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

Zelalem Petros, Ming Ta Michael Lee, Atsushi Takahashi, Yanfei Zhang, Getnet Yimer, Abiy Habtewold, Wondwossen Amogne, Getachew Aderaye, Ina Schuppe-Koistinen, Taisei Mushiroda, Eyasu Makonnen, Michiaki Kubo, Eleni Aklillu

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number755
JournalBMC Genomics
Volume17
Issue number1
DOIs
Publication statusPublished - 26-09-2016

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Genome-Wide Association Study
Tuberculosis
Single Nucleotide Polymorphism
Liver
Chemical and Drug Induced Liver Injury
Pharmaceutical Preparations
Introns
Genome
Exome
Chromosomes, Human, Pair 6
Rifampin
GTP-Binding Proteins
Sample Size
Adenosine Triphosphate
Confidence Intervals
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Genetics

Cite this

Petros, Z., Lee, M. T. M., Takahashi, A., Zhang, Y., Yimer, G., Habtewold, A., ... Aklillu, E. (2016). Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity. BMC Genomics, 17(1), [755]. https://doi.org/10.1186/s12864-016-3078-3
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. / Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity. In: BMC Genomics. 2016 ; Vol. 17, No. 1.
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abstract = "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-na{\"i}ve 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.",
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Petros, Z, Lee, MTM, Takahashi, A, Zhang, Y, Yimer, G, Habtewold, A, Amogne, W, Aderaye, G, Schuppe-Koistinen, I, Mushiroda, T, Makonnen, E, Kubo, M & Aklillu, E 2016, 'Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity', BMC Genomics, vol. 17, no. 1, 755. https://doi.org/10.1186/s12864-016-3078-3

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

In: BMC Genomics, Vol. 17, No. 1, 755, 26.09.2016.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity

AU - Petros, Zelalem

AU - Lee, Ming Ta Michael

AU - Takahashi, Atsushi

AU - Zhang, Yanfei

AU - Yimer, Getnet

AU - Habtewold, Abiy

AU - Amogne, Wondwossen

AU - Aderaye, Getachew

AU - Schuppe-Koistinen, Ina

AU - Mushiroda, Taisei

AU - Makonnen, Eyasu

AU - Kubo, Michiaki

AU - Aklillu, Eleni

PY - 2016/9/26

Y1 - 2016/9/26

N2 - 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.

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