overdominant (TA vs AA + TT) (OR with 95% CI) % = 0.46 [0.26-0.82], p = 0.0071). When stratified by clinical classification in dengue fever and dengue hemorrhagic fever, in the overdominant model there was a significant association for protection against dengue development (OR with 95% CI = 0.46 [0.24-0.89], p = 0.02) and dengue hemorrhagic fever (OR with 95% CI = 0.43 [0.19-0.95], p = 0.034). When the SNPs studied here were analyzed in combination, it was identified that the combination G/T/A (OR with 95% CI = 2.95 [1.187.41]; p = 0.022) was statistically associated with susceptibility to dengue fever and combination G/C/T (OR with 95% CI = 0.28 [0.08 0.90], p = 0.035) with protection against the development of hemorrhagic dengue fever. Our results suggest that genetic polymorphisms involved with molecules of the immune system may affect susceptibility or promote protection for clinical phenotypes of dengue and can be considered as good prognostic markers.