Impacts of clofazimine on the treatment outcomes of drug-resistant tuberculosis.

BACKGROUND: The purpose of this research was to evaluate the effect of clofazimine on drug-resistant tuberculosis treatment outcomes. METHODS: A systematic search was conducted in the PubMed, Web of Science and EMBASE databases to identify eligible studies published up to July 10, 2021. The search terms were as follows: "clofazimine," "tuberculosis," "multidrug resistant tuberculosis" or "extensively drug resistant tuberculosis" and their synonyms or similar words. Two researchers independently screened the titles, abstracts, and full texts for inclusion. Meta-analysis was performed with Stata version 16.0 (Stata Corp., College Station, Texas, USA). Risk ratios (RRs) with 95% CIs were calculated to evaluate the treatment outcome. RESULTS: Eight studies including 3219 participants were included in the meta-analysis. The meta-analysis found that the rates of treatment completion was higher in patients receiving clofazimine-containing regimens than in those not receiving clofazimine-containing regimens (RR: 1.185 (1.060-1.325), P = 0.003). Significant reduction in treatment failure (RR: 0.598 (0.473-0.756), P < 0.001) was found in the clofazimine treatment group. The subgroup analyses of randomized controlled trials (RCTs) found a higher rates of favorable outcomes, treatment completion and cure in the clofazimine group than in the control group (RR: 1.203 (1.029-1.407), P = 0.020; RR: 3.167 (2.043-4.908), P < 0.001; and RR: 1.251 (1.031-1.518), P = 0.023, respectively). Patients receiving clofazimine had a lower risk of treatment failure than those not receiving clofazimine (RR: 0.529 (0.454-0.616), P < 0.001). However, clofazimine treatment did not have a statistically significant effect on all-cause mortality in RCTs. CONCLUSIONS: This study demonstrated that compared with patients who do not receive clofazimine, this drug has the potential to achieve a higher favorable outcome, treatment completion and cure rates, and a lower treatment failure risk among drug-resistant tuberculosis cases.

Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study.

Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is one of the most common adverse reactions that brings great difficulties to the treatment of tuberculosis. Thus, early identification of individuals at risk for ATB-DILI is urgent. We conducted a prospective cohort study to analyze the urinary metabolic and microbial profiles of patients with ATB-DILI before drug administration. And machine learning method was used to perform prediction model for ATB-DILI based on metabolomics, microbiome and clinical data. Methods: A total of 74 new TB patients treated with standard first-line anti-TB treatment regimens were enrolled from West China Hospital of Sichuan University. Only patients with an updated RUCAM score of 6 or more were accepted in this study. Nontargeted metabolomics and microbiome analyses were performed on urine samples prior to anti-tuberculosis drug ingestion to screen the differential metabolites and microbes between the ATB-DILI group and the non-ATB-DILI group. Integrating electronic medical records, metabolomics, and microbiome data, four machine learning methods was used, including random forest algorithm, artificial neural network, support vector machine with the linear kernel and radial basis function kernel. Results: Of all included patients, 69 patients completed follow-up, with 16 (23.19%) patients developing ATB-DILI after antituberculosis treatment. Finally, 14 ATB-DILI patients and 30 age- and sex-matched non-ATB-DILI patients were subjected to urinary metabolomic and microbiome analysis. A total of 28 major differential metabolites were screened out, involving bile secretion, nicotinate and nicotinamide metabolism, tryptophan metabolism, ABC transporters, etc. Negativicoccus and Actinotignum were upregulated in the ATB-DILI group. Multivariate analysis also showed significant metabolic and microbial differences between the non-ATB-DILI and severe ATB-DILI groups. Finally, the four models showed high accuracy in predicting ATB-DILI, with the area under the curve of more than 0.85 for the training set and 1 for the validation set. Conclusion: This study characterized the metabolic and microbial profile of ATB-DILI risk individuals before drug ingestion for the first time. Metabolomic and microbiome characteristics in patient urine before anti-tuberculosis drug ingestion may predict the risk of liver injury after ingesting anti-tuberculosis drugs. Machine learning algorithms provides a new way to predict the occurrence of ATB-DILI among tuberculosis patients.

Plasma metabolomic and lipidomic alterations associated with anti-tuberculosis drug-induced liver injury.

Background: Anti-tuberculosis drug-induced liver injury (ATB-DILI) is an adverse reaction with a high incidence and the greatest impact on tuberculosis treatment. However, there is a lack of effective biomarkers for the early prediction of ATB-DILI. Herein, this study uses UPLC‒MS/MS to reveal the plasma metabolic profile and lipid profile of ATB-DILI patients before drug administration and screen new biomarkers for predicting ATB-DILI. Methods: A total of 60 TB patients were enrolled, and plasma was collected before antituberculosis drug administration. The untargeted metabolomics and lipidomics analyses were performed using UPLC‒MS/MS, and the high-resolution mass spectrometer Q Exactive was used for data acquisition in both positive and negative ion modes. The random forest package of R software was used for data screening and model building. Results: A total of 60 TB patients, including 30 ATB-DILI patients and 30 non-ATB-DILI subjects, were enrolled. There were no significant differences between the ATB-DILI and control groups in age, sex, smoking, drinking or body mass index (p > 0.05). Twenty-two differential metabolites were selected. According to KEGG pathway analysis, 9 significantly enriched metabolic pathways were found, and both drug metabolism-other enzymes and niacin and nicotinamide metabolic pathways were found in both positive and negative ion models. A total of 7 differential lipid molecules were identified between the two groups. Ferroptosis and biosynthesis of unsaturated fatty acids were involved in the occurrence of ATB-DILI. Random forest analysis showed that the model built with the top 30 important variables had an area under the ROC curve of 0.79 (0.65-0.93) for the training set and 0.79 (0.55-1.00) for the validation set. Conclusion: This study demonstrated that potential markers for the early prediction of ATB-DILI can be found through plasma metabolomics and lipidomics. The random forest model showed good clinical predictive value for ATB-DILI.

Efficacy of bedaquiline in the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB) remains a major public health concern worldwide. Bedaquiline, a novel diarylquinoline, was added to the WHO-recommended all-oral regimen for patients with multidrug-resistant tuberculosis. We performed a systematic review and meta-analysis to determine the effect of bedaquiline on tuberculosis treatment outcomes. METHODS: We searched the PubMed, Web of Science and EMBASE databases for relevant studies published up to March 12, 2021. We included studies in which some participants received bedaquiline and others did not. Stata version 16.0 (Stata Corp., College Station, Texas, USA) was used to analyze the results of the meta-analysis. Risk ratios (RRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the effect of bedaquiline on drug-resistant tuberculosis. Between-study heterogeneity was examined by the I-squared test. Randomized controlled trials were assessed for quality using the Jadad scale, and cohort studies were assessed using the Newcastle-Ottawa scale. RESULTS: Eight studies, including 2 randomized controlled trials and 6 cohort studies involving a total of 21,836 subjects, were included. When compared with the control, bedaquiline treatment was associated with higher rates of culture conversion (risk ratio (RR):1.272 (1.165-1.389), P < 0.001). We found substantial evidence of a significant reduction in all-cause death (RR: 0.529 (0.454-0.616), P < 0.001)) in the bedaquiline treatment group. There was no significant reduction in treatment success (RR = 0.980 (0.948-1.013, P = 0.234)). CONCLUSIONS: This study demonstrated that compared with patients who do not receive bedaquiline, this drug has the potential to achieve a higher culture conversion rate and a lower mortality risk among drug-resistant tuberculosis cases.

Polymorphisms in the airway epithelium related genes CDHR3 and EMSY are associated with asthma susceptibility.

BACKGROUND: As a main line of defense of the respiratory tract, the airway epithelium plays an important role in the pathogenesis of asthma. CDHR3 and EMSY were reported to be expressed in the human airway epithelium. Although previous genome-wide association studies found that the two genes were associated with asthma susceptibility, similar observations have not been made in the Chinese Han population. METHODS: A total of 300 asthma patients and 418 healthy controls unrelated Chinese Han individuals were enrolled. Tag-single nucleotide polymorphisms (Tag-SNPs) were genotyped and the associations between SNPs and asthma risk were analyzed by binary logistic regression analysis. RESULTS: After adjusting for confounding factors, the A allele of rs3847076 in CDHR3 was associated with increased susceptibility to asthma (OR = 1.407, 95% CI: 1.030-1.923). For the EMSY gene, the T alleles of both rs2508746 and rs12278256 were related with decreased susceptibility to asthma (additive model: OR = 0.718, 95% CI: 0.536-0.961; OR = 0.558, 95% CI: 0.332-0.937, respectively). In addition, the GG genotype of rs1892953 showed an association with increased asthma risk under the recessive model (OR = 1.667, 95% CI: 1.104-2.518) and the GATCTGAGT haplotype in EMSY was associated with reduced asthma risk (P = 0.037). CONCLUSIONS: This study identified novel associations of rs3847076 in CDHR3, as well as rs1892953, rs2508746 and rs12278256 in EMSY with adult asthma susceptibility in the Chinese Han population. Our observations suggest that CDHR3 and EMSY may play important roles in the pathogenesis of asthma in Chinese individuals. Further study with larger sample size is needed.

Are genetic variations in glutathione S-transferases involved in anti-tuberculosis drug-induced liver injury? A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: As a crucial protective role in the detoxifying mechanisms of drugs, glutathione S-transferases (GSTs) may affect an individual patient's susceptibility to anti-tuberculosis drug-induced liver injury (ATLI). However, the results of studies investigate the association between GSTM1, GSTT1 and GSTP1 polymorphisms and risk of ATLI are inconclusive. A meta-analysis on this topic was performed. METHODS: PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure (CNKI) were systematically searched to identify relevant studies. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and publication bias were also tested. RESULTS AND DISCUSSION: After excluding one study as an outlier, the null GSTM1 genotype was associated with an increased risk of ATLI (OR = 1.270, 95% CI (1.014-1.590, P = .038), especially in East Asians (OR = 1.501, 95% CI (1.303-1.730). With similar exclusion, the null GSTT1 genotype increased the risk of ATLI in the total population (OR = 1.169, 95% CI: 1.028-1.330) and in Indians (OR = 1.732, 95% CI: 1.229-2.416). No statistically significant association was observed between the mutant GSTP1 genotype with risk of ATLI, which may need more rigorous and uniform case-control or cohort studies for more robust inferences. WHAT IS NEW AND CONCLUSION: This up-to-date meta-analysis strongly suggests associations of GSTM1 and GSTT1 polymorphisms with ATLI. The results show the increased risk of ATL1 with the null GSTM1 and GSTT1 genotype on ATLI development. No such association is shown with the mutant GSTP1 genotype.

Functional study of the association of CHI3L1 polymorphisms with asthma susceptibility in the Southwest Chinese Han population.

Background: Chitinase 3-like 1 (CHI3L1) is involved in the Th2 cell mediated pathway, tissue remodeling and fibrosis. Correlations of CHI3L1 gene polymorphisms with asthma in previous studies have been inconsistent. The present study was designed to investigate the association between CHI3L1 polymorphisms and asthma in the southwest Chinese Han population. Methods: Two single nucleotide polymorphisms (SNPs), rs4950928 and rs10399931, were genotyped in 410 asthma patients and 418 healthy controls from Southwest China. Dual-luciferase reporter gene analysis was performed to detect allele-dependent promoter activity of CHI3L1 variants in HEK293 cells. Real-time quantitative PCR was applied to detect the relative mRNA expression associated with different genotypes of CHI3L1 rs10399931. A meta-analysis was performed using data collected from previously published reports and the present study. Results: No significant association was found between rs4950928 and asthma. The rs10399931 CT/TT genotype increased the risk of asthma under the dominant model (P = 0.031, OR = 1.428, 95% CI, 1.033-1.974), while the CT genotype showed the same tendency under the heterozygous model (P = 0.003, OR = 1.680, 95% CI, 1.186-2.380). No statistically significant difference was found between alleles T and C of rs10399931in the dual-luciferase reporter gene analysis (P = 0.201). The rs10399931 CT/TT genotypes reduced the relative mRNA expression detected by real-time quantitative PCR (P = 0.002). There was no significant association between the CHI3L1 rs4950928 polymorphism and the risk of asthma in the meta-analysis. Conclusion: In the southwest Chinese Han population, the CHI3L1 rs10399931 CT/TT genotypes may increase the risk of asthma. rs10399931 may be a functional variant of CHI3L1 due to its effect on mRNA expression.

Association Study of Myosin Heavy Chain 15 Polymorphisms with Asthma Susceptibility in Chinese Han.

BACKGROUND: The Myosin Heavy Chain 15 gene (MYH15) is expressed in the airway epithelium and variants in the gene have been associated with airway responsiveness. The aim of this study was to perform the first investigation of MYH15 polymorphisms in relation to asthma susceptibility. METHODS: A total of 410 asthma patients and 418 controls from the Chinese Han population were enrolled in the study. Tag-single nucleotide polymorphisms were genotyped and associations between the polymorphisms and asthma risk were analyzed by logistic regression analysis adjusting for confounding factors. Dual-luciferase reporter gene analysis was performed to detect allele-dependent promoter activity of MYH15 variants in HEK293 cells. RESULTS: The A allele of rs9288876 decreased risk of asthma (allelic model: OR=0.808, 95% CI: 0.658-0.993, additive model: OR=0.747, 95% CI: 0.588-0.947, dominant model: OR=0.693, 95% CI: 0.502-0.955). The G alleles of both rs7635009 and rs1454197 were associated with decreased risk of asthma under the additive model (OR=0.779, 95% CI: 0.618-0.981 and OR=0.756, 95% CI: 0.600-0.953, respectively). rs9288876 allele A was associated with higher luciferase activity than allele T (P<0.001). The luciferase activity of rs7635009 allele A was lower than allele G (P=0.001), while rs1454197 allele T had lower luciferase activity than allele G (P<0.001). CONCLUSION: This is the first study to report the association of MYH15 gene polymorphisms with asthma. Polymorphisms of rs9288876, rs7635009, and rs1454197 altered transcriptional regulation of MYH15 and may be functional variants conferring susceptibility to asthma. Further study with larger sample size in different ethnic populations is needed.

Abbott RealTime MTB and MTB RIF/INH assays for the diagnosis of tuberculosis and rifampicin/isoniazid resistance.

BACKGROUND: The Abbott RealTime MTB (Abbott-RT) and Abbott RealTime MTB RIF/INH Resistance (Abbott-RIF/INH) assays have been introduced for the detection of tuberculosis (TB) and drug-resistant tuberculosis (DR-TB). We performed a systematic review and meta-analysis to assess the accuracy of Abbott-RT and Abbott-RIF/INH for the detection of TB and DR-TB. METHODS: The Ovid MEDLINE, EMBASE, Cochrane and Web of Science databases were searched to identify eligible articles for the systematic review. The pooled analyses were calculated with a bivariate model. Hierarchical summary receiver operating characteristic curves and the area under the curve (AUC) were used to summarize overall diagnostic performance. Deeks' test was performed to evaluate potential publication bias. RESULTS: For the Abbott-RT assay, 9 studies including 3, 640 patients met the study criteria. The pooled sensitivity of Abbott-RT for detecting TB was 0.96 (95% CI: 0.88-0.99) and specificity was 0.97 (95% CI: 0.93-0.99). For DR-TB, four studies were included to evaluate the diagnosis accuracy of Abbott-RIF/INH. The pooled sensitivity was 0.88 (95% CI, 0.82-0.93) and specificity was 0.99 (95% CI, 0.96-0.99). No publication bias was found. CONCLUSION: Both Abbott-RT and Abbott-RIF/INH assays have good sensitivity, specificity and accuracy for the diagnosis of TB and DR-TB.

Association of PXR and CAR Polymorphisms and Antituberculosis Drug-Induced Hepatotoxicity.

A combination therapy of multiple drugs including isoniazid, rifampicin, ethambutol and pyrazinamide has been proven to be an effective option for the vast majority of tuberculosis (TB) patients. However, various adverse drug reactions (ADRs) limit its merit, with anti-TB drug-induced hepatotoxicity (ATDH) being a common and sometimes severe ADR. This study aimed to investigate the association between polymorphisms in two nuclear receptor genes, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), and the risk of ATDH in a Chinese population. Subjects with or without hepatotoxicity during anti-TB treatment were recruited. DNA was extracted from peripheral blood and genotypes of the selected single nucleotide polymorphisms (SNPs) were determined by using the improved multiplex ligation detection reaction technique. Three genetic models (additive, dominant, and recessive) as well as haplotype, SNP-SNP interaction analyses were used to evaluate the genetic risk of ATDH. A total of 502 subjects (203 ATDH and 299 non-ATDH) were enrolled. The results showed that the minor allele of rs7643645 and the H0010001 haplotype in PXR were associated with decreased risk of ATDH, suggesting that drug-metabolizing enzymes regulated by PXR are involved in the pathogenesis of ATDH. More studies are required to verify this result.

Association of TLR8 and TLR9 polymorphisms with tuberculosis in a Chinese Han population: a case-control study.

BACKGROUND: Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population. METHODS: Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis. RESULTS: The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37-0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11-20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10-2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07-2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41-0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was< 1%. CONCLUSIONS: Our findings in two independent samples indicated that SNPs in TLR8 and TLR9 were associated with the development of TB, and highlight that SNPs may have different effects on disease pathogenesis and progression.

Association between tobacco smoking and drug-resistant tuberculosis.

BACKGROUND: Tobacco smoking is a risk factor for tuberculosis but little is known about the relationship between tobacco smoking and drug-resistant tuberculosis (DR-TB). We undertook a systematic review and meta-analysis to quantitatively assess the association between DR-TB and tobacco smoking. METHODS: We searched for relevant studies in the Ovid MEDLINE, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WANFANG, and WEIPU data-bases from inception to September 1, 2017. Results were expressed as odds ratios (ORs) with accompanying 95% CIs, and subgroup analyses were performed by study design, smoking type, DR-TB type, and multivariate analysis. RESULTS: Thirty-three studies related to tobacco smoking and DR-TB were included. We found substantial evidence that tobacco smoking is associated with an increased risk of DR-TB (OR 1.57, 95% CI 1.33-1.86). Associations were also found in subgroup analyses: for multidrug-resistant tuberculosis (OR 1.49, 95% CI 1.19-1.86) and for any DR-TB (OR 1.70, 95% CI 1.3-2.23); the pooled OR was 1.45 (95% CI 1.11-1.90) for current smoking, 2.25 (95% CI 1.46-3.47) for past smoking, and 1.56 (95% CI 1.22-1.98) for smoking history; and similar ORs were also observed in study design and multivariate analysis subgroup analysis. CONCLUSION: This study demonstrated that tobacco smoking is an independent risk factor for DR-TB.

Polymorphisms in Toll-Like Receptor 10 and Tuberculosis Susceptibility: Evidence from Three Independent Series.

Background: The toll-like receptor 2 (TLR2)-mediated immune response is critical for host defense against Mycobacterium tuberculosis. There is evidence that TLR10, a TLR2 signaling modulator, may be involved in progression of tuberculosis (TB). Methods: Using a self-validating case-control design, we tested for an association between seven TLR10 polymorphisms and susceptibility to TB in three independent series with two distinct populations. Single-nucleotide polymorphism (SNP) genotypes were determined by the SNPscanTM method. Three genetic models (additive, dominant, and recessive) as well as multiple-SNP score analyses were used to evaluate the risk of TB associated with the TLR10 SNPs. Results: By comparing TB patients with healthy controls, we observed two SNPs (rs11466617 and rs4129009) that were associated with decreased risk of TB in the Tibetan population, but did not in the Chinese Han population. Further analysis demonstrated that the rs11466617 Chengdu cohort genotype served as a protective factor against the progression of latent TB infection (LTBI) to active TB under the recessive model. None of the SNPs were significantly different in comparisons of TB-uninfected people with LTBI individuals. Additionally, when the underlying four TB-associated loci were considered together in a multiple-SNP score analysis, we observed an allele dose-dependent decrease in TB risk in Tibetans. Conclusion: Variants of TLR10 may show an ethnic specificity on susceptibility to TB in Tibetan individuals. rs11466617 affected the susceptibility to progress from LTBI to active TB disease, but was not associated with the establishment of LTBI after M. tuberculosis exposure. More studies are needed to verify this genetic epidemiological result and unravel the role of TLR10 SNPs in the pathogenesis of TB.

Bone marrow granulomas in a high tuberculosis prevalence setting: A clinicopathological study of 110 cases.

Granulomas were reported in 0.3% to 3% of bone marrow biopsies. The aim of the study was to evaluate the incidence and etiology of bone marrow granulomas (BMGs) in the West China Hospital, which located at a high tuberculosis (TB) prevalence area in China.A retrospective case review was performed on 11,339 bone marrow biopsies at the West China Hospital of Sichuan University between January 2011 and December 2015. Cases with BMGs were retrieved and their clinical data and histopathological features were collected, examined, and analyzed.Out of 11,339, 110 cases showed granulomatous lesions in the bone marrow biopsies (0.97%). Etiologies were indentified in 80 cases (72.8%), with infections being the most common (64.5%), following by malignancies (4.5%) and autoimmune diseases (3.6%). Among infectious cases, 87.32% (62/71) cases were diagnosed as TB, a positive acid-fast stain or/and polymerase chain reaction (PCR) result for mycobacterium TB DNA fragment amplification was obtained for 35 cases. In 30 cases (27.27%), a definite diagnosis could not be established.In a TB high prevalence region in China, with a combined histological, clinical, serological, and molecular approach, we were able to clarify the cause in 72.73% of the bone marrow granulomatous cases. TB is the most common underlying etiologies. Therefore, acid-fast stain and quantitative PCR for mycobacterium TB DNA amplification are recommended as a routine for bone marrow biopsies in TB high prevalence regions.

Association of UGT2B7 polymorphisms with risk of induced liver injury by anti-tuberculosis drugs in Chinese Han.

Anti-tuberculosis drug-induced liver injury (ATLI) is common during the treatment of tuberculosis (TB). As an important enzyme in the metabolism of many drugs, UGT2B7 (uridine diphosphate glucuronyl transferase 2B7) was associated with drug-induced liver disorder. This study investigated the association between the polymorphisms of UGT2B7 and ATLI in Chinese Han. Totally, 280 newly diagnosed TB patients had been followed up for 3 months after the prescription of anti-TB therapy. Tag-single-nucleotide polymorphism (tag-SNPs) (rs10028494 and rs7668282) were genotyped with the MassARRAY platform. The associations between tag-SNPs and ATLI risk were analyzed by logistic regression analysis adjusting for confounding factors. In this prospective study, 33 patients were lost to follow-up, and 24 patients were diagnosed with ATLI and considered as the case group. The remaining 223 subjects without ATLI were considered as the control group. No significant association was observed in allele and genotype frequencies of UGT2B7 between the two groups. This study is the first attempt to investigate the association of genetic polymorphisms of UGT2B7 with ATLI in Chinese Han. There is no significant association between UGT2B7 polymorphisms and ATLI in Chinese Han.

Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population.

OBJECTIVES: Antituberculosis drug-induced hepatotoxicity (ATDH) remains a common and severe challenge in tuberculosis (TB) chemotherapy. A growing number of studies have revealed that genetic polymorphisms affect an individual's susceptibility to ATDH. The aim of this study was to explore the role of cytochrome P450 family 2 subfamily B member 6 (CYP2B6) gene polymorphisms in the development of ATDH in Chinese TB patients. METHODS: CYP2B6*6 genotypes were determined in TB patients with and without ATDH. Association between polymorphisms and risk of ATDH was estimated by multiple logistic regression analysis. RESULTS: A total of 343 eligible TB patients (166 with ATDH; 177 without ATDH) were included in this study. Analysis of all subjects revealed no statistical differences in genotype distribution between the two groups. However, the CYP2B6 *6/*6 genotype was significantly associated with decreased risk of ATDH in the male subgroup (P=0.039, OR=0.097, 95% CI: 0.011-0.885). Furthermore, in male patients, the presence of the CYP2B6*6 allele was significantly higher in the non-ATDH group compared with the ATDH group (26.2% vs. 15.5%, P=0.020, OR=0.522, 95% CI: 0.301-0.903). CONCLUSIONS: This study is the first to demonstrate an association between CYP2B6 polymorphisms and the risk of ATDH in the Chinese population. We have shown that males who have the CYP2B6 *6/*6 genotype may be less susceptible to the development of ATDH. Further studies are required to confirm this genetic association result.

Analysis of silent information regulator 1 (SIRT1) gene polymorphisms in antituberculosis- drug-induced hepatotoxicity in a prospective cohort study.

OBJECTIVE: Antituberculosisdrug-induced hepatotoxicity (ATDH) is a common and sometimes serious side effect related to tuberculosis (TB) treatment. A number of risk factors and host genetics contribute to the development of ATDH. However, genetic factors of ATDH remain to be identified. Silent Information Regulator 1 (SIRT1), an essential metabolism gene, was proved to be involved in ATDH in mice. The aim of this investigation was to study the association between ATDH and tag-single nucleotide polymorphisms (tag-SNPs) of the SIRT1 gene in a prospective cohort study in patients with TB. METHODS: 280 newly diagnosed TB patients were recruited in this study before starting first line anti-TB treatment and were followed up for 3 months after initiating anti-TB therapy. The tag-SNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese Beijing. Genotyping was performed by polymerase chain reaction (PCR) and the Sequenom MassARRAY iPLEX platform. RESULTS: 24 (9.8%) of the 245 patients included in the final analysis developed hepatotoxicity during the following up period. No significant differences in the allele, genotype, or haplotype frequency distributions of the tag- SNPs (rs7069102, rs2273773, rs4746720) of the SIRT1 gene were identified between the ATDH and non-ATDH groups (all p > 0.05). CONCLUSIONS: The SIRT1 gene may not contribute to the risk for developing hepatotoxicity during anti-TB treatment in the Han Chinese population.