Genetic Risk Factors in Drug-Induced Liver Injury Due to Isoniazid-Containing Antituberculosis Drug Regimens

Clin Pharmacol Ther. 2021 Apr;109(4):1125-1135. doi: 10.1002/cpt.2100. Epub 2020 Dec 5.

Abstract

Drug-induced liver injury (DILI) is a complication of treatment with antituberculosis (TB) drugs, especially in isoniazid (INH)-containing regimens. To investigate genetic risk factors, we performed a genomewide association study (GWAS) involving anti-TB DILI cases (55 Indian and 70 European) and controls (1,199 Indian and 10,397 European). Most cases were treated with a standard anti-TB drug regimen; all received INH. We imputed single nucleotide polymorphism and HLA genotypes and performed trans-ethnic meta-analysis on GWAS and candidate gene genotypes. GWAS found one significant association (rs117491755) in Europeans only. For HLA, HLA-B*52:01 was significant (meta-analysis odds ratio (OR) 2.67, 95% confidence interval (CI) 1.63-4.37, P = 9.4 × 10-5 ). For N-acetyltransferase 2 (NAT2), NAT2*5 frequency was lower in cases (OR 0.69, 95% CI 0.57-0.83, P = 0.01). NAT2*6 and NAT2*7 were more common, with homozygotes for NAT2*6 and/or NAT2*7 enriched among cases (OR 1.89, 95% CI 0.84-4.22, P = 0.004). We conclude HLA genotype makes a small contribution to TB drug-related DILI and that the NAT2 contribution is complex, but consistent with previous reports when differences in the metabolic effect of NAT2*5 compared with those of NAT2*6 and NAT2*7 are considered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics
  • Asians
  • Chemical and Drug Induced Liver Injury / genetics*
  • Female
  • Genome-Wide Association Study
  • Genotype
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Isoniazid / adverse effects*
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Whites

Substances

  • Antitubercular Agents
  • Histocompatibility Antigens Class I
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Isoniazid