NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis

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Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10−4, odds ratio (OR)=4.75 (1.8–12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10−4, OR=3.45 (1.79–6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

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This project was funded by a grant from the Indonesian Directorate General of Higher Education (DIKTI) of the Ministry of Higher Education, Research and Technology of the Republic of Indonesia. We are also thankful to the following institutions/organizations for their support in this project: YARSI Foundation, Pasar Rebo General Hospital, and YARSI Genomic Medicine Research Group. Last, special appreciation goes to our TB collaborators under JSPS (Japan Society for the Promotion of Science) core-to-core program and all TB patients who participated in this study.

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Correspondence to Rika Yuliwulandari.

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