Genome‐Wide Analysis of DNA Methylation and Antituberculosis Drug‐Induced Liver Injury in the Han Chinese Population

Abstract

Tuberculosis (TB) is one of the most prevalent infections. However, anti-TB drugs induce adverse liver injury in up to 40% of patients. Studies on candidate genes have suggested that single-nucleotide polymorphisms account for only a small contribution to the occurrence of anti-TB drug-induced liver injury (ATLI). In this study, whole-genome DNA methylation analysis was performed to systematically screen the ATLI-associated factors in a 49 vs. 51 case-control population. Next, 34 identified candidate probes were validated using MassARRAY in 296 cases and 288 controls. Our results indicated that 12 CpG sites on seven probes were positively associated with ATLI risk. Furthermore, we applied a CRISPR/Cas9-mediated methylation modifiable cell model and demonstrated that four CpGs in or near the gene region of AK2, SLC8A2, and PSTPIP2 affected the cellular response to rifampicin treatment. This study provides new biomarkers associated with ATLI occurrence.Tuberculosis (TB) is one of the most prevalent chronic bacterial infections, with >6 million new cases occurring globally each year. 1 Although the first-line therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol is able to suppress the increasing incidence of TB, 1 it has been reported that ~ 0.8-40% of patients worldwide suffer from anti-TB drug-induced liver injury (ATLI). 2 ATLI is the most common side effect of anti-TB drugs and often leads to the delayed completion or failure of chemotherapy in patients. 3,4 In some extreme cases, ATLI causes irreversible hepatonecrosis or death in patients receiving anti-TB treatment.Recently, the mortality rate of ATLI was estimated to be as high as 22.7%. 2 Therefore, ATLI is regarded as a severe clinical problem that poses a significant challenge to the early control of TB progression.Numerous association studies have attempted to identify the risk factors for ATLI. A number of genetic single-nucleotide polymorphisms (SNPs) in various genes have been reported to be related to the development of ATLI. The majority of these identified genes are involved in the pathways of drug absorption, distribution, metabolism, and excretion (ADME), acquired immunity, innate immune

Collagen type XVIII alpha 1 chain (COL18A1) variants affect the risk of anti‐tuberculosis drug‐induced hepatotoxicity: A prospective study

“…The following 4 mechanisms are considered as the pathogenesis of ATDH: I) the enzymes and pathways about drug metabolizing, such as glutathione S‐transferase (GST) and N ‐acetyl transferase 2 (NAT2); II) the accumulation of bile acids, lipids, and heme metabolites; III) the toxicity mediated by immune system; IV) the increasing oxidant stress 3‐6 . It is noted that ATDH can be curable in the early stage, 7 although this disease has high mortality (22.7%) and morbidity (28%) 8‐10 and adverse effects on the anti‐TB treatment efficiency 11 . However, the ambiguous diagnostic criteria and atypical symptoms interfere with early prediction and diagnosis of ATDH.…”

Predicting Antituberculosis Drug–Induced Liver Injury Using an Interpretable Machine Learning Method: Model Development and Validation Study

“…Anti-TB drugs are one of the most common and effective means of treating TB in the clinical setting and can effectively control disease progression among patients with TB. Nevertheless, studies have suggested that patients are likely to develop DILI during the treatment process owing to the hepatotoxicity of anti-TB drugs [11,[15][16][17][18] and long duration of TB treatment [56]. Clinicians often have difficulties in predicting the efficacy of anti-TB treatment as well as liver injury status in patients with TB.…”

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

“…In support of this hypothesis, a number of clinical studies demonstrated that altered DNA methylation levels within promoter regions of several metabolic enzymes-encoding genes including CYP2E1 , CYP2D6 , GSTP1 , and NAT2 were associated with ATDILI development in TB patients [ 14 , 15 , 26 ]. In addition to this, a genome-wide association study of DNA methylation provided a supporting finding of a correlation between altered DNA methylation levels within various genes and ATDILI progression [ 12 ]. On the basis of the previous findings, we aimed to measure Alu and LINE-1 methylation levels considered a proxy for global DNA methylation in blood leukocyte of TB patients with and without ATDILI within 1–7 days of treatment initiation compared to healthy controls and also found global DNA hypomethylation in TB patients with ATDILI.…”

“…Nonetheless, the occurrence of ATDLI cannot be completely identified by DNA variations. In the past decade, an increasing number of studies have attempted to link epigenetic marks, especially DNA methylation within promoter regions of metabolic enzymes-encoding genes to ATDILI development [12][13][14][15]. DNA methylation, one of epigenetic mechanisms by which DNA base cytosine (C) is converted to 5-methylcytosine (5-mC) by DNA methyltransferases, plays an important role in modulating gene expression without changing DNA sequence, resulting in decreased transcriptional expression or even gene repression [16].…”