Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity.
BACKGROUND
Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations. The objective of this study was to perform genome-wide association study (GWAS) to identify genetic variants associated with the risk for ATD induced liver toxicity in Ethiopian patients.


RESULTS
Treatment-naïve newly diagnosed tuberculosis patients (n = 646) were enrolled prospectively and treated with rifampicin based short course anti-tuberculosis therapy. Whole genome genotyping was done using Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on 48 DILI cases and 354 ATD tolerants. Replication study was carried out for 50 SNPs with the lowest P-values (top SNPs) using an independent cohort consisting of 27 DILI cases and 217 ATD tolerants. In the combined analysis, the top SNP identified was rs10946737 (P = 4.4 × 10-6, OR = 3.4, 95 % confidence interval = 2.2-5.3) in the intron of FAM65B in chromosome 6. In addition, we identified a cluster of SNPs with suggestive genome-wide significance in the intron of ATP/GTP binding protein-like 4 (AGBL4).


CONCLUSIONS
We identified genetic variants that are potentially associated with ATD induced liver toxicity. Further studies with larger sample sizes are essential to confirm the findings.
Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.|Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Zelalem
Z
Petros
Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Ming-Ta Michael
MM
Lee
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Atsushi
A
Takahashi
Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Yanfei
Y
Zhang
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Getnet
G
Yimer
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Abiy
A
Habtewold
Department of Internal Medicine, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Wondwossen
W
Amogne
Department of Internal Medicine, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
Getachew
G
Aderaye
AstraZeneca R&D, Innovative Medicines Personalised Healthcare & Biomarkers, SciLifeLab, Stockholm, Sweden.
Ina
I
Schuppe-Koistinen
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Taisei
T
Mushiroda
Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia. eyasumakonnen@yahoo.com.
Eyasu
E
Makonnen
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. mkubo@src.riken.jp.
Michiaki
M
Kubo
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet, SE-141 86, Stockholm, Sweden. Eleni.Aklillu@ki.se.
Eleni
E
Aklillu
AGBL4; Africa; Anti-tuberculosis; C6ORF32; Drug induced liver injury; Ethiopian; FAM65B; GWAS; Hepatotoxicity; Tuberculosis
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