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Peer-reviewedCC BY 4.0Frontiers in Pharmacology

Whole-exome sequencing reveals cumulative rare variant burden associated with susceptibility to anti-tuberculosis drug-induced liver injury in a Han Chinese cohort

  • Yang Hao1,2
  • Xiaoqing Zhang3
  • Daiyun Huang4
  • Shengyin Qin2
  • Yunxiao Lin2
  • Jianwen Ruan5
  • Lu Shen2
  • Na Zhang2
  • Zhenting Wang6
  • Cong Huai2
  • Jianquan Zhang1
6 affiliations
  1. 1Hepatobiliary and Pancreatic Surgery, Haikou Research Institute of Xiangya School of Medicine, Central South University
  2. 2Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University
  3. 3Department of Pharmacy, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University
  4. 4Wisdom Lake Academy of Pharmacy, Xi’an Jiaotong-Liverpool University
  5. 5Department of Hepatology, Haikou Research Institute of Xiangya School of Medicine, Central South University
  6. 6Department of Urology, Haikou Research Institute of Xiangya School of Medicine, Central South University
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Abstract

Background: Anti-tuberculosis drug-induced liver injury (AT-DILI) complicates 2-28% of tuberculosis treatments, limiting therapy and occasionally causing acute liver failure. Inter-individual susceptibility remains incompletely explained by known genetic factors.

Methods: We performed an integrated whole-exome sequencing (WES) analysis of an AT-DILI cohort, combining common variant association analysis, rare variant burden testing at the gene and pathway levels, and exploratory genotype–phenotype analyses. A matched sub-cohort was further analyzed for cis genetic–epigenetic associations between genetic variants and DNA methylation.

Results: Rare variant burden analysis prioritized PTGS1 as a candidate susceptibility gene (P SKAT-O = 4.58 × 10 ⁻⁴ , Enrichment Ratio = 3.461), with an increased burden of rare functional variants observed among AT-DILI cases. Pathway-level burden analyses further indicated enrichment of biological processes related to xenobiotic metabolism, immune regulation, and cellular stress responses, including regulated cell death. A cis genetic–epigenetic association analysis in a matched sub-cohort (n = 28) identified a nominal association at the GPR132 locus, suggesting a potential relationship between genetic variation and DNA methylation. Furthermore, genotype–phenotype analyses showed that rare variant burden in S100A2 displayed nominal positive correlations with peak alanine aminotransferase (ALT) levels.

Conclusion: These findings provide an integrated characterization of candidate rare variant signals and associated biological processes in AT-DILI. The results prioritize PTGS1 and other candidate loci for further investigation and expand our understanding of potential genetic contributors to inter-individual variability in anti-tuberculosis treatment outcomes.

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Cite

BibTeXRIS
BibTeX
@article{hao2026wholeexome,
  title = {{Whole-exome sequencing reveals cumulative rare variant burden associated with susceptibility to anti-tuberculosis drug-induced liver injury in a Han Chinese cohort}},
  author = {Yang Hao and Xiaoqing Zhang and Daiyun Huang and Shengyin Qin and Yunxiao Lin and Jianwen Ruan and Lu Shen and Na Zhang and Zhenting Wang and Cong Huai and Jianquan Zhang},
  journal = {Frontiers in Pharmacology},
  year = {2026},
  month = oct,
  doi = {10.3389/fphar.2026.1952049},
  url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1952049/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Whole-exome sequencing reveals cumulative rare variant burden associated with susceptibility to anti-tuberculosis drug-induced liver injury in a Han Chinese cohort
AU  - Yang Hao
AU  - Xiaoqing Zhang
AU  - Daiyun Huang
AU  - Shengyin Qin
AU  - Yunxiao Lin
AU  - Jianwen Ruan
AU  - Lu Shen
AU  - Na Zhang
AU  - Zhenting Wang
AU  - Cong Huai
AU  - Jianquan Zhang
PY  - 2026
DA  - 2026/10/12
JO  - Frontiers in Pharmacology
DO  - 10.3389/fphar.2026.1952049
UR  - https://www.frontiersin.org/articles/10.3389/fphar.2026.1952049/full
AB  - Background: Anti-tuberculosis drug-induced liver injury (AT-DILI) complicates 2-28% of tuberculosis treatments, limiting therapy and occasionally causing acute liver failure. Inter-individual susceptibility remains incompletely explained by known genetic factors.  Methods: We performed an integrated whole-exome sequencing (WES) analysis of an AT-DILI cohort, combining common variant association analysis, rare variant burden testing at the gene and pathway levels, and exploratory genotype–phenotype analyses. A matched sub-cohort was further analyzed for cis genetic–epigenetic associations between genetic variants and DNA methylation.  Results: Rare variant burden analysis prioritized PTGS1 as a candidate susceptibility gene (P SKAT-O = 4.58 × 10 ⁻⁴ , Enrichment Ratio = 3.461), with an increased burden of rare functional variants observed among AT-DILI cases. Pathway-level burden analyses further indicated enrichment of biological processes related to xenobiotic metabolism, immune regulation, and cellular stress responses, including regulated cell death. A cis genetic–epigenetic association analysis in a matched sub-cohort (n = 28) identified a nominal association at the GPR132 locus, suggesting a potential relationship between genetic variation and DNA methylation. Furthermore, genotype–phenotype analyses showed that rare variant burden in S100A2 displayed nominal positive correlations with peak alanine aminotransferase (ALT) levels.  Conclusion: These findings provide an integrated characterization of candidate rare variant signals and associated biological processes in AT-DILI. The results prioritize PTGS1 and other candidate loci for further investigation and expand our understanding of potential genetic contributors to inter-individual variability in anti-tuberculosis treatment outcomes.
SN  - 1663-9812
ER  -