Risk Of Anti-tuberculosis Drug-induced Liver Injury Research Articles

HLA-DQB1*05:02 Allele Association with Anti-Tuberculosis Drug Induced Liver Injury: A Single-Hospital Based Study in Jakarta, Indonesian Population

Past studies have delved into the genetic factors underlying anti-tuberculosis drug-induced liver injury (AT-DILI), primarily concentrating on polymorphisms in genes responsible for drug-metabolizing enzymes. However, the immune system's potential impact on drug adverse effects, specifically through genes such as HLA, has received limited attention. Previous research has notably revealed an association between HLA-DQB1*05 and AT-DILI, specifically the prevalence of the HLA-DQB*05:02 allele in AT-DILI patients. In light of this, our study aimed to investigate a potential link between HLA-DQB1*05:02 alleles and AT-DILI. In this study, we included 51 AT-DILI cases and 59 controls belonging to the Javanese ethnic group. The HLA-DQB1*05:02 genotypes were determined using a customized PCR-based typing method, and the results were further confirmed by analyzing five samples via the Luminex assay. Our findings revealed a significant association between HLA-DQA1*05: 02 and the risk of AT-DILI (P = 0.022; OR (95% CI) = 6.11 (1.25-29.74)). Moreover, the consistent results obtained from the Luminex assay validated the reliability of the custom PCR-based genotyping approach. This preliminary study sheds light on the relationship between the HLA-DQB1*05:02 allele and AT-DILI within the Indonesian population. Furthermore, our study demonstrates the dependability of custom PCR-based genotyping in detecting HLA-DQB1*05:02 alleles. Nevertheless, further research is imperative to corroborate and expand upon our findings.

Genetic variants of the nuclear factor erythroid 2-related factor 2/antioxidant reaction element pathway on the risk of antituberculosis drug-induced liver injury: a systematic review.

Aim: To evaluate the effects of genetic variants in the nuclear factor erythroid 2-related factor 2/antioxidant reaction element signaling pathway on antituberculosis drug-induced liver injury (AT-DILI) susceptibility. Methods: The PubMed, Embase, Cochrane, Web of Science, China National Knowledge Infrastructure and Wanfang databases were searched from inception to April 2022. Results: Seven case-control studies with 4676 patients were included. Six genes with 35 SNPs in the pathway have been reported. Among 17 SNPs reported in two or more studies, the meta-analysis indicated that only one SNP (rs3735656 in MAFK) was significantly associated with a decreased risk for AT-DILI under the dominant model (odds ratio: 0.636; 95% CI: 0.519-0.780; p<0.001). Conclusion: SNP rs3735656 in the MAFK gene was significantly associated with the risk of AT-DILI.

CYP2S1 rs338599 polymorphism confers reduced risk to anti-tuberculosis drug-induced liver injury and may be a novel marker for its risk prediction.

PurposeIn the present study, we would like to explore whether Cytochrome P450 2S1 (CYP2S1) rs338599 polymorphism confers risk to anti‐tuberculosis drug‐induced liver injury (ADLI) and provide evidence of being used as novel marker for ADLI risk prediction.Patients and methodsA total of 162 pulmonary tuberculosis patients admitted to Affiliated Hospital of Hebei University from August 2018 to March 2021 were selected. Patients who developed into ADLI were assigned as ADLI group (n = 50), and those who did not developed into ADLI were assigned as non‐ADLI group (n = 112). The CYP2S1 rs338599 polymorphism was detected by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method using binary logistic regression analyses through adjusting for age and sex.ResultsNo difference was detected in age, sex, smoking status, profession, education level, marital status, alcohol consumption, or using liver‐protecting drugs (p > 0.05). Compared with non‐ADLI group, GG genotype and G allele were significantly higher in ADLI group (p < 0.05).ConclusionOur results indicated that CYP2S1 rs338599 polymorphism conferred reduced risk to ADLI. The tuberculosis patients who had GG genotype or G allele were not susceptible to ADLI. CYP2S1 rs338599 polymorphism may be a novel marker for ADLI risk prediction.

The role of the genetic variant FECH rs11660001 in the occurrence of anti-tuberculosis drug-induced liver injury.

The pathogenic mechanism of anti-tuberculosis drug-induced liver injury (AT-DILI) is still largely unknown. Recent studies have indicated that rifampicin and isoniazid cotreatment causes the accumulation of endogenous protoporphyrin IX in the liver through the haem biosynthesis pathway. Alanine synthase 1 (ALAS1) and ferrochelatase (FECH) are the rate-limiting enzymes in the production of haem. The present study aimed to investigate the genetic contribution of the ALAS1 and FECH genes to the risk of AT-DILI in an Eastern Chinese Han population. A 1:4 matched case-control study was conducted, and eight SNPs in the ALAS1 and FECH genes were detected and assessed. A multivariate conditional logistic regression model was used to estimate the association between genotypes and the risk of AT-DILI by the odds ratios (ORs) with 95% confidence intervals (CIs), with liver disease history, hepatoprotectant use, smoking and drinking history as covariates. Overall, 202 AT-DILI cases and 808 controls were included in this study. The female patients carrying polymorphisms of rs11660001 in FECH had an increased risk of AT-DILI under the dominant and additive models (OR=1.831, 95% CI: 1.014-3.307, p=0.045; OR=1.673, 95% CI: 1.015-2.760, p=0.044, respectively). The peak aspartate transaminase level was significantly higher in female patients carrying the GA+AA genotype of rs11660001 than in those with the GG genotype during anti-TB treatment (p=0.032). Based on this 1:4 individual matched case-control study, SNP rs11660001 in the FECH gene may be associated with susceptibility to AT-DILI in Chinese female anti-TB treatment patients. Further studies in larger varied populations are needed to validate our findings.

Interaction between the HIF-1α gene rs1957757 polymorphism and CpG island methylation in the promoter region is associated with the risk of anti-tuberculosis drug-induced liver injury in humans: A case-control study.

HIF-1α gene polymorphisms, including rs11549465, rs11549467, rs1957757 and rs10873142, cause liver cell damage or pulmonary disease. The aim of this study was to analyse the association between the polymorphisms of the loci of the HIF-1α gene and its CpG island methylation in the promoter region with the risk of anti-tuberculosis drug-induced liver injury (ADLI). 286 patients with tuberculosis (TB) and ADLI (case group) and 286 patients with TB but without liver injury (control group) were matched one-to-one, among the 1728 TB patients recruited from July 2019 to July 2020. Genotyping of the four loci of the HIF-1α gene was confirmed using PCR-RFLP technology. Methylation of the HIF-1α gene was measured using the MSP method. The comparison of risk factors, HIF-1α genotype and methylation status between the case group and the control group was all achieved through univariate and multivariate conditional logistic regression. Univariate analysis showed that the frequency of rs1957757 mutation genotype and CpG island methylation was significantly higher in the case group than in the control group (P<0.001, all). In contrast, there was no statistical difference in the frequency of mutated genotypes at the other three loci between the two groups (p=0.21, p=0.12 and p=0.55, respectively). Further, multivariate analysis showed that CpG islands were methylated, the mutation genotype of the rs1957757 locus was independently associated with the high risk of ADLI, and the adjusted OR (95%CI) reached 1.92 (1.32-2.63) and 2.01 (1.32-2.83), respectively. Furthermore, taking the rs1957757 locus wild genotype and CpG islands without methylation as the reference group, the mutation genotype and CpG island methylation increased the risk of ADLI, and the probability of ADLI could reach 4.73 times that of the reference group. This is the first demonstration of the association of HIF-1α gene polymorphism and CpG island methylation with ADLI risk stratification. The interaction between CpG islands methylated in the promoter region of the HIF-1α gene and its rs1957757 locus mutant genotype was associated with a higher risk of ADLI.

Relationship between xanthine oxidase gene polymorphisms and anti-tuberculosis drug-induced liver injury in a Chinese population.

This study was designed to investigate the association of the xanthine oxidase (XO) polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI) in Chinese population. A total of 183 tuberculosis patients were enrolled. Patients with ATDILI were classified as cases and those without ATDILI were classified as controls. Genotyping for XO polymorphisms was determined by polymerase chain reaction and direct sequencing. The allele frequencies and genotype distribution was analyzed using the Chi square test to analyze the association between the gene polymorphisms and ATDILI. Binary logistic regression analysis was performed to assess the risk factors of ATDILI. A total of 21 patients were developed liver injury during anti-tuberculosis treatment in this study, with an incidence of 11.48%. In genotype analysis, no significant difference was observed in the alleles and genotypes frequencies of the six SNPs between two groups (P>0.05). In haplotype analysis, carriers with GGGATA (rs1884725- rs2295475 -rs45523133- rs206812- rs206813- rs7575607) haplotype had a significantly higher risk of ATDILI compared with other haplotypes (OR=2.445, 95%CI: 1.058-5.652, P<0.05). This study suggested that the haplotype GGGATA constructed with rs206812 and rs7575607 mutant alleles might contribute to ATDILI susceptibility in a Chinese population.

CYP2E1, GSTM1, and GSTT1 genetic polymorphisms and their associations with susceptibility to antituberculosis drug-induced liver injury in Thai tuberculosis patients

Antituberculosis drug-induced liver injury (ATDILI) is the common adverse reaction of antituberculosis drugs. Glutathione S-transferases (GSTs), which are phase II metabolizing enzymes for detoxification, are recognized as potential mediators of hepatotoxicity. However, role of GSTs polymorphisms in ATDILI pathogenesis has never been observed in Thais. This study aimed to investigate associations between GSTs and ATDILI susceptibility. This retrospective case-control multicentered study was conducted by the collaboration from ten secondary and tertiary care hospitals across Thailand, including Northern, Central, and Southern parts of Thailand. We enrolled 80 tuberculosis (TB) patients with ATDILI and 174 those without ATDILI into the study. Polymerase chain reaction (PCR) was used to determine genetic polymorphisms of GSTM1 and GSTT1 genes. CYP2E1 genotyping data were derived from microarray data. We illustrated that GSTT1 null and GSTM1/GSTT1 dual null genotypes were correlated with an increased risk of ATDILI with odds ratio (OR) at 1.83 (95% confidence interval (CI), 1.00 to 3.35; P = 0.049) and 2.12 (95%CI, 1.02 to 4.38; P = 0.044), respectively. Interestingly, GSTT1 null and GSTM1/GSTT1 dual null genotypes were found to be correlated with an increased risk of ATDILI in Thai TB patients who carried CYP2E1 wild type phenotype with OR 2.99 (95%CI, 1.07 to 8.39; P = 0.037) and 3.44 (95%CI, 1.01 to 11.71; P = 0.048), respectively. Collectively, GSTT1 null and GSTM1/GSTT1 dual null genotypes were associated with a higher risk of ATDILI in Thai TB patients, which may serve as alternative genetic biomarkers for ATDILI.

NAT2 slow acetylator is associated with anti-tuberculosis drug-induced liver injury severity in indonesian population.

Aim: We investigated the contribution of NAT2variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7×10-7; odds ratio [95% CI] =3.64 [2.21-6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3×10-6; odds ratio [95% CI] =3.37 [2.00-5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.

The genetic variants in calcium signaling related genes influence anti-tuberculosis drug induced liver injury: A prospective study.

Although many genetic variants related to anti-tuberculosis drug induced liver injury (ATDILI) have been identified, the prediction and personalized treatment of ATDILI have failed to achieve, indicating there remains an area for further exploration. This study aimed to explore the influence of single nucleotide polymorphisms (SNPs) in Bradykinin receptor B2 (BDKRB2), Teneurin transmembrane protein 2 (TENM2), transforming growth factor beta 2 (TGFB2), and solute carrier family 2 member 13 (SLC2A13) on the risk of ATDILI.The subjects comprised 746 Chinese tuberculosis (TB) patients. Custom-by-design 2x48-Plex SNPscanTM kit was employed to genotype 28 selected SNPs. The associations of SNPs with ATDILI risk and clinical phenotypes were analyzed according to the distributions of allelic and genotypic frequencies and different genetic models. The odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated.Among subjects with successfully genotyped, 107 participants suffered from ATDILI during follow-up. In BDKRB2, patients with rs79280755 G allele or rs117806152 C allele were more vulnerable to ATDILI (PBonferronicorrection = .002 and .03, respectively). Rs79280755 increased the risk of ATDILI significantly whether in additive (OR = 3.218, 95% CI: 1.686–6.139, PBonferroni correction = .003) or dominant model (PBonferroni correction = .003), as well as rs117806152 (Additive model: PBonferroni correction = .05; dominant model: PBonferroni correction = .03). For TENM2, rs80003210 G allele contributed to the decreased risk of ATDILI (PBonferroni correction = .02), while rs2617972 A allele conferred susceptibility to ATDILI (PBonferroni correction = .01). Regarding rs2617972, significant findings were also observed in both additive (OR = 3.203, 95% CI: 1.487–6.896, PBonferroni correction = .02) and dominant model (PBonferroni correction = .02). Moreover, rs79280755 and rs117806152 in BDKRB2 significantly affected some laboratory indicators. However, no meaningful SNPs were observed in TGFB2 and SLC2A13.Our study revealed that both BDKRB2 and TENM2 genetic polymorphisms were interrogated in relation to ATDILI susceptibility and some laboratory indicators in the Western Chinese Han population, shedding a new light on exploring novel biomarkers and targets for ATDILI.

Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis

ObjectivesThe objective of this study was to investigate the association between genetic polymorphisms of N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), glutathione S-transferase (GST) and solute carrier organic anion transporter...

NAT2 ultra-slow acetylator and risk of anti-tuberculosis drug-induced liver injury: a genotype-based meta-analysis.

NAT2 slow acetylator is a confirmed risk of anti-tuberculosis drug-induced liver injury (ATDILI). However, NAT2 ultra-slow acetylators, a new refinement among NAT2 slow acetylators, have been recently proposed. The patients with NAT2 genotypes of *6A/*6A, *6A/*7B and *7B/*7B are referred to in this group. We aim to prove an association of the NAT2 ultra-slow acetylators with the risk of ATDILI. Systematic review and meta-analysis were performed based on each NAT2 genotype and risk of ATDILI cases and also new classification of the ultra-slow acetylators up to 31 October 2016. Meta-analysis of 18 studies with 822 ATDILI cases and 4630 controls was carried out in the RevMan software, version 5.3 with fixed-effect (low heterogeneity) and random effect (moderate to high heterogeneity) methods. The strong associations between each NAT2 slow acetylator genotypes and ATDILI were confirmed in meta-analysis except for NAT2*5B/*5B [odds ratio (OR): 1.69; 95% confidence interval (CI): 0.96-2.95; P=0.0679]. The NAT2 ultra-slow acetylators contribute to higher risk of ATDILI (OR: 3.60; 95% CI: 2.30-5.63; P=1.76E-08) than all NAT2 slow acetylators (OR: 2.80; 95% CI: 2.20-3.57; P=5.73E-18) as well as fast acetylators. Additional in-vitro study using isoniazid as a substrate supports the existence of ultra-slow acetylator alleles (NAT2*6A and NAT2*7B). This is the first meta-analysis of NAT2 and the risk of ATDILI at the genotypic level. The result demonstrated that NAT2 ultra-slow acetylator genotypes will have the most effect on the increased risk of ATDILI.

Genetic Variations Associated with Anti-Tuberculosis Drug-Induced Liver Injury.

In order to combat the development of drug resistance, the clinical treatment of tuberculosis requires the combined use of several anti-tuberculosis (anti-TB) drugs, including isoniazid and rifampicin. Combinational treatment approaches are suggested by the World Health Organization (WHO) and are widely accepted throughout the world. Unfortunately, a major side effect of the treatment is the development of anti-tuberculosis drug-induced liver injury (AT-DILI). Many factors contribute to isoniazid- and rifampicin-mediated AT-DILI and genetic variations are among the most common factors. The purpose of this review is to provide information on genetic variations associated with isoniazid- and rifampicin-mediated AT-DILI. The genetic variations associated with AT-DILI have been identified in the genomic regions within or near genes encoding proteins in the following pathways: drug metabolizing enzymes (NAT2, CYP2E1, and GSTs), accumulation of bile acids, lipids, and heme metabolites (CYP7A1, BSEP, UGTs, and PXR), immune adaptation (HLAs and TNF-α), and oxidant challenge (TXNRD1, SOD1, BACH1, and MAFK). The information summarized in this review considers the genetic bases of risk factors contributing to AT-DILI and provides information that may help for future studies. Some of the implicated genetic variations can be used in the design of genetic tests and serve as biomarkers for the prediction of isoniazid- and rifampicin-mediated AT-DILI risk in personalized medicine.

NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients.

Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI. To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients. We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing. Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10-8). Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.

Role of polymorphic bile salt export pump (BSEP, ABCB11) transporters in anti-tuberculosis drug-induced liver injury in a Chinese cohort.

Evidence indicates that the polymorphisms in bile salt export pump (BSEP, encoded by ABCB11) may play an important role in the development of anti-tuberculosis drug-induced liver injury (ATDILI) and we aim to investigate the association between genetic variants of ABCB11 and the risk of ATDILI in a Chinese cohort. A total of 89 tuberculosis patients with ATDILI and 356 matched ATDILI -free patients constituted cases and controls. Genetic polymorphisms of ABCB11 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. There were no significant differences in genotype frequencies of ABCB11 between cases and controls. In the subgroup analysis, polymorphisms of rs2287616 were found to be associated with cholestatic/mixed pattern of liver injury under dominant and addictive model (OR = 3.84, 95% CI:1.16–12.75, P = 0.028 and OR = 2.51, 95% CI:1.12–5.62, P = 0.025, respectively), however the significance disappeared after Bonferroni correction. This study suggested that genetic variants of ABCB11 gene might contribute to anti-tuberculosis drug-induced cholestatic liver injury in Chinese patients. Studies in larger, varied populations are required to confirm these findings.

Polymorphism of PXR gene associated with the increased risk of drug-induced liver injury in Indonesian pulmonary tuberculosis patients.

Tuberculosis is still a major infectious disease in Indonesia. Patients are treated mostly using fixed-dose combination treatment in primary public health facilities. The incidence of antituberculosis drug-induced liver injury (AT-DILI) is approximately 10% among Indonesian tuberculosis patients who used standard fixed combination regimens during the intensive phase of treatment. However, information regarding genetic polymorphism associated with the increase risk of drug-induced liver injury is still limited. The aim of this study was to investigate pregnane X receptor (PXR) gene polymorphisms as one of the risk factors of AT-DILI. In this prospective cohort study, we recruited 106 adult patients diagnosed with pulmonary tuberculosis and treated with category I FDC (fixed-dose combination). The identification of SNP -25385C>T (rs3814055) was conducted by ARMS (amplification refractory mutation system). Hepatotoxicity was defined as ALT and/or AST levels above the normal threshold on the second, fourth and sixth months of monitoring during tuberculosis treatment. The logistic regression analysis showed that patients with the TT genotype of PXR gene (rs3814055) significantly had a greater risk of AT-DILI (OR 8·89; 95% CI 1·36-57·93, P < 0·05), compared with those of wild-type CC genotype. The result suggests that in Indonesian patients with tuberculosis, the risk of having AT-DILI was associated with TT genotype of the PXR gene.

&lt;I&gt;GSTM1&lt;/I&gt; and &lt;I&gt;GSTT1&lt;/I&gt; null polymorphisms and susceptibility to anti-tuberculosis drug-induced liver injury: a meta-analysis [Review article

Published data on the association between GSTM1 and GSTT1 polymorphisms and risk of anti-tuberculosis drug-induced liver injury (ATDILI) are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis on this topic was performed. PubMed, Medline, EMBASE and Chinese national knowledge infrastructure were searched for studies on the association of GSTM1 and GSTT1 polymorphisms with risk of ATDILI. Summary odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated. The GSTM1 null genotype was associated with increased risk of ATDILI (OR(random-effects) 1.50, 95%CI 1.15-1.95). When stratifying for study population and median number of cases, statistically significant results were observed in the Chinese population (OR(random-effects) 1.45, 95%CI 1.12-1.92) and in studies with case numbers > 57 (OR(fixed-effects) 1.60, 95%CI 1.31-1.97). No statistically significant association was observed between GSTT1 null genotype or GSTM1/GSTT1 interaction and risk of ATDILI. The meta-analysis suggests that GSTM1 null genotype may be associated with an increased risk of ATDILI, particularly among the Chinese population. The GSTT1 null genotype or GSTM1/GSTT1 interaction may not affect susceptibility to ATDILI.

&lt;I&gt;CYP2E1 RsaI/PstI&lt;/I&gt; polymorphism and risk of anti-tuberculosis drug-induced liver injury: a meta-analysis [Review article

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. 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. 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. This meta-analysis suggests that CYP2E1 RsaI/PstI polymorphism may affect susceptibility to ATDILI, particularly among Chinese and Korean populations.