Possible association of HMOX1 and NQO1 polymorphisms with anti-tuberculosis drug-induced liver injury: A matched case-control study

Abstract

Summary What is known and objective Reactive metabolites from anti‐tuberculosis (anti‐TB) drugs can result in abnormal accumulation of reactive oxygen species (ROS), which plays an important role in anti‐TB drug‐induced liver injury (ATLI). Liver cells could keep the production of ROS in balance by antioxidant activities. The heme oxygenase 1, encoded by the HMOX1 gene and NADH:quinone oxidoreductase 1, encoded by the NQO1 gene are crucial mediators of cellular defense against ROS. The present study aimed to investigate the associations between HMOX1 and NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Methods A matched case‐control study was conducted using 314 ATLI cases and 628 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATLI by the odds ratios (ORs) with 95% confidence intervals (CIs), with weight and use of hepatoprotectant as covariates. Results and discussion Patients carrying the GG genotype at rs2071748 in HMOX1 were at a higher risk of ATLI than those with the AA genotype (adjusted OR = 1.503, 95% CI: 1.005‐2.249, P = 0.047), and significant differences were also found under the recessive (P = 0.015) and additive (P = 0.045) models. Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the recessive and additive models (adjusted OR = 1.714, 95% CI: 1.169‐2.513, P = 0.006; adjusted OR = 1.287, 95% CI: 1.015‐1.631, P = 0.037, respectively). What is new and conclusion This is the first study to explore the relationship between HMOX1, NQO1 polymorphisms and ATLI in Chinese anti‐TB treatment population. Based on a matched case‐control study, genetic polymorphisms of HMOX1 may be associated with susceptibility to ATLI in the Chinese population.

N-Acetyl Cysteine as an Adjunct in the Treatment of Tuberculosis

“…NOS2A encodes the enzyme nitric oxide synthase while BACH1 encodes Bach1, whose binding with Nrf2 leads to the downregulation of antioxidant enzymes. Additionally, loss of function mutations on HMOX1, the gene encoding for heme oxygenase 1 recognized as phase II antioxidant enzyme, and NQO1, which encodes NAD (P)H: quinone oxidoreductase 1, were also associated with susceptibility to anti-TB DILI [84]. A metaanalysis also confirmed the association of polymorphisms [63] NAC: N-acetyl cysteine; AGs: aminoglycosides.…”

“…According to studies on genetic polymorphisms of oxidant-antioxidant systems, mutations leading to reduced antioxidant enzymes or increased prooxidant enzymes resulted in increased susceptibility to anti-TB DILI [81,84,85]. A loss of function mutation on MAFK encoding MafK (small Maf basic leucine zipper proteins) increased susceptibility to anti-TB DILI [81] (Figure 1).…”

Association between genetic polymorphisms of NRF2, KEAP1, MAFF, MAFK and anti-tuberculosis drug-induced liver injury: a nested case-control study

“…Among the 314 ATLI cases, 150 patients (47.8%) had a hepatocellular type; 23 patients (7.3%) had a cholestatic type, and 40 patients (12.7%) had a mixed type of liver injury, with the rest of 101 cases classified as unclear type due to lack of test results of alkaline phosphatase (ALP). The distribution of basic characteristics between ATLI cases and non-ATLI controls are summarized in Table 1 (The basic characteristics in Table 1 has been reported in our previous study) 21 . We used 1:2 individual matching of case: control, and there was no significant difference in age, sex and treatment history, disease severity and drug dosage between the two groups.…”

“…The study patients were recruited from the outpatient departments of four designated TB diagnosis and treatment hospitals between April 2014 and December 2016 based on the ADACS protocol 32 . This cohort of anti-TB treatment patients has been described in our previous study 21 . In brief, before treatment, patients would finish the baseline questionnaire (sex, age, TB treatment history, sputum smear, and other complications) and receive laboratory examinations, including serum hepatitis B virus surface antigen (HBsAg), ALT, AST, direct and total bilirubin levels.…”

Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

“…To date, the effects of various genes (such as cytochrome P4502E1 (CYP2E1) and glutathione S-transferases (GST)) and their polymorphisms on susceptibility to ATT-DILI have been investigated in Chinese, Japanese, and other populations (He et al, 2015;Nanashima et al, 2012;Yang et al, 2019). However, precise prediction and personalized therapy for ATT- DILI have not yet been achieved, and it remains necessary to explore more new targets of ATT-DILI to accelerate the realization of this process.…”