Estudo da ocorrência de polimorfismos de nucleotídeo único em genes codificadores de membros da família das citocinas IL-1 e IL-17 e suas associações com a cardiomiopatia chagásica humana

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, is characterized by an acute phase followed by a chronic phase. Most patients in the chronic phase do not present any clinical signs being clinically classified as indeterminate. On the other hand, about 30% of the patients develop the symptomatic clinical forms (cardiac and/or digestive), and the chronic chagasic cardiomyopathy (CCC) is the most severe form of Chagas disease. The wide variation in clinical presentation of chagasic patients allow us to hypothesize that genetic factors related to the host, particularly genetic polymorphisms, may be responsible, at least in part, by the interindividual differences in the response to the infection. Thus, the present study aimed to assess possible associations between single nucleotide polymorphisms of genes encoding the IL-1, IL-1, IL-1ra, IL-17A and IL-17F and the susceptibility to the development of CCC in Brazilian patients from Minas Gerais. The genotyping of IL1A (-889C/T), IL1B (+3954C/T), IL1RN (+2018T/C), IL17A (-197A/G) e IL17F (+7488T/C) polymorphisms was performed in a sample of 109 patients with CCC and 59 with the indeterminate form, using Real Time PCR. The plasmatic levels of IL-1 were obtained from 20 patients using ELISA reaction. Patients carrying the T variant for IL-1 e IL-1 have two times more chance of developing the cardiac form as compared to the indeterminate form (IL-1:OR=2,01; CI=1,06-3,82; p=0,032; IL-1:OR=2,53; CI=1,18-5,42; p=0,015). The same was observed when we analyzed the allelic frequency (IL-1:OR=1,67; CI=1,01-2,77; p=0,043; IL-1:OR=2,16; CI=1,11-4,19; p=0,020). On the other hand, the heterozygote genotype (TC) of IL-1ra (antagonist receptor of IL-1) was associated with the indeterminate form (OR=2,27; CI=1,02-5,04; p=0,042). Multivariate analysis combining SNPs of IL-1 cluster demonstrated that patients with a more pro-inflammatory profile (carriers of the T variant for both IL-1 and IL-1) have greater chance of developing CCC (OR=3,14; CI=1,35-7,32; p=0,008). No difference was observed in the plasmatic levels of IL-1 between indeterminate and dilated cardiac patients. The study of IL-17A showed that carriers of the A- genotype (GG) have two times more chance of developing the cardiac form as compared with the indeterminate form (OR=2,08; CI=1,08-4,00; p=0.027). A similar result was observed for the allelic frequency (OR=1,71; CI=1,00-2,91; p=0.048). For the IL-17F polymorphism, no association with different forms of Chagas disease was found in the population under study. In summary, our results showed that polymorphisms in IL-1 family and IL-17A genes are associated with different clinical outcomes of Chagas disease