Antituberculosis (anti-TB) drugs are the most common cause of drug-induced liver injury (DILI). There are numerous studies revealing the associations between the polymorphisms of pharmacogenes and the risk of anti-TB DILI (ATDILI). In the present study, relevant studies regarding the pharmacogenes associated with ATDILI were systematically searched in PubMed and Scopus. A total of 24 genes associated with ATDILI were reported on and the top five reported genes in terms of frequency were revealed to be N-acetyltransferase 2, cytochrome P450 family 2 subfamily E member 1, glutathione S-transferases [glutathione S-transferase mu 1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1)] and solute carrier organic anion transporter family member 1B1. As ATDILI may be the result of direct and indirect interactions, the encoded proteins were further analysed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to observe the protein-protein interactions and the associations amongst these proteins. The results suggested that only GSTT1 and GSTM1 were central proteins associated with all the other analysed proteins. Therefore, the association between GSTT1 or GSTM1 and the risk of developing ATDILI were further analysed. The results revealed that a GSTM1 deletion genotype was significantly associated with risk of ATDILI [odds ratio (OR), 1.28; 95% confidence interval (CI), 1.08-1.51; P= 0.004], whereas the GSTT1 deletion genotype and GSTM1/GSTT1 dual-deletion genotype were not significantly associated with risk of ATDILI. Subgroup analysis based on ethnicity was performed and the results demonstrated a significant association between GSTM1 and ATDILI in South Asian individuals (OR, 1.48; 95% CI, 1.12-1.95; P=0.005), which has not been reported previously, to the best of our knowledge. In conclusion, GSTM1 was associated with ATDILI in South Asian individuals.

Pharmacogenomics (PGx) is increasingly being recognized as a potential tool for improving the efficacy and safety of drug therapy. Therefore, several efforts have been undertaken globally to facilitate the implementation process of PGx into routine clinical practice. Part of these efforts include the formation of PGx working groups working on PGx research, synthesis, and dissemination of PGx data and creation of PGx implementation strategies. In Asia, the Southeast Asian Pharmacogenomics Research Network (SEAPharm) is established to enable and strengthen PGx research among the various PGx communities within but not limited to countries in SEA; with the ultimate goal to support PGx implementation in the region. From the perspective of SEAPharm member countries, there are several key elements essential for PGx implementation at the national level. They include pharmacovigilance database, PGx research, health economics research, dedicated laboratory to support PGx testing for both research and clinical use, structured PGx education, and supportive national health policy. The status of these essential elements is presented here to provide a broad picture of the readiness for PGx implementation among the SEAPharm member countries, and to strengthen the PGx research network and practice in this region.

Despite being relatively rare, anti-tuberculosis drug-induced liver injury (AtDiLi) is a leading cause of acute liver failure and a major reason for treatment discontinuation, because of no specific and selective markers for AtDiLi. Herein, this study aimed to investigate whether telomere length, a biological indicator of age-related diseases, is associated with AtDiLi outcomes and could serve as an early ATDILI biomarker. Relative telomere length (RTL) in blood leukocyte of 100 age-and gendermatched healthy controls, 49 tuberculosis patients with ATDILI, and 53 tuberculosis patients with non-ATDILI was quantified using real-time polymerase chain reaction. Both tuberculosis patients with and without ATDILI had significantly shorter RTL than healthy controls. Compared with tuberculosis patients with non-ATDILI, RTL in those with ATDILI was significantly increased. Longer RTL was found to be significantly associated with increased susceptibility to ATDILI. Multivariate linear regression analysis showed that an increment in RtL was independently correlated with elevated values of aspartate aminotransferase and alanine aminotransferase assessed within 60 days after antituberculosis treatment. Kaplan-Meier curve analysis demonstrated that longer RtL was associated with elevated rates of hepatotoxicity in tuberculosis patients. Receiver-operating characteristic curve analysis unveiled a diagnostic accuracy of RtL as a novel indicator for AtDiLi progression (AUc = 0.73), which yielded more sensitive and specific values than traditional liver biomarkers including serum enzyme activities of aminotransferases measured within 7 days after treatment with anti-tuberculosis regimens. Collectively, aberrant RTL in blood leukocyte would reflect hepatotoxicity induced by antituberculosis agents and might have a potential biomarker for early AtDiLi progression.Tuberculosis is a chronic respiratory infectious disease and a leading cause of morbidity and mortality worldwide. The disease is characterized by Mycobacterium tuberculosis (MTB) infection usually affecting the lungs, leading to severe coughing, fever, and chest pains 1 that mimic features of other pathologies, thereby becoming a major public health problem. Currently, standard treatment regimens for tuberculosis patients consist of isoniazid, rifampicin, pyrazinamide, and ethambutol that shorten the treatment period and enhance the therapeutic efficacy 2 . However, these anti-tuberculosis agents have been reported to be the most important causative drug-induced liver injury (DILI) in much of developing world 3 , ultimately leading to irreversible liver failure. Despite refined usage of traditional liver biomarkers including serum enzyme activities of aminotransferases and bilirubin levels 4 , these biomarkers are inadequate for early identification of DILI, and alterations in those conventional tools are not mechanistically informative. For these reasons, it would seem more appropriate to identify and develop new more sensitive and specific DILI biomarkers, which may be he...

No abstract

Glutathione s-transferase (GST) is a family of drug-metabolizing enzymes responsible for metabolizing and detoxifying drugs and xenobiotic substances. Therefore, deletion polymorphisms of GSTs can be implicated in developing several pathological conditions, including antiretroviral drug-induced liver injury (ARVDILI). Notably, GST polymorphisms have been shown to be associated with ARVDILI risk. However, data on GST polymorphisms in the Thai population are limited. Therefore, this study investigated possible associations between GST genetic polymorphisms and ARVDILI development. A total of 362 people living with HIV (PLHIV) and 85 healthy controls from multiple centers were enrolled. GSTM1 and GSTT1 genetic polymorphisms were determined using polymerase chain reactions. In addition, HLA genotypes were determined using a sequence-based HLA typing method. After comparing GST genotypic frequencies, there was no significant difference between PLHIV and healthy volunteers. However, while observing the PLHIV group, GSTT1 wild type was significantly associated with a 2.04-fold increased risk of ARVDILI (95%CI: 1.01, 4.14; p = 0.045). Interestingly, a combination of GSTT1 wild type and HLA-B*35:05 was associated with a 2.28-fold higher risk of ARVDILI (95%CI: 1.15, 4.50; p = 0.02). Collectively, GSTT1 wild type and a combination of GSTT1 wild type plus HLA-B*35:05 were associated with susceptibility to ARVDILI in the Thai population.