Relationship between common telomere length-related genetic variations, telomere length, and risk of antituberculosis drug-induced hepatotoxicity in Chinese Han population: As assessed for causality using the updated Roussel Uclaf Causality Assessment Method.

Antituberculosis drug-induced hepatotoxicity (ATDH) is a significant threat to tuberculosis control, and two recent studies indicated that leukocyte telomere length (LTL) might be a potential biomarker for ATDH. This study aimed to investigate the relationship between common telomere length-related genetic variations, LTL, and risk of ATDH in Eastern Chinese antituberculosis treatment patients. A 1:4 matched case-control study was conducted among 79 ATDH cases assessed for causality using the updated RUCAM and 316 controls. LTL was determined by quantitative real-time PCR, and nine SNPs involved in telomere biology reported by previous GWAS were assessed. Conditional logistic regression model was used to estimate the association between genotypes and risk of ATDH with odds ratios (ORs) and 95% confidence intervals (CIs). The average RUCAM score of cases was 7.1. The average LTL in cases was significantly shorter than that in controls (median = 1.239 vs. 1.481, P = 0.032). Differences in the distribution of LTL were statistically significant among three genotypes of SNP rs2736098 (CC vs. CT vs. TT, median = 1.544 vs. 1.356 vs. 1.337, P = 0.026) and rs2853677 (AA vs. AG vs. GG, median = 1.511 vs. 1.544 vs. 1.159, P = 0.005) in TERT. SNP rs7675998 in NAF1 was statistically associated with the risk of ATDH under the dominant model (adjusted OR = 1.725, 95% CI: 1.021-2.913, P = 0.042). This is the first study to investigate the relationship of LTL, common telomere length-related variations, and risk of ATDH. SNP rs2736098 and rs2853677 in TERT were significantly associated with LTL, and SNP rs7675998 in NAF1 may be associated with ATDH in Chinese population.

The relationship between relative telomere length and anti-tuberculosis drug-induced hepatitis : A case-control study.

AIM: Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc., while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients. METHODS: A 1:4 matched case-control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls. RESULTS: The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P=0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR=0.79, 95% CI: 0.66-0.94, P=0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend=0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P=0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model. CONCLUSION: This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.

The role of the genetic variant FECH rs11660001 in the occurrence of anti-tuberculosis drug-induced liver injury.

WHAT IS KNOWN AND OBJECTIVE: The pathogenic mechanism of anti-tuberculosis drug-induced liver injury (AT-DILI) is still largely unknown. Recent studies have indicated that rifampicin and isoniazid cotreatment causes the accumulation of endogenous protoporphyrin IX in the liver through the haem biosynthesis pathway. Alanine synthase 1 (ALAS1) and ferrochelatase (FECH) are the rate-limiting enzymes in the production of haem. The present study aimed to investigate the genetic contribution of the ALAS1 and FECH genes to the risk of AT-DILI in an Eastern Chinese Han population. METHODS: A 1:4 matched case-control study was conducted, and eight SNPs in the ALAS1 and FECH genes were detected and assessed. A multivariate conditional logistic regression model was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking and drinking history as covariates. RESULTS AND DISCUSSION: Overall, 202 AT-DILI cases and 808 controls were included in this study. The female patients carrying polymorphisms of rs11660001 in FECH had an increased risk of AT-DILI under the dominant and additive models (OR = 1.831, 95% CI: 1.014-3.307, p = 0.045; OR = 1.673, 95% CI: 1.015-2.760, p = 0.044, respectively). The peak aspartate transaminase level was significantly higher in female patients carrying the GA+AA genotype of rs11660001 than in those with the GG genotype during anti-TB treatment (p = 0.032). WHAT IS NEW AND CONCLUSION: Based on this 1:4 individual matched case-control study, SNP rs11660001 in the FECH gene may be associated with susceptibility to AT-DILI in Chinese female anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

Heme oxygenase-1 and hemopexin gene polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity in China.

Objective: To assess whether the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) might be influenced by heme oxygenase-1 (HMOX1) and hemopexin (HPX) gene polymorphisms. Methods: A dynamic anti-tuberculosis treatment cohort was constructed, and the 1:4 matched nested case-control study was analysed. Eight single-nucleotide polymorphisms (SNPs) of the two genes were selected for genotyping and Bonferroni correction was performed to correct for multiple comparison. Results: Overall, 7.8% of patients developed ATDH. SNP rs1807714 in the HMOX1 gene had decreased effects on the risk of moderate and severe hepatotoxicity under the dominant and additive models, and hepatocellular injury under the additive model. SNP rs2682099 in the HPX gene had increased effects on the risk of moderate and severe hepatotoxicity under the recessive model. However, these associations disappeared after Bonferroni correction. Conclusion:HMOX1 and HPX gene polymorphisms might not be associated with susceptibility to ATDH in the Chinese population.

A validation study of the UGT1A4 rs2011404 variant and the risk of anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population.

WHAT IS KNOWN AND OBJECTIVE: Anti-tuberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. A recent study found that the rs2011404 variant of uridine 5'-diphospho-glucuronosyl-transferase 1A4 (UGT1A4) is a marker of susceptibility to ATDH. The present study aimed to validate this relationship in an Eastern Chinese Han anti-TB treatment population. METHODS: A 1:4 matched case-control study was conducted among anti-TB treatment patients in four regions of Jiangsu. ATDH was diagnosed based on the criteria from the Chinese Society of Hepatology and the updated Roussel Uclaf Causality Assessment Method. A conditional logistic regression model was used to estimate the association between rs2011404 genotypes and the risk of ATDH using odds ratios (ORs) with 95% confidence intervals (95% CIs) and smoking, drinking, hepatoprotectant use and liver diseases as covariates. RESULTS AND DISCUSSION: A total of 202 ATDH cases and 808 controls were matched according to age, sex and treatment history. After correcting for potential confounding factors, conditional logistic regression analysis indicated no significant differences in genotypes between the two groups (CC vs. TC: OR = 0.933, 95% CI: 0.457-1.905, p = 0.849). Subgroup analysis suggested that patients carrying the CC genotype at rs2011404 in UGT1A4 were at a reduced risk of moderate or severe liver injury (OR = 0.293, 95% CI: 0.093-0.921, p = 0.036). WHAT IS NEW AND CONCLUSION: Based on a 1:4 individual matched case-control study, possessing the CC genotype at rs2011404 of the UGT1A4 gene reduces the risk of moderate or severe liver injury in Eastern Chinese Han patients receiving anti-TB treatment. Further research is warranted to explain the role of the UGT1A4 gene and its contribution to individual differences in susceptibility to ATDH.

Association between NR1I2 polymorphisms and susceptibility to anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population: A case-control study.

OBJECTIVE: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism is still largely unknown. Pregnane X receptor (PXR, encoded by the NR1I2 gene) is a ligand-dependent transcription factor, and rifampicin is a human PXR-specific activator. Rifampicin and isoniazid co-therapy targets porphyrin biosynthesis via PXR and results in hepatic protoporphyrin IX accumulation and subsequent liver injury. The present study aimed to investigate the associations between genetic polymorphisms in NR1I2 and ATDH in an Eastern Chinese Han population. METHODS: A 1:4 matched case-control study was conducted using 146 ATDH cases and 584 controls. Seven single nucleotide polymorphisms (SNPs) were detected and analysed. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking history and drinking history as covariates. RESULTS: Patients carrying the GG genotype of rs7643645 were at a higher risk of ATDH than those carrying the AA genotype (OR = 1.864, 95% CI: 1.106-3.141, P = .020), and significant differences were also found under the recessive model (P = .029) and additive model (P = .021). Patients with a polymorphism at rs2276707 were at a reduced risk of ATDH under the recessive model (OR = 0.600, 95% CI: 0.364-0.988, P = .045). Subgroup analysis confirmed the relationship in mild hepatotoxicity cases under the additive model (rs7643645, OR = 1.429, 95% CI: 1.027-1.988, P = .034) and recessive model (rs2276707, OR = 0.478, 95% CI: 0.253-0.902, P = .023). Functional annotation using ENCODE data also indicated that rs2276707 and rs7643645 were located in the histone modification regions targeting enhancers or promoter (H3K4Me1, H3K4Me3 and H3K27Ac). CONCLUSIONS: Based on this case-control study, SNPs rs7643645 and rs2276707 in NR1I2 may contribute to susceptibility to ATDH in Eastern Chinese Han anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

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

Reactive metabolites of anti-tuberculosis (anti-TB) drugs can result in excessive reactive oxygen species (ROS), which are responsible for drug-induced liver injury. The nuclear factor erythroid 2-related factor 2 (Nrf2) - antioxidant response elements (ARE) (Nrf2-ARE) signaling pathway plays a crucial role in protecting liver cells from ROS, inducing enzymes such as phase II metabolizing enzymes and antioxidant enzymes. Based on a Chinese anti-TB treatment cohort, a nested case-control study was performed to explore the association between 13 tag single-nucleotide polymorphisms (tagSNPs) in the NRF2, KEAP1, MAFF, MAFK genes in Nrf2-ARE signaling pathway and the risk of anti-TB drug-induced liver injury (ATLI) in 314 cases and 628 controls. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting weight and usage of hepatoprotectant. Patients carrying the TC genotype at rs4243387 or haplotype C-C (rs2001350-rs6726395) in NRF2 were at an increased risk of ATLI (adjusted OR = 1.362, 95% CI: 1.017-1.824, P = 0.038; adjusted OR = 2.503, 95% CI: 1.273-4.921, P = 0.008, respectively), whereas patients carrying TC genotype at rs2267373 or haplotype C-G-C (rs2267373-rs4444637-rs4821767) in MAFF were at a reduced risk of ATLI (adjusted OR = 0.712, 95% CI: 0.532-0.953, P = 0.022; adjusted OR = 0.753, 95% CI: 0.587-0.965, P = 0.025, respectively). Subgroup analysis also detected a significant association between multiple tagSNPs (rs4821767 and rs4444637 in MAFF, rs4720833 in MAFK) and specific clinical patterns of liver injury under different genetic models. This study shows that genetic polymorphisms of NRF2, MAFF and MAFK may contribute to the susceptibility to ATLI in the Chinese anti-TB treatment population.

Relevance of NAT2 genotype to anti-tuberculosis drug-induced hepatotoxicity in a Chinese Han population.

BACKGROUND: Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction. The slow acetylator status of N-acetyl transferase 2 (NAT2) is a well-established risk factor for ATDH. One novel tagging single nucleotide polymorphism (tagging SNP), rs1495741, in NAT2 has been found to be highly predictive of the NAT2 phenotype. The present study aimed to validate the relationships between tagging SNP rs1495741 and ATDH in a Chinese Han population. METHODS: A 1:2 matched case-control study was conducted using 235 ATDH cases and 470 controls. Conditional or unconditional logistic regression analysis was used to estimate the association between genotypes and the risk of ATDH according to the odds ratio (OR) with a 95% confidence interval (CI). RESULTS: Patients carrying the AA genotype of tagging SNP rs1495741 were at higher risk of ATDH than those carrying the GG genotype (OR = 1.653, 95% CI = 1.050-2.601; p = 0.030). Subgroup analysis suggested that the AA genotype was a risk factor for ATDH in patients aged older than 50 years (OR = 2.486, 95% CI = 1.313-4.706; p = 0.005), weighing over 50 kg (OR = 1.757, 95% CI = 1.016-3.038; p = 0.044) or using a hepatoprotectant (OR = 1.611, 95% CI = 1.009-2.572; p = 0.046). Tagging SNP rs1495741 was not a significant risk factor for moderate and severe hepatotoxicity but appears to be relevant to risk of mild hepatotoxicity specifically. CONCLUSIONS: The present study is the first to validate the relationships between the tagging SNP rs1495741 and ATDH in a Chinese population. Based on this case-control study, the NAT2 rs1495741 polymorphism is a risk factor for mild but not more severe ATDH in Chinese Han patients.

Home-based Anti-Tuberculosis Treatment Adverse Reactions (HATTAR) study: a protocol for a prospective observational study.

INTRODUCTION: Tuberculosis (TB) continues to be an important public health problem throughout much of the world. Drug treatment is the only effective treatment method, but adverse drug events (ADEs) and adverse drug reactions (ADRs) can affect medication adherence. As the number of drug-resistant TB patients and the number of anti-TB drugs have increased, it is necessary to explore the risk factors for ADEs/ADRs to reduce their occurrence. This study aims to build a home-based anti-TB treatment cohort and to recognise the incidences, prognosis and risk factors of anti-TB drug-induced ADEs/ADRs in real-world experiences. METHODS AND ANALYSIS: This study is a multicentre, prospective observational cohort study. The study population will consist of 3200 newly diagnosed TB patients between January 2019 and December 2020. After initiating the anti-TB treatment, all patients will be followed up until finishing treatment unless they withdraw, and we will record personal drug use and signs and/or symptoms of discomfort. Patients will receive scheduled laboratory tests in designated hospitals every 2 weeks during the first 2 months, and the residual blood sample after conducting the laboratory tests will be preserved. The ADEs/ADRs will be placed into eight categories: liver dysfunction, gastrointestinal reactions, drug allergy, arthralgia or muscle pain, nervous system disorders, haematological system disorders, renal impairment and others. ETHICS AND DISSEMINATION: This study protocol has been approved by the ethics committees of Nanjing Medical University. All patients will give written informed consent before enrollment. The findings of the study will be published in peer-reviewed journals and will be presented at national and international conferences.

The A/A Genotype of XPO1 rs4430924 Is Associated With Higher Risk of Antituberculosis Drug-Induced Hepatotoxicity in Chinese Patients.

Antituberculosis (anti-TB) drug-induced hepatotoxicity may be related to the excessive reactive oxygen species induced by hepatotoxic metabolites. Antioxidant activity involves the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. The BTB domain and CNC homologue 1 (Bach1) may compete with Nrf2 for binding to transcriptional enhancers. Elimination of Bach1-mediated transcriptional repression depends on nuclear exporter exportin 1 (Xpo1). Thus, Xpo1 may indirectly affect antioxidant activity. The present study aimed to examine the role of tag single-nucleotide polymorphisms in XPO1 in Chinese anti-TB treatment patients. A 1:2 matched case-control study was conducted using 314 anti-TB drug-induced hepatotoxicity cases and 628 controls. After correcting for weight and hepatoprotectant use, conditional logistic regression analysis showed that patients carrying the AA genotype of rs4430924 in XPO1 were at higher risk of anti-TB drug-induced hepatotoxicity than those carrying the GG genotype based on the subgroup of probable cases (adjusted OR, 1.938; 95%CI, 1.035-3.628; P = .039), and marginally significant differences were also found under the recessive model (P = .048) and the additive model (P = .047). Based on this 1:2 matched case-control study, the AA genotype of rs4430924 in XPO1 may be associated with higher risk of anti-TB drug-induced hepatotoxicity in Chinese anti-TB treatment patients. Further studies in larger and more varied populations are required to validate this relationship.

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

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.

Association of FAM65B, AGBL4, and CUX2 genetic polymorphisms with susceptibility to antituberculosis drug-induced hepatotoxicity: validation study in a Chinese Han population.

OBJECTIVE: Antituberculosis (anti-TB) drug-induced hepatotoxicity (ATDH) is a serious adverse drug reaction, and its pathogenic mechanism has not been elucidated thoroughly to date. A recent genome-wide association study reported that seven single-nucleotide polymorphisms (SNPs) in the family with sequence similarity 65, member B gene (FAM65B), ATP/GTP-binding protein-like 4 gene (AGBL4), and cut-like homeobox 2 gene (CUX2) were associated strongly with ATDH in Ethiopian patients. We validated this relationship in a Chinese Han anti-TB treatment population. PATIENTS AND METHODS: A 1 : 2 matched case-control study was carried out of 235 ATDH cases and 470 controls. Multivariate conditional logistic regression analysis was used to estimate the association between genotypes and risk of ATDH by odds ratios with 95% confidence intervals, and weight and hepatoprotectant use were used as covariates. RESULTS: Patients with a polymorphism at rs10946737 in the FAM65B gene were at an increased risk of moderate and severe liver injury under the dominant model (adjusted odds ratio=2.147, 95% confidence interval: 1.067-4.323, P=0.032). No other genotypes or genetic risk scores were found to be significantly related to ATDH. CONCLUSION: This is the first study to explore and validate the relationships between seven SNPs in the FAM65B, AGBL4, and CUX2 genes and ATDH in a Chinese population. On the basis of this case-control study, SNP rs10946737 in FAM65B may be associated with susceptibility to ATDH in Chinese Han anti-TB treatment patients. Further research is warranted to explain the role of the FAM65B gene and its contribution toward individual differences in susceptibility to ATDH.