Genetic polymorphisms in metabolic enzymes and susceptibility to anti-tuberculosis drug-induced hepatic injury

Abstract

ABSTRACT. We examined the relationships between N-transacetylase 2 (NAT2), cytochrome P450 (CYP) 2E1 enzyme, glutathione S-transferase M1, T1 (GSTM1/GSTT1) gene polymorphisms, and anti-tuberculosis drug-induced hepatic injury (ADIH). A one-to-one matched case-control study was carried out using clinical data. NAT2, CYP2E1, GSTM1, and GSTT1 polymorphisms were identified in 173 pairs of research subjects. Statistical analysis was performed to determine risk factors of ADIH. The results showed that low body mass index and alcohol consumption were risk factors of ADIH, with odds ratios of 6.852 and 3.203, respectively. The frequencies of NAT2 slow acetylator, CYP2E1 -1259G>C, -1019C>T wild-type, and the GSTM1 null genotype were higher in the case group than in the control group, with odds ratios of 2.260, 2.696, 4.714, and 2.440, respectively. GSTT1 was not found to be related to ADIH. Interactive analysis showed that NAT2 slow acetylator and the GSTM1 null genotype were mutually synergistic, while an antagonistic relationship was observed between the CYP2E1 wild-type genotype and the other 3 genetic types. The risks of hepatic injury were higher after anti-tuberculosis therapy in patients carrying the NAT2 slow acetylator, CYP2E1 -1259G>C, -1019C>T wild-type, and GSTM1 null genotype.

The role of NAT2 polymorphism and methylation in anti‐tuberculosis drug‐induced liver injury in Mongolian tuberculosis patients

“…All of this confirms that slow acetylation could increase the incidence of liver injury in TB patients. Research has confirmed that the risk of liver injury from a slow acetylation agent was 2.26 to 3.8 times than that of rapid acetylation agents . More importantly, data show that in the study of NAT2 genotypes, the NAT2*4/5 genotype (intermediate acetylated type) was a risk factor for ATLI in Mongolian tuberculosis patients during standardized treatment.…”

Update meta-analysis of theCYP2E1 RsaI/PstI andDraI polymorphisms and risk of antituberculosis drug-induced hepatotoxicity: evidence from 26 studies

“…As Huang et al . first reported that susceptibility to ATDH was associated with CYP2E1 genotypes, a number of association studies have been performed . However, these studies have yielded inconsistent results.…”

Association of variants within the GST and other genes with anti-tubercular agents related toxicity: a systematic review and meta-analysis

“…Twenty-two articles employed a case–control design (7, 24, 25, 27, 29–38, 40, 44, 45, 48–52), and 13 articles employed a prospective cohort design (22, 23, 26, 28, 41–43, 46, 47, 53–56). Only one (29) of the 22 articles describing case-control studies reported that the two groups were genotyped in mixed batches.…”

“…Nineteen articles (7, 23, 25–27, 30, 31, 34–37, 42, 48, 51–56) reported testing for HWE for all SNPs investigated, and a further two (43, 49) tested for HWE for a subset of SNPs. The remaining 14 articles did not report on HWE testing.…”

“…Sixteen articles made a specific assumption regarding the underlying mode of inheritance (22, 24, 27–29, 32, 33, 36, 38, 41, 44, 45, 47, 49, 54, 55). Of these, only four provided a rationale for this assumption (28, 44, 45, 54); for the remaining 12 articles, there is a risk of selective reporting where several analyses under different modes of inheritance may have been conducted, with only the most statistically significant being reported (18).…”