Genetic Polymorphisms of Delta-Like 1 Homolog Influence the Susceptibility to Antituberculosis Drug-Induced Hepatotoxicity.

This study was designed to investigate the relationship between Delta-like 1 homolog (DLK1) polymorphisms and the occurrence of antituberculosis drug-induced hepatotoxicity (ATDH) in the Western Chinese Han population. A total of 746 tuberculosis patients including 118 ATDH cases and 628 non-ATDH cases were enrolled from West China Hospital of Sichuan University during 2016-2018. Ten single nucleotide polymorphisms (rs11160604, rs7149242, rs7141210, rs7155375, rs876374, rs57098752, rs2400940, rs12431758, rs4900472, and rs6575802) within DLK1 were studied by the improved multiplex ligation detection reaction method genotyping technology assay. It was found that G allele of rs11160604 was associated with an increased risk for ATDH (p = 0.001) and G allele of rs4900472 showed a protective effect for ATDH (p = 0.030). Recessive model and dominant model of rs11160604 were observed as a risk factor for ATDH predisposition, whereas the recessive model of rs4900472 was a protective one. Moreover, the interaction genetic model composed of rs11160604, rs57098752, and rs12431758 showed a combined effect for the occurrence of ATDH. Our finding was a novel one indicating that the G allele of DLK1 rs11160604 might serve as a hazard for the development of ATDH in the Western Chinese Han population.

Association of POR and PPARα polymorphisms with risk of anti-tuberculosis drug-induced liver injury in Western Chinese Han population.

OBJECTIVES: Anti-tuberculosis drug-induced liver injury (ATDILI) is a common and sometimes severe adverse drug reaction (ADR). This study was conducted to investigate the relationship between polymorphisms of two genes, cytochrome P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor α (PPARα), and the risk of ATDILI in Western Chinese Han population. METHODS: A total of 118 tuberculosis (TB) patients with ATDILI and 628 TB patients without ATDILI during anti-TB treatment were recruited from West China Hospital of Sichuan University. DNA was extracted from peripheral blood, and genotypes of the selected 12 single nucleotide polymorphisms (SNPs) (3 SNPs in the POR gene and 9 SNPs in the PPARα gene) were determined. Three genetic models (additive, dominant, and recessive), as well as a haplotype, were used to test the genetic risk of ATDILI. Extended subgroup analysis was conducted according to age, sex and different causality assessments. RESULTS: The mutant allele, genotype and genetic model of rs3898649 in the POR gene were found to be associated with increased risk of ATDILI, especially in the younger (<50 years old), female and pulmonary tuberculosis subgroup. The other two SNPs rs28737229 and rs4728533 in the POR gene showed only a potential association with susceptibility to ATDILI after Bonferroni correction (P < .05 but PBonferroni > .05). The other 9 SNPs loci (rs135549, rs9626730, rs4253712, rs4823613, rs4253730, rs6007662, rs4253728, rs2024929 and rs135561) in the PPARα gene showed no significant differences between ATDILI and non-ATDILI in either allele frequencies or genotype (all P >.05). CONCLUSIONS: The results demonstrated the strong correlation between POR gene SNP rs3898649 and ATDILI susceptibility, suggesting the importance of POR rs3898649 in the pathogenesis and development of ATDILI. Therefore, our results indicated that POR rs3898649 might be a valuable biomarker potentially involved in ATDILI.

Genetic polymorphisms in PXR and NF-κB1 influence susceptibility to anti-tuberculosis drug-induced liver injury.

BACKGROUND: Pregnane X receptor (PXR) regulates the expression of drug-metabolizing enzymes and transport enzymes. NF-κB not only plays a role in liver homeostasis and injury-healing processes by regulating inflammatory responses but may also regulate the transcription of PXR. Currently, genetic polymorphisms in PXR are associated with adverse drug effects. Because little is known about the association between NF-κB1 genetic polymorphisms and adverse drug reactions, we explored the association between PXR and NF-κB1 single nucleotide polymorphisms (SNPs) and susceptibility to anti-tuberculosis drug-induced liver injury (ATDILI). MATERIALS AND METHODS: A total of 746 tuberculosis patients (118 with ATDILI and 628 without ATDILI) were prospectively enrolled at West China Hospital between December 2014 and April 2018. Nine selected SNPs (rs3814055, rs13059232, rs7643645 and rs3732360 in PXR and rs78872571, rs4647992, rs60371688, rs1598861 and rs3774959 in NF-κB1) were genotyped with a custom-designed 2x48-plex SNP Scan TM Kit. The frequencies of the alleles, genotypes and genetic models of the variants were compared between patients with or without ATDILI, while joint effect analysis of the SNP-SNP interactions was performed using multiplicative and additive models. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated. RESULTS: The T allele of rs3814055 in PXR was associated with a decreased risk for ATDILI (OR 0.61; 95% CI: 0.42-0.89, p = 0.0098). The T alleles of rs78872571 and rs4647992 in NF-κB1 were significantly associated with an increased risk for ATDILI (OR 1.91; 95% CI: 1.06-3.43, p = 0.028 and OR 1.81; 1.06-3.10, p = 0.029, respectively). The allele, genotype and genetic model frequencies were similar in the two groups for the other six SNPs (all P>0.05). There were no multiplicative or additive interactions between the SNPs. CONCLUSION: Our study is the first to reveal that rs3814055 variants in PXR and rs78872571 and rs4647992 variants in NF-κB1 are associated with susceptibility to ATDILI caused by first-line anti-tuberculosis combination treatment in the Han Chinese population.

The Variant at TGFBRAP1 but Not TGFBR2 Is Associated with Antituberculosis Drug-Induced Liver Injury.

BACKGROUND: TGFBRAP1 and TGFBR2 play important roles in the TGF-ß/smad signalling pathway and may disturb liver homeostasis by regulating liver injury and renewal. However, little is known about the association between their genetic polymorphisms and antituberculosis drug-induced liver injury (ATDILI), so we explored the association between their variants and the susceptibility to ATDILI. MATERIALS AND METHODS: A total of 746 tuberculosis patients were prospectively enrolled, and fifteen selected SNPs were genotyped. The allele, genotype, and genetic model frequencies of the variants were compared between patients with or without ATDILI, as well as the joint effect analysis of SNP-SNP interactions. The odds ratio (OR) with the corresponding 95% confidence interval (CI) was calculated. RESULTS: The A variant at rs17687727 was significantly associated with an increased risk for ATDILI (OR 1.55; 95% CI: 1.08-2.22; p = 0.016), which is consistent with the results in the additive and dominant models. Other allele, genotype, and genetic model frequencies were similar in the two groups for the other fourteen SNPs (all p > 0.05). CONCLUSION: Our study first implied that the A variant of rs17687727 in TGFBRAP1 influenced the susceptibility to ATDILI in first-line antituberculosis combination treatment in the Han Chinese population in a dependent manner.