Associação entre polimorfismos funcionais em genes codificadores de citocinas e sua expressão fenotípica com cardiopatia reumática clínica e latente.

Abstract

Background: The inflammatory response associated with rheumatic heart disease (RHD) is influenced by gene polymorphisms, as well as by the levels of inflammatory cytokines. However, the identification of immunologic and genetic factors that allow predicting the establishment and progression of valve disease is still lacking. Using an unbiased machine-learning analysis, we searched for inflammatory predictive factors amongst patients with latent RHD and clinical RHD, the later distinguished by the presence of valve disfunction according with current guidelines. Methods: A total of 212 individuals were included, 77 with latent RHD (17 definite, 60 borderline according to World Heart Federation criteria), 100 with clinical RHD followed in an outpatient basis, and 35 with no heart disease. Gene polymorphism analyses were performed using RT-PCR for the following genes: IL2 (rs2069762 G/T), IL4 (rs2243250 C/T), IL6 (rs1800795 C/G), IL10 (rs1800896 T/C), IL17A (rs2275913 A/G), TNF-alfa (rs361525 A/G) and IL23 (rs11209026 A/G). Circulating cytokine levels of 27 soluble factors were evaluated using BD-Bioplex assay. Results: Median age was 15 years (IQR 13-16) in the latent RHD group and 43 years in the clinical RHD group (IQR 33-51). Healthy individuals were slightly younger with a mean age of 13 years (IQR 9-15). Serum levels of all cytokines were higher in clinical RHD and in latent RHD patients than in normal individuals. IL-4, IL-8, IL-1RA, IL-9, CCL5 and PDGF emerged in the final multivariate model as predictive factors for clinical RHD when compared with latent RHD individuals. IL-4, IL-8 and IL1RA had the greater power to predict clinical RHD in this scenario. In the univariate analysis, polymorphisms in IL2 and IL4 were associated to clinical RHD and in the logistic analysis via lasso, genotypes in IL6 (GG+CG), IL10 (CT+TT), IL2 (CA+AA) and IL4 (CC) were also associated with RHD. Conclusion: Despite higher serum levels of all cytokines in clinical RHD patients, IL-4, IL-8 and IL-1RA were the best predictors of clinical disease presence. An association of polymorphisms in the IL2, IL4, IL6 and IL10 genes were related to clinical RHD. Amongst the variables analyzed, gene polymorphism and phenotypic expression of IL-4 appear to have an important role in predicting clinical RHD in relation to latent RHD and normal individuals.