Investigação de polimorfismos no gene TNF em pacientes com hepatotoxicidade induzida por medicações antituberculosas no norte do Brasil

Abstract

Tuberculosis still remains a serious public health problem worldwide. The hepatotoxicity induced by anti-tuberculosis drugs causes a large number of hospitalizations and may be fatal if treatment is not interrupted. The hepatitis induced by anti-tuberculosis drugs are not yet fully understood and clinical studies suggests that immunological mechanisms are involved in its pathogenesis. The cytokine TNF-α is a major mediator of inflammatory and immune changes in the levels of this cytokine may be related to pathogenesis of drug-induced hepatitis. These changes observed may be related to polymorphisms in the TNF gene. The knowledge of which polymorphisms in the TNF gene are involved in the risk of developing hepatotoxicity anti-tuberculosis drugs will permit the use of these molecular markers to improve the therapeutic management of these patients. This study investigated the influence of polymorphisms -308C>T (rs1800629), -1031C>T (rs1799964), -238A>G (rs361525) and -857C>T (rs1799724) in the TNF gene with drug-induced hepatotoxicity. The study included 68 patients with tuberculosis who had hepatotoxicity of the basic regimen consisting of rifampicin, isoniazid, pyrazinamide and ethambutol (2RHZE/4R) and 191 patients without adverse therapy effects. The polymorphisms were determined by real-time PCR with TaqMan probes. Comparing the frequency of genotypes between cases and controls, a significant difference in the distribution of genotypes of the SNP -1031C>T was identified (p = 0.003). The frequency of homozygous -1031CC was higher in the case group (8.8%) than in the control group (1.6%). The -1031CC homozygous patients had an increased risk for the development of hepatotoxicity when compared to homozygous -1031TT or the T allele carriers (OR = 8.632, p = 0.014, OR = 11.355, p = 0.004). We concluded that -1031C>T SNP was significantly associated with susceptibility to induced hepatitis anti-tuberculosis drugs in the north population of Brazil.