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

被引：35

作者：

Petros, Zelalem ^{[1
,2
]}

Lee, Ming-Ta Michael ^{[1
]}

Takahashi, Atsushi ^{[3
]}

Zhang, Yanfei ^{[1
]}

Yimer, Getnet ^{[2
]}

Habtewold, Abiy ^{[2
]}

Amogne, Wondwossen ^{[4
]}

Aderaye, Getachew ^{[4
]}

Schuppe-Koistinen, Ina ^{[5
]}

Mushiroda, Taisei ^{[6
]}

Makonnen, Eyasu ^{[2
]}

Kubo, Michiaki ^{[7
]}

Aklillu, Eleni ^{[8
]}

机构：

[1] RIKEN Ctr Integrat Med Sci, Lab Int Alliance Genom Res, Yokohama, Kanagawa, Japan

[2] Univ Addis Ababa, Coll Hlth Sci, Sch Med, Dept Pharmacol, Addis Ababa, Ethiopia

[3] RIKEN Ctr Integrat Med Sci, Lab Stat Anal, Yokohama, Kanagawa, Japan

[4] Univ Addis Ababa, Coll Hlth Sci, Sch Med, Dept Internal Med, Addis Ababa, Ethiopia

[5] AstraZeneca R&D, SciLifeLab, Innovat Med Personalised Healthcare & Biomarkers, Stockholm, Sweden

[6] RIKEN Ctr Integrat Med Sci, Lab Pharmacogen, Yokohama, Kanagawa, Japan

[7] RIKEN Ctr Integrat Med Sci, Lab Genotyping Dev, Yokohama, Kanagawa, Japan

[8] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Div Clin Pharmacol,Dept Lab Med, C1 68, S-14186 Stockholm, Sweden

来源：

BMC GENOMICS | 2016年 / 17卷

基金：

瑞典研究理事会;

关键词：

Anti-tuberculosis; Drug induced liver injury; Ethiopian; FAM65B; C6ORF32; GWAS; AGBL4; Hepatotoxicity; Africa; Tuberculosis; INDUCED HEPATOTOXICITY; GENETIC POLYMORPHISMS; SUSCEPTIBILITY; INJURY; POPULATION; PROGRESS; COMPLEX; RISK;

D O I：

10.1186/s12864-016-3078-3

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

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-naive 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 x 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.

引用

页数：8

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