(C39) Genetic polymorphism and risk of anti-tuberculosis drug-induced liver injury (ATDILI): a systematic review and meta-analysis

Publication Number: 983

Background: Anti-tuberculosis (TB) drugs such as isoniazid, rifampin, and ethambutol have been related to serious side effects, most importantly hepatotoxicity leading to treatment termination. Genome-wide association studies (GWAS) have identified several significant variants associated with developing anti-tuberculosis drug-induced liver injury (ATDILI). However, the findings from replicating genotype-phenotype associations are conflicting.

Objectives: This study aimed to systematically summarize the results of previous observational studies and quantify the association between genetic polymorphisms and the ATDILI risk among adult individuals.

Methods: PubMed, EMBASE, and Cochrane Library databases were searched from inception to January 10, 2023. The Newcastle–Ottawa Scale checklist was used to assess the methodological quality of included studies. Pooled odds ratios (OR) with 95% confidence intervals (CIs) were employed using a random effect model, with the I2 statistic to estimate the heterogeneity of results.

Results: In total, 20,537 individuals from 64 candidate gene studies and 2 GWAS were included in our review. However, due to heterogeneity, only 10 studies (n=3,322) from Asian ancestry were meta-analyzed. Our results showed the contribution of genetic variants in drug-metabolizing enzymes, including N-acetyltransferase 2 (NAT2), cytochrome P450 2E1 (CYP2E1), and in the pregnane X receptor (PXR) associated with the ATDILI risk.
The risk of ATDILI was significantly increased with CYP2E1 C1/C1 (3 studies (n=741); OR= 2.49, 95% CI: 1.37-4.50; I2:0.0%) and slow acetylators of NAT2*6A/*6A (7 studies (n=1,441); OR=4.24, 95% CI: 2.87-6.26; I2: 0.0%), NAT2*6A/*7B (7 studies (n=1,441); OR=3.78, 95% CI: 2.11-6.76; I2: 51%), NAT2*7B/*7B (6 studies (n=1,278); OR=2.68, 95% CI: 1.30-5.51; I2: 0.0%) and NAT2*5B/*7B (5 studies (n=867); OR=2.93, 95% CI: 1.40-6.12; I2: 45%) genotypes. Conversely, the risk of ATDILI was decreased with rapid acetylators of NAT2*4/*4(OR=0.49, 95% CI: 0.36-0.66; I2: 18% and NAT2*4/*7B (OR=0.40, 95% CI: 0.27-0.58; I2: 49%) in 7 studies (n=1,441). No significant association was found between CYP2E1*B C1/C2, NAT2(*4/*6A, *4/*5B, *5B/*5B) and PXR with the ATDILI risk.

Conclusions: Our study showed a causal relationship between NAT2 slow acetylator genotypes and CYP2E1 C1/C1 with the risk of ATDILI and suggested that genetic variants in drug-metabolizing enzymes regulated by NAT2 and CYP2E1 are involved in the pathogenesis of drug-induced liver injury in users of these medications.