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 i...

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Published inBMC 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
LanguageEnglish
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
Online AccessGet full text
ISSN1471-2164
1471-2164
DOI10.1186/s12864-016-3078-3

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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-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.
AbstractList 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. 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 x 10.sup.-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). 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.
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. 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 , 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). 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.
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 × 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.
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.
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.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.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).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).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.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.
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 x 10.sup.-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. Keywords: Anti-tuberculosis, Drug induced liver injury, Ethiopian, FAM65B, C6ORF32, GWAS, AGBL4, Hepatotoxicity, Africa, Tuberculosis
ArticleNumber 755
Audience Academic
Author Lee, Ming-Ta Michael
Yimer, Getnet
Makonnen, Eyasu
Aderaye, Getachew
Amogne, Wondwossen
Petros, Zelalem
Aklillu, Eleni
Takahashi, Atsushi
Kubo, Michiaki
Habtewold, Abiy
Zhang, Yanfei
Schuppe-Koistinen, Ina
Mushiroda, Taisei
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  email: Eleni.Aklillu@ki.se
  organization: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68, Karolinska Institutet
BackLink https://www.ncbi.nlm.nih.gov/pubmed/27671213$$D View this record in MEDLINE/PubMed
http://kipublications.ki.se/Default.aspx?queryparsed=id:134267199$$DView record from Swedish Publication Index
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Issue 1
Keywords Drug induced liver injury
GWAS
Tuberculosis
Africa
C6ORF32
Ethiopian
Anti-tuberculosis
Hepatotoxicity
AGBL4
FAM65B
Language English
License Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Snippet Background Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations....
Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations. The objective...
Background Drug-induced liver injury (DILI) is a well-recognized adverse event of anti tuberculosis drugs (ATD) possibly associated with genetic variations....
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SubjectTerms 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
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Title Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity
URI https://link.springer.com/article/10.1186/s12864-016-3078-3
https://www.ncbi.nlm.nih.gov/pubmed/27671213
https://www.proquest.com/docview/1870225396
https://www.proquest.com/docview/1835412849
https://pubmed.ncbi.nlm.nih.gov/PMC5037629
http://kipublications.ki.se/Default.aspx?queryparsed=id:134267199
Volume 17
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