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Tang S.-W.,Peking University | Lv X.-Z.,Peking University | Zhang Y.,Peking University | Wu S.-S.,Peking University | And 7 more authors.
Journal of Clinical Pharmacy and Therapeutics | Year: 2012

What is Known and Objective: The pathogenic mechanism of antituberculosis drug-induced hepatotoxicity (ATDH) is thought to involve drug-metabolizing enzymes including N-acetyl transferase2 (NAT2), cytochrome P4502E1 (CYP2E1) and glutathione S-transferase (GST) M1, T1. The associations between genetic polymorphisms of those genes and ATDH have been reported but with inconsistent results. Moreover, most studies were hospital-based retrospective studies and not prospective. We aimed to investigate possible associations of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms with ATDH using a more robust case-control study nested in a population-based prospective antituberculosis treatment cohort. Methods: A total of 4304 patients with smear-positive tuberculosis (TB) who received standard short-course chemotherapy were monitored for 6-9 months. Incidence density sampling method was adopted to select controls and 4: 1 matched with each ATDH cases by age (±5 years), sex, treatment history, disease severity and drug dosage. The CYP2E1, GSTM1 and GSTT1 polymorphisms were genotyped using PCR-RFLP and multiplex PCR methods. Conditional logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. Results and Discussion: A total of 89 ATDH cases and 356 controls were included in this study. There was no statistically significant association between CYP2E1 RsaI c1/c1 genotype or DraI C/C genotype and ATDH (OR = 0.99, 95% CI:0.62-1.59; OR = 1.13, 95% CI: 0.40-3.20, respectively) compared with CYP2E1 RsaI c1/c2 or c2/c2 genotypes or DraI D/D genotype, or between GSTM1/GSTT1 null genotypes and ATDH (OR = 1.22, 95% CI: 0.76-1.96; OR = 0.96, 95% CI: 0.60-1.52, respectively) compared with non-null genotypes. What is new and Conclusion: This is the first study of the involvement of CYP2E1, GSTM1 and GSTT1 genetic polymorphisms in ATDH using a nested case-control population-based prospective cohort design. We could not confirm positive associations of genetic polymorphisms of CYP2E1 RsaI, CYP2E1 DraI, GSTM1 null and GSTT1 null with ATDH reported by various groups, in our Chinese TB population. © 2012 Blackwell Publishing Ltd.


Tang S.,Peking University | Tang S.,Nanjing Medical University | Lv X.,Peking University | Zhang Y.,Peking University | And 8 more authors.
PLoS ONE | Year: 2013

Objective: The pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort. Methods and Design: A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology. Results: Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis. Conclusion: Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population. © 2013 Tang et al.


Chen R.,Peking University | Wang J.,Peking University | Tang S.,Nanjing Medical University | Zhang Y.,McMaster University | And 8 more authors.
Tuberculosis | Year: 2015

Summary This study investigated the association between genetic variants in two hepatic uptake transporter genes (SLCO1B1 and SLC10A1) and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) in a Chinese cohort. The frequencies and distributions of single nucleotide polymorphisms (SNPs) and haplotypes of these genes were compared among 89 incident ATDH cases and 356 matched ATDH-free controls using a multivariate conditional logistic regression analysis. After correction for potential confounding factors, significant differences were found in polymorphism of rs4149014 under an addictive model (P = 0.008) and a recessive model (P = 0.016). The result of haplotype analysis suggested that patients carrying at least one SLCO1B1∗15 haplotype had a higher risk of ATDH (odds ratio (OR) = 1.74, 95% confidence intervals (CI): 1.04-2.90, P = 0.034) in comparison with those carrying SLCO1B1∗1a or SLCO1B1∗1b haplotypes. These findings indicate that genetic variants of SLCO1B1 are associated with the development of ATDH in Chinese population. © 2014 Elsevier Ltd. All rights reserved.


Wang J.,Peking University | Chen R.,Peking University | Tang S.,Peking University | Tang S.,Nanjing Medical University | And 8 more authors.
PLoS ONE | Year: 2015

Objectives: To investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH) in Chinese Han population. Methods: The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (±5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH. Results: A total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107), STAT3 (rs1053004, rs1053023, rs1053005) and HSPA1L (rs2227956). In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004) haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001). Conclusion: This study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings. © 2015 Wang et al.


Lv X.,Peking University | Tang S.,Peking University | Xia Y.,National Center for Control and Prevention | Zhang Y.,Peking University | And 10 more authors.
Annals of Hepatology | Year: 2012

Background. Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the most prevalent and serious adverse drug reactions in the course of anti-tuberculosis (TB) treatment. Some researchers suggested that determination of N-acetyltransferase 2 (NAT2) genotype may be clinically useful to identify patients at high risk of developing ATDH. Aim. To evaluate whether the NAT2 genotype could be as a predictor for ATDH in Chinese community TB population. Material and methods. A total of 4304 community-based TB patients were followed up six to nine months prospectively. A nested case-control study was designed. Each ATDH case was 1:4 matched with controls by age (within 5 years old), gender, treatment history, disease severity and drug dosage. The polymorphisms of NAT2 were determined using polymerase chain reaction with restriction fragment length polymorphism. Conditional Logistic regression model was used to calculate odds ratio (OR) and 95% confidence interval (CI), as well as corresponding P-values. Results. A total of 89 ATDH cases and 356 controls were included in this study. Allele frequency of NAT2*5, NAT2*6 and NAT2*7 in cases and controls were 4.5 and 3.2%, 25.3 and 26.5%, and 13.5 and 13.5%, respectively. Frequencies of genotypes and alleles of NAT2*5, NAT2*6 and NAT2*7 did not differ significantly between cases and controls. The OR of intermediate acetylator and slow acetylator compared with rapid acetylator was 1.040 (95%CI 0.616-1.758) and 0.990 (95%CI 0.509-1.925), respectively. The NAT2 haplotype distribution in cases was similar to controls. Conclusions. In conclusion, we did not find significant association between NAT2 genotype and ATDH in community-based Chinese population. It may be deficient to take NAT2 genotype as a predictor for ATDH in Chinese community TB patients.


PubMed | Beijing Institute for Tuberculosis Control, McMaster University, Nanjing Medical University, Peking University and Center for Tuberculosis Control and Prevention
Type: Journal Article | Journal: PloS one | Year: 2015

To investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH) in Chinese Han population.The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH.A total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107), STAT3 (rs1053004, rs1053023, rs1053005) and HSPA1L (rs2227956). In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004) haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001).This study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings.


PubMed | McMaster University, Nanjing Medical University, Peking University, Center for Drug Reassessment and 3 more.
Type: Journal Article | Journal: Tuberculosis (Edinburgh, Scotland) | Year: 2014

This study investigated the association between genetic variants in two hepatic uptake transporter genes (SLCO1B1 and SLC10A1) and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) in a Chinese cohort. The frequencies and distributions of single nucleotide polymorphisms (SNPs) and haplotypes of these genes were compared among 89 incident ATDH cases and 356 matched ATDH-free controls using a multivariate conditional logistic regression analysis. After correction for potential confounding factors, significant differences were found in polymorphism of rs4149014 under an addictive model (P = 0.008) and a recessive model (P = 0.016). The result of haplotype analysis suggested that patients carrying at least one SLCO1B1*15 haplotype had a higher risk of ATDH (odds ratio (OR) = 1.74, 95% confidence intervals (CI): 1.04-2.90, P = 0.034) in comparison with those carrying SLCO1B1*1a or SLCO1B1*1b haplotypes. These findings indicate that genetic variants of SLCO1B1 are associated with the development of ATDH in Chinese population.


Lv X.,Peking University | Tang S.,Peking University | Tang S.,Nanjing Medical University | Xia Y.,National Center for Tuberculosis Control and Prevention | And 13 more authors.
PLoS ONE | Year: 2013

Background:More than 1 million tuberculosis (TB) patients are receiving directly observed treatment strategy (DOTS) therapy in China every year. As to the profile of adverse drug reactions (ADRs) due to DOTS therapy, no consensus has been reached. There is no report regarding ADRs due to DOTS therapy with a large Chinese TB population. This study aimed to determine the incidence and prognosis of ADRs due to DOTS therapy, and to evaluate their impact on anti-TB treatment in China.Methods:A prospective population-based cohort study was performed during 2007-2008. Sputum smear positive pulmonary TB patients who received DOTS therapy were included and followed up for six to nine months in 52 counties of four regions in China. The suspected ADRs were recorded and reviewed by Chinese State Food and Drug Administration.Results:A total of 4304 TB patients were included in this study. 649 patients (15.08%) showed at least one ADR and 766 cases in total were detected. The incidence (count) of ADR based on affected organ was: liver dysfunction 6.34% (273), gastrointestinal disorders 3.74% (161), arthralgia 2.51% (108), allergic reactions 2.35% (101), neurological system disorders 2.04% (88), renal impairment 0.07% (3) and others 0.05% (2). Most cases of ADRs (95%) had a good clinical outcome, while two with hepatotoxicity and one with renal impairment died. Compared with patients without ADRs, patients with ADRs were more likely to have positive smear test results at the end of the intensive phase (adjusted OR, 2.00; 95%CI, 1.44-2.78) and unsuccessful anti-TB outcomes (adjusted OR, 2.58; 95%CI, 1.43-4.68).Conclusions:The incidence of ADRs due to DOTS therapy was 15.08%. Those ADRs had a substantial impact on TB control in China. This highlighted the importance of developing strategies to ameliorate ADRs both to improve the quality of patient care and to control TB safely. © 2013 Lv et al.


Xia Y.Y.,Peking University | Hu D.Y.,Centers for Disease Control and Prevention | Liu F.Y.,Center for Disease Control and Prevention in Guangxi Zhuang Autonomous Region | Wang X.M.,Centers for Disease Control and Prevention | And 14 more authors.
BMC Public Health | Year: 2010

Background. More than 1 million tuberculosis (TB) patients are receiving the standard anti-TB treatment provided by China National Tuberculosis Prevention and Control Scheme (CNTS) in China every year. Adverse reactions (ADRs) induced by anti-TB drugs could both do harm to patients and lead to anti-TB treatment failure. The ADACS aimed to explore ADRs' incidences, prognoses, economical and public health impacts for TB patients and TB control, and build a DNA bank of TB patients. Methods/Design. Multiple study designs were adopted. Firstly, a prospective cohort with 4488 sputum smears positive pulmonary tuberculosis patients was established. Patients were followed up for 6-9 months in 52 counties of four regions. Those suspected ADRs should be checked and confirmed by Chinese State Food and Drug Administration (SFDA). Secondly, if the suspected ADR was anti-TB drug induced liver injury (ATLI), a nested case-control study would be performed which comprised choosing a matched control and doing a plus questionnaire inquiry. Thirdly, health economical data of ADRs would be collected to analyze financial burdens brought by ADRs and cost-effectiveness of ADRs' treatments. Fourthly, a drop of intravenous blood for each patient was taken and saved in FTA card for DNA banking and genotyping. Finally, the demographic, clinical, environmental, administrative and genetic data would be merged for the comprehensive analysis. Discussion. ADACS will give an overview of anti-TB drugs induced ADRs' incidences, risk factors, treatments, prognoses, and clinical, economical and public health impacts for TB patients applying CNTS regimen in China, and provide suggestions for individualized health care and TB control policy. © 2010 Xia et al; licensee BioMed Central Ltd.


Wu S.,Peking University | Xia Y.,Center for Tuberculosis Control and Prevention | Lv X.,Peking University | Zhang Y.,Peking University | And 10 more authors.
BMC Public Health | Year: 2012

Background: Data on effect of regular liver function monitoring during anti-TB treatment is limited in China. This study aimed to evaluate the effects of scheduled liver function monitoring on identification of asymptomatic liver damage and anti-TB treatment outcomes during anti-TB treatment. Methods: A retrospective analysis was performed based on a national-level cohort study. A total of 273 patients developing liver dysfunction were divided into two groups, 111 patients who were diagnosed through scheduled liver function test within two months after initiation of anti-TB treatment formed scheduled monitoring group, others who were diagnosed due to developing symptoms formed passive detection group (n = 162). The two groups were compared through clinical features, prognosis of liver dysfunction and impact on anti-TB treatment using propensity score weighting analysis. Results: 33.3% of 273 patients did not have any clinical symptoms, including 8 with severe hepatotoxicity. 1.8% in scheduled monitoring group and 11.1% in passive detection group required hospitalization (P = 0.004). Regarding the prognosis of liver dysfunction, most patients recovered, no death happened in scheduled monitoring group while 3 died in passive detection group. In terms of impact on anti-TB treatment, 35.1% in scheduled monitoring group and 56.8% in passive detection group changed their anti-TB treatment (P = 0.001). Conclusions: Scheduled monitoring is effective in identifying asymptomatic liver damage, reducing hospitalization rate and improving compliance of anti-TB treatment. © 2012 Wu et al.; licensee BioMed Central Ltd.

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