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

Nicoletti, Paola; Devarbhavi, Harshad; Goel, Ashish; Venkatesan, Radha; Eapen, Chundamannil E.; Grove, Jane I.; Zafer, Samreen; Bjornsson, Einar; Lucena, M. Isabel; Andrade, Raul J.; Pirmohamed, Munir; Wadelius, Mia; Larrey, Dominique; Maitland-van der Zee, Anke-Hilse; Ibanez, Luisa; Watkins, Paul B.; Daly, Ann K.; Aithal, Guruprasad P.

Abstract

Drug‐induced liver injury (DILI) is a complication of treatment with anti‐tuberculosis (TB) drugs, especially in isoniazid‐containing regimens. To investigate genetic risk factors, we performed a genome‐wide association study (GWAS) involving anti‐TB DILI cases (55 Indian, 70 European) and controls (1199 Indian, 10397 European). Most cases were treated with a standard anti‐TB drug regimen; all received isoniazid. 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%CI 1.63‐4.37; P=9.4x10‐5). 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.

Citation

Nicoletti, P., Devarbhavi, H., Goel, A., Venkatesan, R., Eapen, C. E., Grove, J. I., Zafer, S., Bjornsson, E., Lucena, M. I., Andrade, R. J., Pirmohamed, M., Wadelius, M., Larrey, D., Maitland-van der Zee, A.-H., Ibanez, L., Watkins, P. B., Daly, A. K., & Aithal, G. P. (2021). Genetic Risk Factors in Drug‐Induced Liver Injury Due to Isoniazid‐Containing Antituberculosis Drug Regimens. Clinical Pharmacology and Therapeutics, 109(4), 1125-1135. https://doi.org/10.1002/cpt.2100

• Journal Article Type: Article
• Acceptance Date: Oct 15, 2020
• Online Publication Date: Dec 5, 2020
• Publication Date: 2021-04
• Deposit Date: Oct 22, 2020
• Publicly Available Date: Dec 6, 2021
• Journal: Clinical Pharmacology & Therapeutics
• Print ISSN: 0009-9236
• Electronic ISSN: 1532-6535
• Publisher: American Society for Clinical Pharmacology and Therapeutics
• Peer Reviewed: Peer Reviewed
• Volume: 109
• Issue: 4
• Pages: 1125-1135
• DOI: https://doi.org/10.1002/cpt.2100
• Keywords: drug-induced liver injury, HLA genes, adverse drug reactions, genetic polymorphisms, N-acetyltransferase 2, isoniazid
• Public URL: https://nottingham-repository.worktribe.com/output/4983499
• Publisher URL: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.2100
• Additional Information: Received: 2020-07-20; Accepted: 2020-10-15; Published: 2020-12-05