Rika Yuliwulandari1,2,3, Kinasih Prayuni2, Retno Wilujeng Susilowati2,4, Abdul Salam M Sofro2,5, Katsushi Tokunaga6, Jae-Gook Shin7,8. 1. Department of Pharmacology, Faculty of Medicine, YARSI University, Jakarta, Indonesia. 2. Genetic Research Center, YARSI Research Institute, YARSI University, Jakarta, Indonesia. 3. The Indonesian Pharmacogenomics Working Group, Jakarta, Indonesia. 4. Department of Histology, Faculty of Medicine, YARSI University, Jakarta, Indonesia. 5. Department of Biochemistry, Faculty of Medicine, YARSI University, Jakarta, Indonesia. 6. Genome Medical Science Project (Toyama), National Center for Global Health & Medicine, Tokyo, Japan. 7. Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea. 8. Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
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.
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.
Authors: Luis Jaramillo-Valverde; Kelly S Levano; David D Tarazona; Silvia Capristano; Roberto Zegarra-Chapoñan; Cesar Sanchez; Velia M Yufra-Picardo; Eduardo Tarazona-Santos; Cesar Ugarte-Gil; Heinner Guio Journal: Mol Genet Genomic Med Date: 2022-06-24 Impact factor: 2.473