Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity

BMC Genomics

Research Article

Ina Schuppe-Koistinen¹  Wondwossen Amogne²  Getachew Aderaye²  Abiy Habtewold³  Eyasu Makonnen³  Getnet Yimer³  Eleni Aklillu⁴  Michiaki Kubo⁵  Yanfei Zhang⁶  Ming-Ta Michael Lee⁶  Zelalem Petros⁷  Taisei Mushiroda⁸  Atsushi Takahashi⁹ 

[1] AstraZeneca R&D, Innovative Medicines Personalised Healthcare & Biomarkers, SciLifeLab, Stockholm, Sweden;Department of Internal Medicine, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia;Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia;Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet, SE-141 86, Stockholm, Sweden;Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;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;Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;

关键词: Anti-tuberculosis;    Drug induced liver injury;    Ethiopian;    FAM65B;    C6ORF32;    GWAS;    AGBL4;    Hepatotoxicity;    Africa;    Tuberculosis;   

DOI  :  10.1186/s12864-016-3078-3

 received in 2015-12-18, accepted in 2016-09-08,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundDrug-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.ResultTreatment-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).ConclusionWe identified genetic variants that are potentially associated with ATD induced liver toxicity. Further studies with larger sample sizes are essential to confirm the findings.

【 授权许可】

CC BY   
© The Author(s). 2016