Do genetic polymorphisms of B-cell CLL/lymphoma 2 confer susceptibility to anti-tuberculous therapy-associated drug-induced liver injury?

OBJECTIVES: The aim of this study was to identify the relationship between B-cell CLL/lymphoma 2 (BCL2) polymorphisms and susceptibility to anti-tuberculous therapy-associated drug-induced liver injury (ATT-DILI). METHODS: A total of 746 tuberculosis (TB) patients were enrolled in this study. Twenty-one selected single nucleotide polymorphisms in BCL2 were analyzed by custom-by-design 2×48-Plex SNPscan kit. The allele and genotype frequencies between patients with and without ATT-DILI were compared using three different genetic models. RESULTS: A total of 727/746 participants were successfully genotyped, and 112 of them were diagnosed with ATT-DILI. The A allele of rs8085707, G allele of rs76986960, and A allele of rs949037 conferred an increased risk of ATT-DILI, with estimated odd ratios (ORs) of 2.181 (95% confidence interval (CI) 1.345-3.536, p=0.001), 1.983 (95% CI 1.060-3.709, p=0.029), and 1.390 (95% CI 1.032-1.873, p=0.03), respectively. Bonferroni correction indicated that the A allele of rs8085707 was a risk factor for ATT-DILI (Bonferroni correction: p=0.026). The additive model suggested that patients with the AA genotype of rs8085707 had a significantly higher risk of ATT-DILI compared with those with the GG genotype (Bonferroni correction: p=0.036). The influence of BCL2 polymorphisms on clinical characteristics (clinical symptoms, disease subtypes, and laboratory indicators) was also identified. CONCLUSIONS: This study is novel in suggesting an association between BCL2 polymorphisms and the risk of ATT-DILI.

Integrating physiologically based kinetic (PBK) and Monte Carlo modelling to predict inter-individual and inter-ethnic variation in bioactivation and liver toxicity of lasiocarpine.

The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants Vmax and Km, physiologically based kinetic (PBK) modelling and Monte Carlo simulation. CSAFs were derived covering the 90th and 99th percentile of the population distribution of pyrrole glutathione adduct (7-GS-DHP) formation, reflecting bioactivation. The results revealed that in the Chinese population, as compared to the Caucasian population, the predicted 7-GS-DHP formation at the geometric mean, the 90th and the 99th percentile were 2.1-, 3.3- and 4.3-fold lower respectively. The CSAFs obtained using the 99th percentile values were 8.3, 17.0 and 19.5 in the Chinese, the Caucasian population and the two populations combined, respectively, while the CSAFs were generally 3.0-fold lower at the 90th percentile. These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. Altogether, the results obtained demonstrate that integrating PBK modelling with Monte Carlo simulations using human in vitro data is a powerful strategy to quantify inter-individual variations in kinetics, and can be used to refine the human risk assessment of pyrrolizidine alkaloids.

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.

Correlation between CAT polymorphism and susceptibility to DMAc-induced abnormal liver function: a case-control study of Chinese population.

CONTEXT: Acute or chronic exposure of N,N-dimethylacetamide (DMAc) is responsible for abnormal liver function. It appears that DMAc is mainly metabolized by cytochrome P450 in the liver and thereby produces reactive oxygen species (ROS). The elimination of ROS and the repairing of ROS-induced DNA damage are relevant to the ultimate toxicity of DMAc. OBJECTIVE: To investigate whether the polymorphisms in the CAT (rs564250, rs769214 and rs7943316), hOGG1 (rs2072668 and rs159153) and XRCC1 (rs25487 and rs1799782) genes are associated with susceptibility to DMAc-induced abnormal liver function in Chinese population. METHODS: Samples were obtained from 108 workers with DMAc-induced abnormal liver function and 108 workers with normal liver function. RESULTS: Subjects with the CAT rs769214 GA/GG genotypes had a reducing risk of abnormal liver function, which was more evident in the subgroups exposed to DMAc <10 years, exposed to DMAc <5 mg/m3, never smoked and never drank. CONCLUSIONS: CAT rs769214 (-844 G > A) polymorphism may be associated with DMAc-induced abnormal liver function in Chinese population.

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.

Age-related common miRNA polymorphism associated with severe toxicity in lung cancer patients treated with platinum-based chemotherapy.

Platinum-based chemotherapy toxicity severely impedes successful treatment in lung cancer patients. MicroRNAs (miRs) have a significant impact on the occurrence and survival rate of lung cancer. The purpose of this study was to investigate the association between common miRNA variants and platinum-based chemotherapy toxicity in lung cancer patients. A total of eight functional single nucleotide polymorphisms (SNPs) of miRNA were genotyped in 408 lung cancer patients by MALDI-TOF mass spectrometry. All the patients were histologically confirmed as lung cancer, and were treated with platinum-based chemotherapy for at least two cycles. It was found that the polymorphism rs2042553 of miR-5197 had a significant association with overall severe toxicity in both additive (P=.031, odds ratio [OR]=1.41, 95% confidence interval [CI] 1.03-1.93) and dominant (P=.009, OR=1.80, 95% CI 1.16-2.80) models. MiR-605 rs2043556 was significantly related to severe hepatotoxicity in dominant model (P=.022, OR=2.51, 95% CI 1.12-4.14). In addition, rs2910164 of miR-146a had marginal statistical effect on severe hepatotoxicity in additive model (P=.054). The subgroup analyses showed that miR-27a rs895819 was related to gastrointestinal toxicity in age >56 years old, smoking and non-smoking patients. Taken together, our results revealed that polymorphisms of miR-5197, miR-605, miR-146a, and miR-27a contributed to the chemotherapy toxicity of lung cancer, which may serve as a predictive tool for toxicity evaluation of platinum-based chemotherapy in lung cancer patients.

[Incidence and outcome of anti-tuberculosis drug-induced hepatotoxicity in tuberculosis inpatients].

OBJECTIVE: Based on the medical records and follow-up records of hospitalized patients who received anti-tuberculosis therapy in the Third People's Hospital of Zhenjiang in Jiangsu province from 2006 to 2012, we investigated the incidence and outcome of anti-tuberculosis drug induced hepatotoxicity(ATDH)and provided evidence for the prevention of ATDH. METHODS: According to tuberculosis patients' medical information and liver function test records, ATDH patients were diagnosed according to the criteria of International Consensus Meeting and American Thoracic Society respectively, then the related factors and outcomes were analyzed. RESULTS: A total of 1 967 hospitalized tuberculosis patients were reviewed retrospectively, in which 1 403(71.3%)were men, 1 790(91.0%)were pulmonary tuberculosis patients, 1 528(77.8%)were patients receiving initiative treatment, 979(49.8%)were sputum smear-positive patients, and 1 297(65.9%)had other complicated diseases. According to the criterion of International Consensus Meeting, the incidence of ATDH was 16.5%, the median time of onset was 25 days. According to the criterion of American Thoracic Society, the incidence of ATDH was 8.3%, the median time of onset was 23 days. The incidence of ATDH was significantly higher in males and HRZE therapy group(P<0.05). Under the two liver criteria, 69.5% and 70.1% of the patients changed primary therapy respectively after ATDH occurred. 89.8% and 88.4% patients' liver function returned to normal range after changing or stopping therapy. CONCLUSION: According to two liver injury criteria, the incidences of ATDH were 16.5% and 8.3% in hospitalized tuberculosis patients respectively, and ATDH mainly occurred in the first month of anti-tuberculosis treatment. The monitoring of liver function should be strengthened in males and HRZE therapy group to reduce the incidence of ATDH.

[Study on polymorphisms of genes with susceptibility to drug induced liver injury in a cohort receiving anti-tuberculosis treatment].

OBJECTIVE: To investigate the association between the polymorphisms of genes involving in drug metabolism and transport as well as immunological reaction and the risk of anti-tuberculosis drug-induced liver injury(ATLI)in Chinese. METHODS: This 1∶4 matched case-control study was conducted by using the data from a cohort study of Anti-tuberculosis Drugs Induced Adverse Reactions in National Tuberculosis Prevention and Control Progtam of China. Genes involving in three phase of drug metabolism and transport as well as related immunological reaction were chosen and single nucleotide polymorphisms(SNPs)were genotyped by TaqMan allele discrimination technology. Lasso regression and multivariate conditional logistic regression analysis were used to select susceptible genes. RESULTS: A total of 33 genes with 75 SNPs were tested. The combined results of Lasso and regression logistic regression analysis showed that genetic polymorphism of SLCO1B1 rs4149014, HSPA1L rs2227956, STAT3 rs1053023 and IL-6 rs2066992 were significantly associated with the risk of ATLI(P<0.05). CONCLUSION: SLCO1B1, HSPA1L, STAT3 and IL-6 might be the susceptibility genes of drug induced liver injury in patients receiving anti-tuberculosis treatment.

The Latin American DILI Registry Experience: A Successful Ongoing Collaborative Strategic Initiative.

Drug induced liver injury (DILI) is a rare but well recognized serious adverse reaction. Pre-marketing studies may not detect liver injury, and DILI becomes very often apparent after the drug is launched to the market. Specific biomarkers for DILI prediction or diagnosis are not available. Toxic liver reactions present with a wide spectrum of phenotypes and severity, and our knowledge on the mechanisms underlying idiosyncratic reactions and individual susceptibility is still limited. To overcome these limitations, country-based registries and multicenter research networks have been created in Europe and North America. Reliable epidemiological data on DILI in Latin America (LA), a region with a large variety of ethnic groups, were however lacking. Fortunately, a LA network of DILI was set up in 2011, with the support of the Spanish DILI Registry from the University of Malaga. The primary aim of the Latin DILI Network (LATINDILIN) Registry was to prospectively identify bona fide DILI cases and to collect biological samples to study genetic biomarkers. Physicians involved in the project must complete a structured report form describing the DILI case presentation and follow-up which is submitted to a Coordinator Center in each country, where it is further assessed for completeness. During the last four years, several LA countries (Argentina, Uruguay, Chile, Mexico, Paraguay, Brazil, Ecuador, Peru, Venezuela and Colombia) have joined the network and committed with this project. At that point, to identify both our strengths and weaknesses was a very important issue. In this review, we will describe how the LATINDILI Registry was created. The aims and methods to achieve these objectives will be discussed in depth. Additionally, both the difficulties we have faced and the strategies to solve them will be also pinpointed. Finally, we will report on our preliminary results, and discuss ideas to expand and to keep running this network.

Translational biomarkers of acetaminophen-induced acute liver injury.

Acetaminophen (APAP) is a commonly used analgesic drug that can cause liver injury, liver necrosis and liver failure. APAP-induced liver injury is associated with glutathione depletion, the formation of APAP protein adducts, the generation of reactive oxygen and nitrogen species and mitochondrial injury. The systems biology omics technologies (transcriptomics, proteomics and metabolomics) have been used to discover potential translational biomarkers of liver injury. The following review provides a summary of the systems biology discovery process, analytical validation of biomarkers and translation of omics biomarkers from the nonclinical to clinical setting in APAP-induced liver injury.

HLA-allelotype associations with nevirapine-induced hypersensitivity reactions and hepatotoxicity: a systematic review of the literature and meta-analysis.

OBJECTIVE: Various studies have investigated associations between immunogenetic (HLA-allelotypes) factors and the risk of nevirapine-induced hypersensitivity reactions. However, results from individual studies have been inconsistent. To evaluate the association between HLA alleles and nevirapine hypersensitivity, a systematic review and meta-analysis was carried out. METHODS: A literature review of articles published up to December 2014 was performed. Where both allelotype and phenotype data from two or more studies could be combined, a Mantel-Haenszel random effects model was used to obtain a pooled odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: Thirteen case-control studies investigating nevirapine hypersensitivity and HLA-allelotypes were identified. The OR (95% CI) for HLA-B*35 and cutaneous adverse drug reactions (cADRs) was 2.45 (95% CI: 1.10-5.48), with significant heterogeneity (I²=69%). The association between HLA-B*58:01 and hepatotoxicity in black African patients showed an OR of 3.51 (95% CI: 1.72-7.19) with no between study heterogeneity (I²=0%). For HLA-C*04 carriage, the OR in four different ethnic populations for cADRs was 2.63 (95% CI: 1.97-3.52; I²=0%). The OR for carriage of HLA-DRB1*01 in a multiethnic cohort was 2.94 (95% CI: 1.92-4.50; I²=0%) for nevirapine hepatotoxicity. CONCLUSION: HLA-C*04 carriage may be a common risk factor for cADRs to nevirapine in populations of differing ethnicity, whereas HLA-B*35 and HLA-DRB1*01 appear to be driven predominantly by an association within Thai and White populations, respectively. Heterogeneity between studies could be reduced by undertaking an individual patient data meta-analysis allowing the standardization of phenotype definitions and investigation of common haplotypes between populations.

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

WHAT IS KNOWN AND OBJECTIVE: 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. 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-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. RESULTS AND DISCUSSION: 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. WHAT IS NEW AND CONCLUSION: 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.

Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients.

AIM: To determine the clinicopathological characteristics of nonsteroidal anti-inflammatory drug (NSAID)-induced acute hepato-nephrotoxicity among Chinese patients. METHODS: We conducted a retrospective chart review of patients using the International Classification of Diseases, Ninth Revision diagnosis code for acute kidney injury (AKI) (584.5 or 584.9) and for acute liver injury (ALI) (570.0 or 573.3) from January 2004 to December 2013. Medical records were reviewed to confirm the diagnosis of AKI and ALI and to quantify NSAID administration. RESULTS: Seven of 59 patients (11.8%) were identified with acute hepato-nephrotoxicity induced by NSAIDs. Five patients (71.4%) received over the recommended NSAIDs dose. Compared with NSAIDs-associated mere AKI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), a high prevalence of alcohol use (71.4%) and positive hepatitis B virus (HBV) markers (85.7%). Compared with NSAIDs-associated mere ALI, the risk factors of NSAIDs-induced acute hepato-nephrotoxicity are age older than 60 years (57.1%), increased extracellular volume depletion (71.4%), and renin-angiotensin-aldosterone system (RAAS) inhibitor combined use (57.1%). Acute interstitial nephritis and acute tubulointerstitial disease were apparent in three out of six (42.9%) kidney biopsy patients, respectively. Acute hepatitis was found in four out of six (66.7%) liver biopsy patients. Overall complete recovery occurred in four patients within a mean of 118.25 ± 55.42 d. CONCLUSION: The injury typically occurred after an overdose of NSAIDs. The risk factors include age older than 60 years, alcohol use, positive HBV markers, extracellular volume depletion and RAAS inhibitor combined use.

Association of CYP3A4*18B and CYP3A5*3 polymorphism with cyclosporine-related liver injury in Chinese renal transplant recipients.

OBJECTIVE: The purpose of this study was to investigate the associations between CYP3A4*18B and CYP3A5*3 polymorphism and cyclosporine-related liver injuries in Chinese renal transplant recipients. METHODS: We genotyped 339 renal transplant recipients treated with a triple immunosuppressive regimen including cyclosporine for CYP3A4*18B and CYP3A5*3 polymorphism using the polymerase chain reaction restriction fragment length polymorphism assay. RESULTS: The incidence of liver injury in the study population was 36.9% (125/339). At 1 month after transplantation, the trough concentration of cyclosporine (C0) in the group with CYP3A4*1/*1(GG alleles) was significantly higher than in the group with CYP3A4*18B/*1 8B(AA alleles) (p < 0.05). At 3 months after transplantation, the C0 in the group with CYP3A4*1/*1 and group with CYP3A4*1/*18B was markedly higher than in the group with CYP3A4*18B/*18B (p < 0.05). The GG genotypes of CYP3A4*18B were more common in the liver injury group compared with the control group (p < 0.05). Univariate logistic regression analysis showed that subjects carrying the GG genotypes had a 5.136- and 2.528-fold higher risk of developing cyclosporine-related liver injury than those with the AA and GA genotypes. When adjusted for sex, the risk of the CYP3A4*18B genotypes was OR = 4.969 for GG compared to AA (p = 0.030), and OR = 2.634 for GG compared to GA (p = 0.025). However, no association was observed between CYP3A5*3 polymorphisms with cyclosporine-related liver injury. CONCLUSIONS: These results suggested that the wild type of CYP3A4*18B is a risk factor for the development of cyclosporine- related liver injuries in Chinese renal transplant recipients.

Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs.

BACKGROUND AND AIM: Treatment with antituberculosis (TB) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N-acetyltransferase 2 (NAT-2) and cytochrome P450 2E1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT-2 and CYP2E1 polymorphisms with the development of anti-TB drug-induced hepatotoxicity (ATDH). METHODS: One hundred and seventy-five TB patients who had been treated with anti-TB drugs were studied. The allelic and genotypic frequency distributions of the NAT-2 and CYP2E1 enzymes were studied using polymerase chain reaction-restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity. RESULTS: Having a slow acetylator status (odds ratio [OR] = 2.615; confidence interval [CI] = 1.264-5.411; P = 0.01), being female (OR = 2.734; CI = 1.325-5.639, P = 0.006), and having Bolivian ethnicity (OR = 2.711; CI = 1.307-6.625, P = 0.007) were found to be independent predictor variables for ATDH. CONCLUSIONS: This study showed that a patient's NAT-2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP2E1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients' acetylator status prior to or at the beginning of the TB treatment regimen.

CYP2E1 RsaI/PstI polymorphism and risk of anti-tuberculosis drug-induced liver injury: a meta-analysis.

BACKGROUND AND OBJECTIVE: A number of studies have evaluated the association between cytochrome P450 2E1 (CYP2E1) RsaI/PstI polymorphism and the risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, the results were inconsistent. We conducted a meta-analysis to clarify the role of this polymorphism in ATDILI. DESIGN: Two authors independently searched the PubMed, Medline, EMBASE and Chinese National Knowledge Infrastructure databases for studies on the association of CYP2E1 RsaI/PstI polymorphism with risk of ATDILI. Summary odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated. RESULTS: The combined results showed that the CYP2E1 c1/c1 genotype was associated with increased ATDILI risk compared to variant genotypes (c1/c2+c2/c2) (OR 1.36, 95%CI 1.09-1.69). When stratifying for study population, statistically significant results were observed in Chinese (OR 1.47, 95%CI 1.12-1.92) and Korean populations (OR 1.85, 95%CI 1.04-3.30). In comparison with CYP2E1 c1/c2 or c2/c2 with rapid/intermediate acetylators, the risk of ATDILI increased from 1.88 (95%CI 1.14-3.09) for CYP2E1 c1/c1 with rapid/intermediate acetylators to 6.44 (95%CI 3.47-11.97) for CYP2E1 c1/c1 with slow acetylators. CONCLUSION: This meta-analysis suggests that CYP2E1 RsaI/PstI polymorphism may affect susceptibility to ATDILI, particularly among Chinese and Korean populations.

NAT2 genetic polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in Chinese community population.

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.

Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.

BACKGROUND & AIMS: Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. METHODS: We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. RESULTS: AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). CONCLUSIONS: Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis.

BACKGROUND AND AIM: Antituberculosis drugs, isoniazid and rifampicin, in combination, are known to develop drug-induced hepatotoxicity (DIH). A higher risk of DIH during antituberculosis treatment (ATT) has been reported in the Indian subcontinent compared to its Western counterparts. The role of genetic factors in a higher incidence of ATT hepatotoxicity in the Indian population is still unclear. The present study was aimed at investigating the role of the N-acetyltransferase2 (NAT2) and cytochrome P4502E1 (CYP2E1) gene polymorphisms in ATT hepatotoxicity. METHODS: The study population included 218 pulmonary tuberculosis patients who were started on ATT and followed up for the occurrence of ATT-induced hepatitis. The genetic polymorphisms of the NAT2 and CYP2E1 genes were studied by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The occurrence of DIH was 18.8% (41/218). There was a higher prevalence of NAT2 slow-acetylator genotypes in DIH (70.73%) compared to non-DIH (44.63%; P < 0.05). The frequency of the NAT2*5/*7 and NAT2*6/*7 genotypes was significantly higher in DIH than non-DIH (19.51% vs 6.78%, and 19.51% vs 5.08%). No association of the CYP2E1 RsaI polymorphism could be demonstrated with DIH. However, the DraI C/D genotype of the CYP2E1 gene was mostly prevalent in DIH (85.37%), compared to non-DIH (64.41%) (P < 0.05). Slow-acetylator status and the CYP2E1 C/D or C/C genotype together showed a higher frequency in DIH (65.85%) compared to non-DIH (28.81%) (P < 0.0001). CONCLUSION: The study demonstrates for the first time a possible association between the DraI polymorphism of the CYP2E1 gene and the risk of ATT hepatotoxicity. The genotyping of the NAT2 and CYP2E1 genes could possibly identify the groups at highest risk of developing ATT-induced hepatitis prior to medication.