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

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.

• Authors: Paola Nicoletti, Harshad Devarbhavi, Ashish Goel, Radha Venkatesan, Chundamannil E Eapen, Jane I Grove, Samreen Zafer, Einar Bjornsson, M Isabel Lucena, Raul J Andrade, Munir Pirmohamed, Mia Wadelius, Dominique Larrey, Anke-Hilse Maitland-van der Zee, Luisa Ibanez, Paul B Watkins, Ann K Daly, Guruprasad P Aithal
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 109 Issue 4 Pg. 1125-1135 (04 2021) ISSN: 1532-6535 [Electronic] United States
• PMID: 33135175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

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

Topics

• Adult
• Aged
• Antitubercular Agents (adverse effects)
• Arylamine N-Acetyltransferase (genetics)
• Asian People
• 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
• White People