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

• Published in: BMC genomics Vol. 17; no. 1; p. 755
• Main Authors: Petros, Zelalem, Lee, Ming-Ta Michael, Takahashi, Atsushi, Zhang, Yanfei, Yimer, Getnet, Habtewold, Abiy, Amogne, Wondwossen, Aderaye, Getachew, Schuppe-Koistinen, Ina, Mushiroda, Taisei, Makonnen, Eyasu, Kubo, Michiaki, Aklillu, Eleni
• Format: Journal Article
• Language: English
• Published: London BioMed Central 26.09.2016; BioMed Central Ltd
• Subjects: Animal Genetics and Genomics; Antitubercular agents; Biomedical and Life Sciences; Complications and side effects; Dosage and administration; Drugs; Genetic diversity; Genetic variance; Genomics; Health aspects; Human and rodent genomics; Life Sciences; Liver; Liver diseases; Microarrays; Microbial Genetics and Genomics; Plant Genetics and Genomics; Proteomics; Research Article; Risk factors; Toxicity; Tuberculosis; Ethiopia; Drug induced liver injury; GWAS; Tuberculosis; Africa; C6ORF32; Ethiopian; Anti-tuberculosis; Hepatotoxicity; AGBL4; FAM65B
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-016-3078-3

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. Result 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 ). Conclusion 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.