Avaliação das variantes de base única em Genes de miRNA na Tuberculose

Abstract

Pulmonary tuberculosis (PTB) is an infectious disease caused by the Mycobacterium tuberculosis complex. It is estimated that 25% of the world’s population is infected with this bacillus, which possesses several mechanisms that confer adaptability through interaction with the human host. Through this interaction, the pathogen is able to modulate the gene expression of miRNAs (short regulatory RNA sequences that act in different signaling pathways) in order to survive and persist during infection. In some infected individuals, the immune response is capable of eliminating the bacillus through innate mechanisms or even through the development of an adaptive immune response. In other individuals, however, the bacillus may remain alive and confined within granulomas, with potential reactivation under certain conditions, leading to active disease. Individual immunogenetic factors may account for this diversity of outcomes arising from the pathogen–host interaction. Thus, aiming to contribute to the elucidation of this dynamic, this study evaluated, in patients with PTB and healthy individuals, the frequency of single nucleotide variants (SNVs) in miRNA genes rs6505162 (MIR423), rs4713693 (MIR1275), rs2910164 (MIR146A), and rs895819 (MIR27A), as well as the possible associations of these SNVs with disease susceptibility. A total of 457 PTB patients and 429 controls were recruited in Manaus, Amazonas, Brazil. SNV genotyping was performed by qPCR using TaqMan probes. Additionally, the concentrations of inflammatory cytokines (IL-6, IFN-γ, IL-1β, and IL-18) were measured in plasma samples to investigate whether these SNVs may interfere with the production of these molecules. The frequency of the minor alleles of these variants was higher than 0.30 in the studied population. An initial association of rs4713693 with protection against PTB was observed under the dominant model (C/T + C/C vs. T/T; p = 0.0278; OR = 0.73; 95%CI = 0.55–0.97); however, after correction for multiple comparisons, this association did not remain statistically significant (pBonferroni = 0.556). An interaction between rs6505162 (A/C genotype) and rs895819 (C/C genotype) was identified and associated with protection against PTB (pBonferroni = 0.0466; OR = 0.13; 95%CI = 0.04–0.42). The rs4713693 C/C genotype was also associated with lower plasma IFN-γ concentrations in patients. These findings contribute to understanding the role of genetic variants in miRNAs in susceptibility to PTB in a region highly endemic for the disease.