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Objectives: Anti-tuberculosis drug-induced liver injury (ATDILI) is a common and sometimes severe adverse drug reaction (ADR). This study was conducted to investigate the relationship between polymorphisms of two genes, cytochrome P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor α (PPARα), and the risk of ATDILI in Western Chinese Han population., Methods: A total of 118 tuberculosis (TB) patients with ATDILI and 628 TB patients without ATDILI during anti-TB treatment were recruited from West China Hospital of Sichuan University. DNA was extracted from peripheral blood, and genotypes of the selected 12 single nucleotide polymorphisms (SNPs) (3 SNPs in the POR gene and 9 SNPs in the PPARα gene) were determined. Three genetic models (additive, dominant, and recessive), as well as a haplotype, were used to test the genetic risk of ATDILI. Extended subgroup analysis was conducted according to age, sex and different causality assessments., Results: The mutant allele, genotype and genetic model of rs3898649 in the POR gene were found to be associated with increased risk of ATDILI, especially in the younger (<50 years old), female and pulmonary tuberculosis subgroup. The other two SNPs rs28737229 and rs4728533 in the POR gene showed only a potential association with susceptibility to ATDILI after Bonferroni correction (P < .05 but P Bonferroni  > .05). The other 9 SNPs loci (rs135549, rs9626730, rs4253712, rs4823613, rs4253730, rs6007662, rs4253728, rs2024929 and rs135561) in the PPARα gene showed no significant differences between ATDILI and non-ATDILI in either allele frequencies or genotype (all P >.05)., Conclusions: The results demonstrated the strong correlation between POR gene SNP rs3898649 and ATDILI susceptibility, suggesting the importance of POR rs3898649 in the pathogenesis and development of ATDILI. Therefore, our results indicated that POR rs3898649 might be a valuable biomarker potentially involved in ATDILI., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests that are directly relevant to the content of this study., (Copyright © 2019. Published by Elsevier B.V.)

Background: Antituberculosis drug-induced liver injury (ATDILI) is increasing globally and, hence, it is crucial to predict its risk in the clinical management of antituberculosis therapy. As a major antioxidant, superoxide dismutase (SOD) is mainly responsible for providing defence against oxidative stress, which is involved in ATDILI. The present study aimed to investigate the associations between polymorphisms in SOD genes, including Cu/ZnSOD (SOD1), mitochondrial manganese SOD (MnSOD or SOD2) and extracellular SOD (SOD3), as well as the susceptibility to ATDILI in a Chinese Han population., Methods: In total, 1060 Chinese Han subjects highly suspected to have tuberculosis (TB) were prospectively enrolled from West China Hospital of Sichuan University. Overall, 746 subjects comprising 118 ATDILI and 628 ATD-tolerant TB patients were eligible and were genotyped for seven single-nucleotide polymorphisms in three SOD genes (SOD1: rs4816407 and rs1041740; SOD2: rs4880; SOD3: rs699473, rs2536512, rs2855262 and rs8192290)., Results: Logistic regression analysis showed that none of the seven genetic variants in the three SOD genes were significantly associated with susceptibility to ATDILI in the Chinese Han population after Bonferroni correction, except for a potential association for the SOD2 rs4880 A>G (G allele, p = 0.190, odds ratio = 1.53, 95% confidence interval = 1.05-2.23; GG genotype, p = 0.155)., Conclusions: The promising application of single-nucleotide polymorphisms in the SOD1, SOD2 and SOD3 genes as genetic markers for ATDILI is challenged, and further studies are needed with larger sample sizes and different ethnicities, especially for SOD2 rs4880., (© 2019 John Wiley & Sons, Ltd.)

Background: Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI)., Materials and Methods: A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated., Results: The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42-0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06-3.43, p = 0.028 and OR 1.81; 1.06-3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs., Conclusion: Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population., Competing Interests: The authors have declared that no competing interests exist.

Background: Little knowledge about the biological functions of RP11-37B2.1, a newly defined long noncoding RNA (lncRNA) molecule, is currently available. Previous studies have shown rs160441, located in the RP11-37B2.1 gene, is significantly associated with tuberculosis (TB) in a Ghanaian and the Gambian populations., Methods: We investigated the influence of single-nucleotide polymorphisms (SNPs) within lncRNA RP11-37B2.1 on the risk of TB and the possible correlation with adverse drug reactions (ADRs) from TB treatment in a Western Chinese population. Four SNPs within lncRNA RP11-37B2.1 were genotyped in 554 TB cases and 561 healthy subjects using the improved multiplex ligation detection reaction method, and the patients were followed up monthly to monitor the development of ADRs., Results: No significant association between the SNPs of lncRNA RP11-37B2.1 and TB susceptibility was observed (all P > 0.05). Surprisingly, significant association was observed between two SNPs (rs218916 and rs160441) and thrombocytopenia development during anti-TB therapy under the dominant model (P = 0.003 and 0.014, respectively)., Conclusions: Our findings firstly exhibit that rs218916 and rs160441 within lncRNA RP11-37B2.1 significantly associate with the occurrence of thrombocytopenia and suggest RP11-37B2.1 genetic variants are potential biosignatures for thrombocytopenia during anti-TB treatment., (© 2019 The Authors. Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Antituberculosis drug-induced adverse drug reactions (ATD-ADRs) are increasing globally, and it is key to identify candidate ATD-ADRs loci for clinical management. We prospectively enrolled 1,235 highly suspicious tuberculosis (TB) inpatients to investigate the profiles and genetic risk factors of ATD-ADRs in the liver, kidneys, and blood. Overall, 644 subjects were eligible and genotyped for seven polymorphisms in drug-metabolizing enzymes and transporter genes. Clinical follow-up and blood analysis were performed regularly. We found that a notable rate of ATD-ADRs (incidence: 16.5%, drug intervention rate: 10.4%), mainly involving hepatotoxicity (10.6%) and leukopenia (3.3%) in western China. CYP2D6 rs1135840 and NUDT15 rs116855232 increased the risks of hepatotoxicity and leukopenia with an odds ratio of 2.52 and 4.97, respectively. Both variants showed excellent negative predictive values (93.7% and 98.1%, respectively) but moderate sensitivities (72.7% and 52.4%, respectively). These data provide new insight into ATD-ADRs in the Chinese population and may offer future leads for diagnosis and treatment., (© 2017 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

To investigate the epidemiology, clinical features, and drug-resistance profile of urinary tuberculosis (UTB) in south-western China to improve UTB diagnostics.After the screening of 1036 cases of suspected UTB, 193 patients with UTB were enrolled during 2009 to 2014. Urine samples were collected for routine urinalysis, smear, tuberculosis DNA (TB-DNA) detection, and drug-resistant analysis, whereas blood samples were collected for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and renal function evaluation. Clinical features (such as symptoms and outcome) and imageology results (such as B ultrasonic, computerized tomography, intravenous pyelography, and renography) were also collected and analyzed to investigate the epidemiology, clinical features, and drug-resistance profile.The most common presenting symptoms were urinary irritation (61.1%) and lumbago (49.2%). High proportions of microscopic hematuria (63.2%) and microscopic proteinuria (45.6%) were also observed. The positive rate for TB-DNA was 66.3%. The positive rate for culture was 13.1% and for smear it was 9.8%. The abnormal outcome rates of the computerized tomography, ultrasonography, intravenous pyelography, and the nephrogram were 76.9%, 70.1%, 29.8%, and 37.0%, respectively. The total rate of drug-resistant TB (resistant to at least 1 drug) was 39.7%, of which 20.7% was multidrug-resistance TB. The most prevalent mutation sites were katG S315T1, rpoB S531L, and gyrA D94G.We observed a serious epidemic of drug-resistant UTB and a substantial number of new UTB cases with multidrug resistance TB. Molecular diagnostics is crucial in the definite diagnosis of UTB, and our finding is a supplement and further confirmation of polymerase chain reaction usage for TB diagnosis. We recommend real-time polymerase chain reaction for TB-DNA identification instead of culture, and GenoType tests (MTBDRplus and MTBDRsl assay) for drug resistance as routine assays for patients with suspected UTB.

Tuberculous meningitis continues to be a serious problem for physicians because it is difficult to make an early diagnosis and the consequences of delaying treatment are severe. The objective of this study is to provide data for the optimization of diagnostic and timely treatment of tuberculous meningitis. Of the 401 human immunodeficiency virus (HIV)-negative tuberculous meningitis patients in our study, 332 were found to have an impaired blood brain barrier (82.8%). Nearly 17.0% of patients failed to be timely diagnosed. Headache (53.6%) and fever (48.6%) were the most common features, and Computed Tomography/Magnetic Resonance Imaging (CT/MRI) detected 96 patients (23.9%) with abnormal meningeal imaging. Cerebrospinal fluid real-time polymerase chain reaction was positive in 73.8% of the tuberculous meningitis patients, whereas, smears and cultures detected only 6.7% and 5.2%, respectively. Further analysis identified striking differences between drug-resistant and drug-susceptible tuberculous meningitis. Patients with drug resistance correlated with grave prognosis. Tuberculous meningitis diagnosis should overall embody clinical symptoms, laboratory and cerebral imaging findings, and more sensitive diagnostic approaches are still warranted. Our data suggest cerebrospinal fluid polymerase chain reaction for mycobacterial DNA and molecular drug susceptibility testing as routine assays for suspected tuberculous meningitis patients, and observation of the blood brain barrier function could be performed for individual management.

Background. The accumulation of the hepatotoxic substance protoporphyrin IX (PPIX) induced by aminolevulinate synthase 1 (ALAS1) activation is one of the important mechanisms of antituberculosis drug-induced hepatotoxicity (ATDH). Forkhead box protein O1 (FOXO1) may activate ALAS1 transcription. However, little is known about their roles in ATDH; we performed a study to determine the association between polymorphisms in the two genes and ATDH susceptibility. Then, we verified this possible association by cellular functional experiments. Materials and Methods. Tag single-nucleotide polymorphisms (TagSNPs) in the two genes were genotyped in 746 tuberculosis patients. The frequencies of the alleles, genotypes, genetic models, and haplotype distribution of the variants were compared between the case and control groups. L-02 cells and HepG2 cells were incubated with the indicated concentration of isoniazid (INH) and rifampicin (RIF) for the desired times, and then the expression levels of ALAS1 and FOXO1 mRNAs and proteins were detected. HepG2 cells were transiently transfected with FOXO1 siRNA to observe the effect of changes in the FOXO1 expression on the cell survival rate and ALAS1 expression. Results. The C allele at rs2755237 and the T allele at rs4435111 in the FOXO1 gene were associated with a decreased risk of ATDH. The expression of ALAS1 in both L-02 cells and HepG2 cells was increased by the coadministration of INH/RIF (600/200 μM) for 24 h. Although FOXO1 expression was reduced slightly by the same treatment, its content in the nucleus was significantly increased. However, the cell survival rate and ALAS1 expression level were not significantly altered by the downregulation of FOXO1 in HepG2 cells. Conclusions. Variants of the rs4435111 and rs2755237 loci in the FOXO1 gene were associated with susceptibility to ATDH. Coadministration of INH/RIF promoted the transfer of FOXO1 from the cytoplasm to the nucleus, but the functional significance of its nuclear translocation requires further verification. [ABSTRACT FROM AUTHOR]

Background. TGFBRAP1 and TGFBR2 play important roles in the TGF-β/smad signalling pathway and may disturb liver homeostasis by regulating liver injury and renewal. However, little is known about the association between their genetic polymorphisms and antituberculosis drug-induced liver injury (ATDILI), so we explored the association between their variants and the susceptibility to ATDILI. Materials and Methods. A total of 746 tuberculosis patients were prospectively enrolled, and fifteen selected SNPs were genotyped. The allele, genotype, and genetic model frequencies of the variants were compared between patients with or without ATDILI, as well as the joint effect analysis of SNP-SNP interactions. The odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated. Results. The A variant at rs17687727 was significantly associated with an increased risk for ATDILI (OR 1.55; 95% CI: 1.08–2.22; p=0.016), which is consistent with the results in the additive and dominant models. Other allele, genotype, and genetic model frequencies were similar in the two groups for the other fourteen SNPs (all p>0.05). Conclusion. Our study first implied that the A variant of rs17687727 in TGFBRAP1 influenced the susceptibility to ATDILI in first-line antituberculosis combination treatment in the Han Chinese population in a dependent manner. [ABSTRACT FROM AUTHOR]