Influência de polimorfismos dos genes TLR (toll-like receptors) sobre a Tuberculose em uma população da Amazônia

Abstract

Tuberculosis (TB) is an infectious disease caused by mycobacteria of the Mycobacterium tuberculosis Complex. This disease has a worldwide distribution poses a serious problem to global health. Brazil is among the 22 countries with the highest numbers of TB cases, and the state of Amazonas has the highest incidence in Brazil. These data concern and stimulates more detailed research on the factors associated with the disease in our region. The Toll-like Receptors (TLRs) are important pattern recognition receptors essential for directing the immune response. Therefore, polymorphisms in these receptors are often associated with tuberculosis. This study investigated whether the changes observed in TLR1 (10 SNPs), TLR2 (7 SNPs), TLR4 (8 SNPs), TLR6 (10 SNPs) TLR9 (5 SNPs) are associated with susceptibility and/or resistance to TB. The genotyping of SNPs in TLR was performed by Sanger sequencing involving a population of Amazon with 263 TB patients and 232 healthy controls. Allele and genotype frequencies of most investigated SNPs were considered rare or undifferentiated between the two groups included. SNPs 2088C/A (Ser696Arg) TLR2, 928G/A (Val310Ile) TLR4, 564A/G (Thr188Thr) and 782C/T (Thr261Met), and the TLR6 SNP -1438C/T in promoter region of TLR9 have not been described yet. The association study determined that for the TLR9-1237AG genotype (OR = 0,62, 95% CI = 0,39-0,97, p = 0,05) was associated TB protection. Evaluation for the SNP 1805T / G (Ile602Ser) of TLR1 did not observe significant differences in allele and genotype frequencies between patients and controls. However, when were stratified patients according their bacterial load, it was demonstrated that genotype 1805TT is more common among paucibacillary patients (OR = 0,38, 95% CI = 0,19-0,76). Additionally it was observed that the genotype 1805TG was more common among multibacillary patients (OR = 3,72, 95% CI = 1,67-8,4). The analysis of demographic questionnaires between patients and controls showed that TB was associated with health problems such as smoking (OR = 6,55, 95% CI = 3,15-13,59; p = 0.0001) and alcohol and or drugs abuse (OR = 7.14, 95% CI = 3,67-13.9; p = 0.0001). Being more commonly observed among men (OR = 3,66; 95% CI = 2,52-5,31; p = 0.0001). The multivariate logistic regression demonstrated that alcohol and drugs consumption (OR = 2,93, 95% CI = 1,05-8.16, p = 0,03) and 1805G allele (OR = 2.75, 95% CI = 1,33-5,7; p = 0,006) were predictive variables associated with the risk for multibacillary form of TB, responsible for maintaining the transmission cycle of the disease. Thus we suggest that the 1805G allele is an immunogenic factor, active in the epidemiology of TB, and together with environmental, sociodemographic and behavioural factors, partly explain the high incidence of TB in our region. Future large-scale studies and assesses the functional effect of SNP 1805G / T still need to be performed to fully elucidation the role this SNP for the regulation of the immune response and immunopathogenesis of TB on the study.