Global DNA hypomethylation of Alu and LINE-1 transposable elements as an epigenetic biomarker of anti-tuberculosis drug-induced liver injury

Abstract

Despite being highly effective, anti-tuberculosis (TB) drugs often induce adverse liver injury, anti-TB drug-induced liver injury (ATDILI), leading to treatment failure given no sensitive and selective ATDILI markers. Herein, we conducted a case-control association study to determine whether global DNA methylation of Alu and LINE-1 transposable elements responsible for genomic stability and transcriptional regulation was correlated with clinical parameters indicating ATDILI in TB patients and might serve as an ATDILI biomarker. Alu and LINE-1 methylation levels in blood leukocyte of 130 TB patients (80 ATDILI cases and 50 non-ATDILI cases) and 100 healthy controls were quantified using quantitative combined bisulfite restriction analysis.Both TB patients with and without ATDILI had significantly lower methylation levels of Alu and LINE-1 elements than healthy controls. Compared with non-ATDILI patients, Alu methylation levels were significantly decreased in ATDILI patients, commensurate with LINE-1 methylation analysis. Hypomethylation of Alu and LINE-1 measured within 1-7 days of TB treatment was independently associated with raised levels of serum aminotransferases assessed within 8-60 days 3 of TB treatment. Receiver operating characteristic curve analysis uncovered that Alu and LINE-1 methylation levels were both more sensitive and specific for differentiating ATDILI cases from non-ATDILI cases than serum aminotransferases after starting TB treatment within 1-7 days.Kaplan-Meier analysis displayed a significant association between hypomethylation of Alu and LINE-1 elements and an increased rate of ATDILI occurrence in TB patients. Collectively, global DNA hypomethylation of Alu and LINE-1 elements would reflect ATDILI progression and might serve as novel sensitive and specific ATDILI biomarkers.

Assessment of Effective Anti-TB Regimens and Adverse Outcomes Related Risk Factors in the Elderly and Senile-Aged TB Patients

“…Multiple studies have suggested that age is a risk factor for the occurrence of ATDILI, which may be related to organ aging, decreased physiological function, impact on drug pharmacokinetics in the elderly, and the frequent comorbidities of multiple diseases and other medications in the elderly. 35,36 The mechanism may be related to the reduction of liver regeneration function in the elderly, the reduction of mitochondrial DNA replication, the impact on the quality and quantity, the more likely occurrence of mitochondrial dysfunction, the general decline of immune function, the increase in the secretion of proinflammatory factors, as well as the damage of the intestinal barrier in the elderly, the increase of intestinal permeability, and the proliferation of proinflammatory factors into the blood. The results of this study showed that the incidence of anti-tuberculosis drug induced liver damage in elderly TB patients was 12.85% (153/1191), but its occurrence was not statistically correlated with the treatment outcomes of elderly TB patients.…”