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Whole exome sequencing identifies rare variants involved in PPIX-metabolizing pathway in anti-TB drug-induced

Yu Wu1, Lihuan Lu2, Fei Wang1

  • 1Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, P. R. China.

Pharmacogenomics
|December 10, 2025
PubMed
Abstract

Insights

Rare variants in the NCOA3 gene, specifically rs2230782, are linked to anti-tuberculosis drug-induced hepatitis (AT-DIH). This finding may help predict AT-DIH risk in patients undergoing tuberculosis treatment.

Area of Science:

  • Genetics
  • Pharmacogenomics
  • Hepatology

Background:

  • Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a significant clinical concern.
  • The protoporphyrin IX (PPIX)-metabolizing pathway is implicated in drug metabolism and potential toxicity.
  • Identifying genetic factors influencing AT-DIH risk is crucial for personalized treatment strategies.

Purpose of the Study:

  • To screen and validate rare genetic variants within the PPIX-metabolizing pathway associated with AT-DIH.
  • To investigate the role of the nuclear receptor coactivator 3 (NCOA3) gene in AT-DIH susceptibility.
  • To identify specific NCOA3 variants that predict the risk of developing AT-DIH.

Main Methods:

  • A two-stage matched case-control study design was employed, involving whole exome sequencing (WES) for screening and TaqMan genotyping for validation.
  • Statistical analyses included the optimal sequence kernel association test (SKAT-O) and set-based tests, with false discovery rate (FDR) correction for multiple comparisons.
  • In silico algorithms were used to predict the deleteriousness of identified NCOA3 rare variants.

Main Results:

  • The NCOA3 gene was significantly associated with AT-DIH risk.
  • Seven prediction algorithms identified four rare NCOA3 variants as potentially deleterious.
  • The CC genotype of the NCOA3 rs2230782 polymorphism was strongly associated with an increased risk of AT-DIH (OR = 15.074).

Conclusions:

  • The NCOA3 gene, particularly the rs2230782 polymorphism, is significantly associated with AT-DIH in Chinese patients treated for tuberculosis.
  • These findings suggest that NCOA3 rs2230782 genotype may serve as a potential biomarker for predicting AT-DIH risk.
  • Further research is warranted to elucidate the precise mechanisms linking NCOA3 variants to drug-induced liver injury.
Keywords:
Whole exome sequencinganti- tuberculosis treatmentdrug-induced hepatitisnuclear receptor coactivator 3protoporphyrin IXrare variants

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