Research Article

NAT2 slow acetylator is associated with anti-tuberculosis drug-induced liver injury severity in indonesian population

*Author for correspondence: Tel.: +82 6221 420 6674; Fax: +82 6221 424 3117;

E-mail Address: rika.yuliwulandari@yarsi.ac.id

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Department of Pharmacology, Faculty of Medicine, YARSI University, Jakarta, Indonesia

Genetic Research Center, YARSI Research Institute, YARSI University, Jakarta, Indonesia

The Indonesian Pharmacogenomics Working Group, Jakarta, Indonesia

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Kinasih Prayuni

Genetic Research Center, YARSI Research Institute, YARSI University, Jakarta, Indonesia

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Retno Wilujeng Susilowati

Genetic Research Center, YARSI Research Institute, YARSI University, Jakarta, Indonesia

Department of Histology, Faculty of Medicine, YARSI University, Jakarta, Indonesia

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Subagyo

Department of Pulmonology, Pasar Rebo General Hospital, Jakarta, Indonesia

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Soedarsono

Department of Pulmonology & Respiratory Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia

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Abdul Salam M Sofro

Genetic Research Center, YARSI Research Institute, YARSI University, Jakarta, Indonesia

Department of Biochemistry, Faculty of Medicine, YARSI University, Jakarta, Indonesia

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Katsushi Tokunaga

Genome Medical Science Project (Toyama), National Center for Global Health & Medicine, Tokyo, Japan

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Jae-Gook Shin

Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea

Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea

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Published Online:8 Nov 2019https://doi.org/10.2217/pgs-2019-0131

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Abstract

Aim: We investigated the contribution of NAT2 variants and acetylator status to anti-tuberculosis drug-induced liver injury (AT-DILI) severity. Materials & methods: 100 patients with clinically severe AT-DILI and 210 non-AT-DILI controls were subjected to NAT2 genotyping by direct DNA sequencing. Results: NAT2 slow acetylator was significantly associated with AT-DILI risk (p = 2.7 × 10^-7; odds ratio [95% CI] = 3.64 [2.21–6.00]). Subgroup analysis of NAT2 ultra-slow acetylator revealed a stronger association with AT-DILI risk (p = 4.3 × 10^-6; odds ratio [95% CI] = 3.37 [2.00–5.68]). Subset analysis of NAT2 acetylator status and severity grade confirmed these results in AT-DILI patients with more severe disease whereas fast and intermediate acetylator phenotypes were associated with a decreased AT-DILI risk. Conclusion: We elucidated the role of NAT2 phenotypes in AT-DILI in Indonesian population, suggesting that NAT2 genotype and phenotype determination are important to reduce AT-DILI risk.

Keywords:

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Vol. 20, No. 18

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History

Received 14 September 2019

Accepted 14 October 2019

Published online 8 November 2019

Published in print December 2019

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: https://www.futuremedicine.com/doi/suppl/10.2217/pgs-2019-0131

Author contributions

R Yuliwulandari is an investigator that oversaw all aspects of this study; All authors were responsible for study conception and design; R Yuliwulandari, RW Susilowati, Soebagyo and Soedarsono were responsible for sample collections; K Prayuni was responsible for data acquisition; R Yuliwulandari and K Prayuni were responsible for data analysis and interpretation; R Yuliwulandari, K Tokunaga and JG Shin validated the study results; All authors discussed and revised the manuscript for submission.

Acknowledgments

The authors are thankful to the following institutions/organizations for their support in this project: YARSI Foundation, and YARSI Research Center. We also thank all the patients who participated in this study.

Financial & competing interests disclosure

This study 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 (National Competitive Grant; Grant No. 010/INT/UM/WRII/UY/VI/2019). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The study protocol was approved by the ethical review committee at YARSI University (No. 127/KEP-UY/BIA/VIII/2019). All participating patients gave their written informed consent prior to participating in the study.

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