Genes linked to TB drug liver injury risk

Treatment for tuberculosis can be lifesaving, but the standard drugs isoniazid and rifampin sometimes damage the liver, forcing patients to stop therapy. Genome-wide association studies (GWAS) have pointed to genetic differences that might explain who develops anti-tuberculosis drug-induced liver injury (AT-DILI), but results have been inconsistent. To bring clarity, a team led by corresponding author Fariba Ahmadizar performed a systematic review and meta-analysis of observational studies that looked for links between genetic polymorphisms and AT-DILI risk in adults. The investigators searched major medical databases to collect all relevant studies, evaluated the quality of the evidence, and combined findings across studies. Their goal was to see whether specific versions of genes that help the body process drugs were consistently associated with higher or lower risk of liver harm from anti-TB therapy. By pooling data, the researchers aimed to reveal patterns that individual small studies could miss and to identify genetic markers that might explain why some patients suffer toxicity while others do not.

The researchers searched PubMed, EMBASE, and Cochrane Libraries up to January 10, 2023, and assessed study quality using the Newcastle-Ottawa Scale checklist. They pooled results using odds ratios (OR) with 95% confidence intervals (CIs) in a random-effect model and reported heterogeneity with the I 2 statistic. Ten studies met their criteria, totaling 3,322 participants of Asian ancestry. Across these studies, variants in drug-metabolizing enzyme genes NAT2, CYP2E1, and the regulator PXR were examined for links to AT-DILI. The analysis found that CYP2E1 C1/C1 and several NAT2 slow acetylator genotypes—NAT2*6A/6A, NAT26A/7B, NAT27B/7B, and NAT25B/7B—were associated with increased risk of AT-DILI. Conversely, rapid acetylator genotypes NAT24/4 and NAT24/7B were linked to decreased risk. No significant associations were found for CYP2E1B C1/C2, NAT2(*4/*6A, *4/*5B, *5B/*5B), or PXR. The authors conclude that NAT2 slow acetylator genotypes or CYP2E1 C1/C1 are causally linked to AT-DILI risk.

These findings highlight that genetic differences in the enzymes that process anti-TB drugs contribute to who will develop liver injury while taking isoniazid and rifampin. By pointing specifically to NAT2 slow acetylator genotypes and CYP2E1 C1/C1 as causal factors, the study narrows the search for biological mechanisms behind AT-DILI and supports the idea that drug-metabolizing pathways are central to this adverse effect. For clinicians and researchers, the results suggest that testing for these genetic markers could eventually help identify patients at higher risk, inform monitoring strategies, and stimulate research into safer treatment approaches for people with susceptible genotypes. The review also shows where evidence is still lacking—several NAT2 variants and PXR did not show clear links—so future work can focus on confirming the most important genetic predictors and understanding how they interact with drugs, dose, and patient factors to produce liver injury.