Genetic risk factors in drug-induced liver injury due to isoniazid-containing anti-tuberculosis 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 et al (show 8 more authors) (2020) Genetic risk factors in drug-induced liver injury due to isoniazid-containing anti-tuberculosis drug regimens. Clinical Pharmacology and Therapeutics, 109 (4). pp. 1125-1135.

[img] Text
TBv19 101020GPA (002).docx - Author Accepted Manuscript
Download (219kB)
[img] Text
Figure1forTBpaper.pdf - Author Accepted Manuscript
Download (7kB) | Preview
[img] Text
Nicoletti 2020 Anti_TB CPT Fig 070720.pdf - Author Accepted Manuscript
Download (1MB) | Preview

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.

Item Type: Article
Uncontrolled Keywords: Humans, Isoniazid, Arylamine N-Acetyltransferase, Histocompatibility Antigens Class I, Antitubercular Agents, Risk Factors, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, Chemical and Drug Induced Liver Injury, Asian People, White People
Depositing User: Symplectic Admin
Date Deposited: 10 Nov 2020 10:35
Last Modified: 13 Feb 2023 11:12
DOI: 10.1002/cpt.2100
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3106355
Dimensions
Altmetric
CORE (COnnecting REpositories)