Risk Of Anti-tuberculosis Drug-induced Hepatotoxicity Research Articles

Association of Cytochrome P450 2E1 and N-Acetyltransferase 2 Genotypes with Serum Isoniazid Level and Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Cross-Sectional Study.

Anti-tuberculosis drug-induced hepatotoxicity can result from genetic polymorphism of the isoniazid (INH) metabolizing enzyme. This study aimed to determine the effect of genetic polymorphism of N-acetyltransferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) genes on serum isoniazid level and drug-induced hepatotoxicity. A cross-sectional study was conducted on 120 patients (with and without hepatotoxicity) with pulmonary tuberculosis from June 2019 to April 2022 in Tehran (Iran). High-performance liquid chromatography was used to measure the serum concentration of INH and acetylisoniazid (AcINH). NAT2 and CYP2E1 genotypes were determined using polymerase chain reaction and restriction fragment length polymorphism methods. Data were analyzed using SPSS software (version 22.0) with independent two-sample t test, Chi square test, or Fisher's exact test. P<0.05 was considered statistically significant. A total of 40 patients showed hepatotoxicity. The risk of anti-tuberculosis drug-induced hepatotoxicity was significantly higher in patients who are slow acetylator (SA) phenotype than in rapid or intermediate acetylator (P<0.001). NAT2*4/*4 genotypes were not found in patients with hepatotoxicity. The frequency of NAT2*5 and NAT2*6 haplotypes and serum INH concentration was significantly higher in patients with hepatotoxicity than in those without (P=0.003, P<0.001, and P<0.001, respectively). NAT2*4 haplotype was correlated with protection against hepatotoxicity. A combination of SA and CYP2E1 C1/C1 genotype was significantly associated with hepatotoxicity (P<0.001). Hepatotoxicity in Iranian patients with tuberculosis was confirmed due to the presence of NAT2 SA polymorphism. Determining NAT2 and CYP2E1 genotypes and/or INH concentration can be a valuable tool to identify patients susceptible to hepatotoxicity.

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.

NAT2 polymorphism and clinical factors that increase antituberculosis drug-induced hepatotoxicity.

Aim: Hepatotoxicity is a known adverse effect of antituberculosis drugs. The NAT2 gene polymorphism has been associated with an increased risk of antituberculosis drug-induced hepatotoxicity (ATDIH). Materials & methods: This study investigates the association of NAT2 polymorphism and clinical risk factors that may contribute to the development of ATDIH. The authors sequenced the NAT2 region of 33 tuberculosis patients who developed ATDIH and 100 tuberculosis patients who did not develop ATDIH during tuberculosis treatment. NAT2 haplotypes were inferred and NAT2 acetylator status was predicted from the combination of the inferred haplotypes. Multiple logistic regression was performed to identify possible factors that are associated with ATDIH. Results: The TT genotype of NAT2*13A and the AA genotype of NAT2*6B were found to be substantially linked with the risk of ATDIH, with odds ratios of 3.09 (95% CI: 1.37-6.95) and 3.07 (95% CI: 1.23-7.69), respectively. NAT2 slow acetylators are 3.39-times more likely to develop ATDIH. Factors that were associated with ATDIH include underlying diabetes mellitus (adjusted odds ratio[AOR]: 2.96; 95% CI: 1.05-8.37), pre-treatment serum bilirubin (AOR: 1.09; 95% CI: 1.02-1.16) and NAT2 slow acetylator (AOR: 3.77; 95% CI: 1.51-9.44). Conclusion: Underlying diabetes mellitus, having a higher baseline bilirubin and being a slow acetylator are identified as the risk factors associated with ATDIH among patients in Malaysia.

Association of ABCG2 polymorphisms with susceptibility to anti-tuberculosis drug-induced hepatotoxicity in the Chinese population

The accumulation of endogenous hepatotoxin protoporphyrin IX (PPIX) in the liver was proposed to be a novel mechanism of anti-tuberculosis drug-induced hepatotoxicity (ATDH). ATP-binding cassette transporter G2 (ABCG2) plays an important role in modulating PPIX concentrations. This study aimed to explore the role of ABCG2 genetic polymorphisms in the risk of ATDH in Chinese patients. A 1:4 matched case–control study was performed among 202 ATDH cases and 808 controls. Conditional logistic regression model was used to estimate the association between genotypes and the risk of ATDH by odds ratios (ORs) with 95% confidence intervals (CIs). Male patients with CC genotype of rs2622605 had an increased risk of ATDH (adjusted OR = 1.615, 95% CI: 1.119–2.332, p = 0.011). The peak value of alkaline phosphatase (ALP) was significantly higher in male patients with CC genotype of rs2622605 than in those with TT + TC genotype during antituberculosis treatment (102.0 U/L vs. 98.0 U/L, p = 0.029). This is the first attempt to evaluate the association between ABCG2 genetic variants and the risk of ATDH. Based on the 1:4 matched case–control study, the polymorphism at rs2622605 in the ABCG2 gene may be associated with the susceptibility to ATDH in Chinese male patients.

Relevance of gene polymorphisms of NAT2 and NR1I2 to anti-tuberculosis drug-induced hepatotoxicity

The recommended treatment regimen for tuberculosis is a combination of agents with antitubercular activity, during which hepatotoxicity is one of the most common side effects. In addition to the N-acetyltransferase 2 (NAT2) genotype, rs3814055 in nuclear receptor subfamily 1, group I, member 2 (NR1I2) has been demonstrated to be associated with anti-tuberculosis drug-induced hepatotoxicity (ATDH), but previous results have been inconsistent. A retrospective nested hospital-based case–control study was performed to investigate the association between genetic polymorphisms and the risk of ATDH. Fifteen genetic variants (13 SNPs and two null genotypes) in cytochrome P450 2E1, NR1I2, UDP-glucuronosyltransferase 1A1, NAT2, superoxide dismutase 1, superoxide dismutase 2, and glutathione S-transferases (GSTT1, GSTM1, GSTP1) were genotyped. Odds ratios with 95% confidence intervals were calculated with drug doses, body mass index comorbidity of diabetes mellitus, and baseline alanine transaminase value as covariates. Conditional logistic regression demonstrated that the NAT2 slow acetylation genotype and the T allele of rs3814055 in NR1I2 may contribute to susceptibility to ATDH. Stratified association analysis demonstrated that in NAT2 non-slow acetylators, the T allele of rs3814055 was a risk factor for ATDH, whereas the T allele did not increase the susceptibility to ATDH in slow acetylators.

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 genotypingand 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.

Hepatitis C Virus and Helicobacter pylori infections in Patients with Pulmonary Tuberculosis: A Prevalence based study in Southern Punjab, Pakistan

Aims and objectives: The control of pulmonary tuberculosis (PTB) mainly depends upon prompt diagnosis and effective treatment which can be hindered by co-infections affecting organs like gastrointestinal system and liver involved in drug bioavailability and metabolism. Among those, Helicobacter pylori (H. pylori) causes chronic gastritis leading to peptic ulcer and related gastric malignancies and liver malfunctions induced by Hepatitis C virus (HCV) co-infections increase the risk of anti-tuberculosis drug-induced hepatotoxicity. The rates of Hepatitis C virus and Helicobacter pylori infections seem to increase day by day in pulmonary tuberculosis patients which need proper investigation followed by timely control and prevention form disease. Methods: The hospital-based study was performed in the area of Southern Punjab, Pakistan. The Tehsil Headquarter hospital in the area, where the study was conducted contained TB Clinic. Inclusion and exclusion criteria of suspected patients of pulmonary tuberculosis included in the study. A total of 132 subjects were screened for PTB, HCV and H. pylori infections for finding the role of co-infection. The positive PTB subjects were screened for HCV and H. pylori infections. Both infections (H. pylori and HCV) were also found among TB patients. Results: A total of 52.27% were positive for PTB in which 50.72% and 17.39% cases were found in H. pylori and HCV infections respectively. H. pylori had increased rate of infection among PTB cases when compared with that of non-TB cases. HCV was also found to be associated with PTB when compared with non-TB cases. Non-significant gender and age-based differences were present, among study population. Among all PTB patients, HCV and H. pylori coinfections were also found in 5.8% patients in current study. Conclusions: Our study showed a high prevalence of HCV and H. pylori infections among PTB patients, which suggest that PTB patients must be screened for the two infections which might be helpful in the control of further complications during the treatment of PTB.

Collagen type XVIII alpha 1 chain (COL18A1) variants affect the risk of anti-tuberculosis drug-induced hepatotoxicity: A prospective study.

BackgroundThe role of collagen type XVIII alpha 1 chain (COL18A1) in anti‐tuberculosis drug‐induced hepatotoxicity (ATDH) has not been reported. This study aimed to explore the association between of COL18A1 variants and ATDH susceptibility.MethodsA total of 746 patients were enrolled in our study from December 2016 to April 2018, and all subjects in the study signed an informed consent form. The custom‐by‐design 2x48‐Plex SNPscanTM kit was used to genotype all selected 11 SNPs. Categorical variables were compared by chi‐square (χ2) or Fisher's exact test, while continuous variables were compared by Mann‐Whitney's U test. Plink was utilized to analyze allelic and genotypic frequencies, and genetic models. Multivariate logistic regression analyses were used to adjust potential factors. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were also calculated.ResultsAmong patients with successfully genotyping, there were 114 cases and 612 controls. The mutant A allele of rs12483377 conferred the decreased risk of ATDH (OR = 0.13, 95%CI: 0.02–0.98, P = 0.020), and this significance still existed after adjusting age and gender (P = 0.024). The mutant homozygote AA genotype of rs12483377 was associated with decreased total protein levels (P = 0.018).ConclusionOur study first revealed that the A allele of COL18A1 rs12483377 was associated with the decreased risk of ATDH in the Western Chinese Han population, providing new perspective for the molecular prediction, precise diagnosis, and individual treatment of ATDH.

NR1I2 genetic polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity: A systematic review and meta-analysis.

Anti‐tuberculosis drug‐induced hepatotoxicity (ATDH) is a serious adverse drug reaction. Conflicting results have been obtained regarding the associations of nuclear receptor subfamily 1 group I member 2 (NR1I2) gene polymorphisms on susceptibility to ATDH. Therefore, we aimed to evaluate the associations using a systematic review/meta‐analysis approach. PubMed, Medline, Cochrane Library, Web of Science and SinoMed databases were searched for all eligible studies from inception to June 10, 2020. Pooled adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were employed to evaluate the strength of the association between the NR1I2 polymorphisms and the risk of ATDH. Subgroup analysis was performed by region of origin, and meta‐regression were performed to detect potential sources of heterogeneity. A total of five case‐control studies involving 572 cases and 1867 controls were identified. Fourteen SNPs in the NR1I2 gene have been reported, and the most heavily studied SNPs were rs3814055 and rs7643645. The pooled estimates did not exhibit any significant associations between SNPs rs3814055 and rs7643645 and the risk of ATDH (rs3814055: dominant model, OR = 1.00, 95% CI: 0.82‐1.22, P = 1.00; recessive model, OR = 1.17, 95% CI: 0.76‐1.78, P = .48; rs7643645: dominant model, OR = 1.04, 95% CI: 0.64‐1.68, P = .89; recessive model, OR = 0.98, 95% CI: 0.65‐1.49, P = .93). Subgroup analysis obtained similar negative results in Chinese patients, and the diagnostic criteria of ATDH may be the source of heterogeneity. Based on the meta‐analysis described in this report, we did not observe any association between NR1I2 gene polymorphisms and ATDH susceptibility. However, this conclusion should be interpreted with caution due to the low number of studies and the relatively small sample size.

Seroprevalence of HCV and HIV Antibodies in Tuberculosis Confirmed Patients in Ekiti State, Nigeria

This study was conducted to determine the seroprevalence of HCV and HIV antibodies in TB confirmed patient attending the Federal Medical Centre (FMC), Ido Ekiti, Ekiti State, Nigeria. A total of 500 tuberculosis confirmed patients were selected by random sampling. Their blood samples were collected and assayed for HCV and HIV antibodies using Clinotech diagnostic Anti-HCV detection test and Abbot determine HIV ½ in conjunction with Chembio HIV ½ STAT-PAK assay kit respectively. Out of 500 TB patients tested, 10(2.0%), 21(4.2%) and 3(0.6%) tested positive to HCV, HIV, and HCV/HIV antibodies respectively. Age group 36-45 was the most prevalence of HCV, HIV, and HCV/HIV antibodies with P-value 0.000, 0.000 and 0.002 respectively. The associated risk factors were alcoholism 14 (45.2%), being the highest identified risk factor, followed by previous unprotected sex, multiple sex partner, previous blood donor, previous transfusion, tattoos, and history of the Sexually transmitted disease being the least risk factor 3 (9.68%). The degree of disparity in regards to HCV, HIV and co-exists of HCV/HIV antibodies between 302 male and 198 female that participated were not statistically significant. (P-value 0.531, 0.549,and 0.824 for HCV, HIV and HCV/HIV antibodies respectively).These findings confirmed that both HCV and HIV can co-exist in TB patients, and may increase the risk of antituberculosis drug-induced hepatotoxicity, if overlooked, there will be a greater risk for TB patients, and these infections will continue to spread through the associated risk factors. However, in managing the TB patients, there is a need to screen for Anti- HCV, as it has been for HIV antibody.

Association of Genetic Polymorphism of GSTM1 and GSTT1 with the Susceptibility to Antituberculosis Drug-induced Hepatotoxicity in Chinese Population

Objective To investigate the relationship between the polymorphism of glutathione S transferase M1, T1(GSTM1, GSTT1) gene and the susceptibility to antituberculosis drug induced hepatotoxicity (ATDH) in patients with tuberculosis. Methods GSTM1 and GSTT1 gene polymorphisms in patients with or without liver toxicity after antituberculous treatment were analyzed using multiple PCR method. Results In ATDH group and control group, the proportion of GSTM1 gene deletion was 58.0% and 50.7%respectively, and the difference was not statistically signifcant (OR=1.322, 95%CI=0.921~1.878), the frequencies of GSTT1 deletion were 46.3% and 49.3%, respectively, and there was no signifcant difference between them. There was no signifcant difference in frequency of GSTM1 and GSTT1 variation between case group and control group (P&gt; 0.05), and no synergistic effect of those two gene polymorphism were detected in the occurrence of antituberculosis drug-induced hepatotoxicity. Conclusion The polymorphisms of GSTM1 and GSTT1 genes may not be associated with the risk of ATDH.

Rs1800796 of the IL6 gene is associated with increased risk for anti-tuberculosis drug-induced hepatotoxicity in Chinese Han children

Previous studies have revealed the important contribution of the immune response and oxidative stress to the development of anti-tuberculosis drug-induced hepatotoxicity (ATDH). To investigate whether single-nucleotide polymorphisms (SNPs) of the cytokine gene interleukin-6 (IL6) and oxidative stress genes xanthine dehydrogenase/oxidase (XO) and inducible nitric oxide synthase (NOS2) were associated with susceptibility to ATDH, we performed a case-control study including 41 ATDH cases and 116 ATDH-free controls in Chinese Han children. Significant difference in the allele distribution of rs1800796 in the IL6 gene was observed between the case and control groups, and the G allele of rs1800796 was associated with an increased risk for ATDH (odds ratio: 2.48, 95%CI: 1.40–4.40, P = 0.002). However, no significant difference was observed in the allele and genotype distributions of the other SNPs of the IL6, XO and NOS2 genes between the case and control groups after Bonferroni correction. In addition, no interaction was found between all selected SNPs. These findings indicate that genetic variants of the IL6 gene might contribute to the development of ATDH in the Chinese Han pediatric population.

Rs7574865 polymorphism of STAT4 and risk of anti-tuberculosis drug-induced hepatotoxicity in Chinese Han

Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is the most frequent, and potentially fatal adverse effect in the treatment of tuberculosis (TB). The rs7574865 polymorphism in the signal transducer and activator of transcription 4 gene (STAT4) was reported to be associated with drug-induced liver injury. However, there was no study aimed to this association in Chinese patients. The aim of this study was to investigate the influence of STAT4 polymorphisms on the susceptibility to ATDH in a Chinese Han population. A total of 280 TB patients with the prescription of anti-TB therapy, of Chinese Han origin, were enrolled. They were followed up for 3 months and demographic, clinical, laboratory and therapeutic data at each visit were collected. Two single nucleotide polymorphisms (SNPs) (rs7574865 and rs7582694) of STAT4 were genotyped with the MassARRAY platform. The associations between SNPs and ATDH risk were analyzed by logistic regression adjusting for confounding factors. A total of 24 patients were diagnosed with ATDH and considered as the case group, and 33 patients were lost to follow-up; the remaining 223 subjects without ATDH were considered as the control group. There was strong linkage disequilibrium (LD) between rs7574865 and rs7582694 (r2 = 0.928 and D′ = 1). No significant association was found between SNPs or haplotypes of STAT4 and ATDH after correction for confounding factors. This prospective study is the first to investigate the association of genetic polymorphisms of STAT4 and ATDH in Chinese individuals. There was no significant association between the rs7574865 of STAT4 and ATDH in a Chinese Han population.

HLA-DQ B1*0201 and A1*0102 Alleles Are Not Responsible for Antituberculosis Drug-Induced Hepatotoxicity Risk in Spanish Population.

To evaluate the role of human leukocyte antigen (HLA) class II DQB1*0201 and DQA1*0102 in the risk of antituberculosis drug (ATD)-induced hepatotoxicity (ATDH) in a cohort of tuberculosis patients of Caucasian origin from Spain. Matched case-control study including active tuberculosis (TB) patients from Spain (Caucasian) treated with first-line ATD (Isoniazid, Rifampin, and Pyrazinamide). Presence or absence of HLA class II DQB1*0201 and DQA1*0102 alleles were compared between cases and controls. We included 110 TB patients, 55 ATDH cases, and 55 sex-matched controls. The analysis of the presence of HLA-DQB1*0201 and HLA-DQA*0102 did not show significative differences between both groups [presence of HLA-DQB1*0201 53.6% of the cases vs. 45.4% of the controls, OR: 1.63 95% CI (0.62-4.52) p = 0.38; presence of HLA-DQA*0102 7.5% of cases vs. 20% of controls, OR: 0.36 95% CI (0.08-1.23) p = 0.12]. After multivariate logistic regression analysis including in the model, other potential risk factors of hepatotoxicity HLA class II DQB1*0201 and DQA1*0102 alleles were not found significantly associated with the risk of development ATDH. We could not demonstrate an association between HLA-DQA1*0102 and HLA-DQB1*0201 with the risk of ATDH in this Caucasian population of Spanish origin.

Update meta-analysis of the CYP2E1 RsaI/PstI and DraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies.

Several studies have investigated the association of the CYP2E1 RsaI/PstI and/or DraI polymorphisms with susceptibility to antituberculosis drug-induced hepatotoxicity (ATDH), but the results have been inconsistent. Therefore, we performed a large meta-analysis to determine a more precise estimation of this relationship. The PubMed, EMBASE, China National Knowledge Infrastructure and Chinese Biomedical Literature databases were systematically searched to identify relevant studies. Meta-analyses based on the entire population and subgroups were performed to examine the association between CYP2E1 polymorphisms and susceptibility to ATDH. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of the associations. Twenty-six studies with a total of 7423 participants were analysed. The overall ORs of relevant studies demonstrated that the CYP2E1 RsaI/PstI C1/C1 genotype was associated with an elevated risk of ATDH (OR = 1·32, 95% CI 1·03-1·69, P = 0·027), but for the DraI polymorphism there was no increase in risk (OR = 1·05, 95% CI 0·80-1·37, P = 0·748). In subgroup analyses of the RsaI/PstI polymorphism, significant results were found in East Asians, patients who used isoniazid + rifampicin + pyrazinamide + ethambutol and patients with twice the upper limit of normal as the minimum standard for defining ATDH. This meta-analysis suggests that there is an increased risk of ATDH in individuals carrying the C1/C1 genotype of the CYP2E1 RsaI/PstI polymorphism. However, no association was found for the DraI polymorphism.

Association of polymorphisms in drug transporter genes (SLCO1B1 and SLC10A1) and anti-tuberculosis drug-induced hepatotoxicity in a Chinese cohort

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.

Interleukin-4 and interleukin-10 polymorphisms and antituberculosis drug-induced hepatotoxicity in Chinese population.

Evidence demonstrates that the delicate balance between pro- and anti-inflammatory cytokines determines the further progress to severe injury or recovery. Therefore, understanding which cytokines are associated with the development of drug-induced hepatotoxicity (DIH) might guide the prevention and therapeutic direction. Some polymorphisms of cytokine genes have been reported to be associated with DIH involving interleukin-4 (IL-4), interleukin-10 (IL-10) and tumour necrosis factor-α (TNF-α); however, these studies are still scanty with inconsistent results. In addition, most of these associations have not been investigated in antituberculosis drug-induced hepatotoxicity (ATDH) patients with the exception of TNF-α polymorphisms. Therefore, we aimed to investigate the association between IL-4 and IL-10 gene polymorphisms with the risk of ATDH in a Chinese 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 (±5years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-4 and IL-10 were determined by TaqMan single nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model. A total of 89 incident ATDH cases and 356 controls undergoing antituberculosis treatment were included. Six SNPs were selected for genotyping, which were rs2243289, rs2243250 and rs2070874 for IL-4, and rs1800896, rs1800871 and rs1800872 for IL-10. No significant difference was observed in genotypes frequencies of the six selected SNPs between case and control group, and the distributions of IL-4 and IL-10 haplotypes were similar in ATDH patients and controls. This study is the first attempt to evaluate the associations of genetic polymorphisms of IL-4 and IL-10 genes with ATDH using a nested case-control study design. We provide preliminary evidence that there is no statistically significant association between IL-4 and IL-10 genotypes/haplotypes and the risk of ATDH in Chinese population.

Improvements in Algorithms for Phenotype Inference: The NAT2 Example

Numerous studies have analyzed the impact of N-acetyltransferase 2 (NAT2) polymorphisms on drug efficacy, side effects as well as cancer risk. Here, we present the state of the art of deriving haplotypes from polymorphisms and discuss the available software. PHASE v2.1 is currently considered a gold standard for NAT2 haplotype assignment. In vitro studies have shown that some slow acetylation genotypes confer reduced protein stability. This has been observed particularly for G191A, T341C and G590A. Substantial ethnic variations of the acetylation status have been described. Probably, upcoming agriculture and the resulting change in diet caused a selection pressure for slow acetylation. In recent years much research has been done to reduce the complexity of NAT2 genotyping. Deriving the haplotype from seven SNPs is still considered a gold standard. However, meanwhile several studies have shown that a two-SNP combination, C282T and T341C, results in a similarly good distinction in Caucasians. However, attempts to further reduce complexity to only one 'tagging SNP' (rs1495741) may lead to wrong predictions where phenotypically slow acetylators were genotyped as intermediate or rapid. Numerous studies have shown that slow NAT2 haplotypes are associated with increased urinary bladder cancer risk and increased risk of anti-tuberculosis drug-induced hepatotoxicity. A drawback of the current practice of solely discriminating slow, intermediate and rapid genotypes for phenotype inference is limited resolution of differences between slow acetylators. Future developments to differentiate between slow and ultra-slow genotypes may further improve individualized drug dosing and epidemiological studies of cancer risk.

The association between CYP2E1 polymorphisms and hepatotoxicity due to anti-tuberculosis drugs: A meta-analysis

BackgroundAlthough there have been previous studies on the potential association between cytochrome P450 2E1 (CYP2E1) polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH), the results have generally been controversial. MethodsWe searched Medline/PubMed, EMBASE, Web of Science, and the Cochrane Library using the following key words: cytochrome P450 2E1, CYP2E1, polymorphism, tuberculosis and TB. The strength of the association between the CYP2E1 PstI/RsaI and DraI polymorphism and ATDH risk as measured by odds ratios (OR) with 95% confidence intervals (CIs) was studied. ResultsCompared with the wild genotype (c1/c1), the OR of ATDH was 1.41 (95% CI: 1.1–1.82, P=0.007) for the PstI/RsaI polymorphism, and 0.78 (95% CI: 0.51–1.18, P=0.23) for the DraI polymorphism. Compared with individuals with N-acetyltransferase 2 (NAT2) fast or intermediate acetylator genotype and c1/c1 genotype patients who were NAT2 slow acetylators and carried the high activity CYP2E1 c1/c1 genotype had higher risk for ATDH (OR=3.10, P<0.0001). ConclusionThe present meta-analysis indicates that the CYP2E1 c1/c1 genotype may be a risk factor for ATDH, and the concomitant presence of the slow acetylator NAT2 genotype may further increase this risk.

Hepatitis C Virus Co-Infection Increases the Risk of Anti-Tuberculosis Drug-Induced Hepatotoxicity among Patients with Pulmonary Tuberculosis

BackgroundThe country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection. PurposeTo determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy.MethodsProspective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity) were obtained at baseline and monthly during treatment. ResultsAmong 326 study patients with culture-confirmed TB, 68 (21%) were HCV co-infected, 14 (4.3%) had chronic hepatitis B virus (HBV) infection (hepatitis B virus surface antigen positive [HBsAg+]), and 6 (1.8%) were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio [aHR]=3.2, 95% CI=1.6-6.5) was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB.ConclusionA high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV) was rare.