Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV- and ARV-ATD-induced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G→A, R919Q, p = 1.4 × 10-6, odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH (p = 5.3 × 10-7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalOMICS A Journal of Integrative Biology
Volume21
Issue number4
DOIs
Publication statusPublished - 01-04-2017

Fingerprint

Genome-Wide Association Study
Tuberculosis
Genes
Pharmaceutical Preparations
Polymorphism
Single Nucleotide Polymorphism
Nucleotides
efavirenz
HIV
Chromosomes
Therapeutics
Odds Ratio
Long Noncoding RNA
Confidence Intervals
Exome
Chromosomes, Human, Pair 12
Untranslated RNA
Precision Medicine
Chromosomes, Human, Pair 17
Africa South of the Sahara

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Petros, Zelalem ; Lee, Ming Ta Michael ; Takahashi, Atsushi ; Zhang, Yanfei ; Yimer, Getnet ; Habtewold, Abiy ; Schuppe-Koistinen, Ina ; Mushiroda, Taisei ; Makonnen, Eyasu ; Kubo, Michiaki ; Aklillu, Eleni. / Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs. In: OMICS A Journal of Integrative Biology. 2017 ; Vol. 21, No. 4. pp. 207-216.
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abstract = "Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV- and ARV-ATD-induced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-na{\"i}ve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G→A, R919Q, p = 1.4 × 10-6, odds ratio [OR] = 18.2, 95{\%} confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH (p = 5.3 × 10-7, OR = 5.4, 95{\%} CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.",
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Petros, Z, Lee, MTM, Takahashi, A, Zhang, Y, Yimer, G, Habtewold, A, Schuppe-Koistinen, I, Mushiroda, T, Makonnen, E, Kubo, M & Aklillu, E 2017, 'Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs', OMICS A Journal of Integrative Biology, vol. 21, no. 4, pp. 207-216. https://doi.org/10.1089/omi.2017.0019

Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs. / Petros, Zelalem; Lee, Ming Ta Michael; Takahashi, Atsushi; Zhang, Yanfei; Yimer, Getnet; Habtewold, Abiy; Schuppe-Koistinen, Ina; Mushiroda, Taisei; Makonnen, Eyasu; Kubo, Michiaki; Aklillu, Eleni.

In: OMICS A Journal of Integrative Biology, Vol. 21, No. 4, 01.04.2017, p. 207-216.

Research output: Contribution to journalArticle

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AU - Lee, Ming Ta Michael

AU - Takahashi, Atsushi

AU - Zhang, Yanfei

AU - Yimer, Getnet

AU - Habtewold, Abiy

AU - Schuppe-Koistinen, Ina

AU - Mushiroda, Taisei

AU - Makonnen, Eyasu

AU - Kubo, Michiaki

AU - Aklillu, Eleni

PY - 2017/4/1

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N2 - Drug-induced hepatotoxicity (DIH) is a common adverse event that is associated with both antiretroviral (ARV) and anti-tuberculosis drugs (ATD). Moreover, the genetic variations predisposing ARV- and ARV-ATD-induced liver toxicity in African populations are not well investigated, despite the two diseases being the major global health problems in sub-Saharan Africa. We performed a genome-wide association study (GWAS) and replication study to identify the genetic variants linked to the risk of developing DIH due to ARV drugs alone, and ARV-ATD co-treatment in Ethiopian HIV-positive patients. Treatment-naïve newly diagnosed HIV patients (n = 719) with or without tuberculosis (TB) co-infection were enrolled prospectively and received efavirenz-based ARV therapy with or without rifampicin-based short course ATD, respectively. Whole-genome genotyping was performed by using the Illumina Omni Express Exome Bead Chip genotyping array with 951,117 single nucleotide polymorphisms (SNPs) on a total of 41 cases of DIH, and 452 people without DIH (treatment tolerants). The replication study was carried out for 100 SNPs with the lowest p-values (top SNPs) by using an independent cohort consisting of 18 DIH cases and 208 treatment tolerants. We identified a missense SNP rs199650082 (2756G→A, R919Q, p = 1.4 × 10-6, odds ratio [OR] = 18.2, 95% confidence interval [CI] = 7.1-46.9) in an endoplasmic reticulum to the nucleus signaling-1 (ERN1) gene on chromosome 17 to be associated with DIH in the ARV-only cohort. In the ARV-ATD co-treatment groups, rs4842407, a long intergenic noncoding RNAs (lincRNAs) transcript variant on chromosome 12, was associated with DIH (p = 5.3 × 10-7, OR = 5.4, 95% CI = 2.8-10.3). These genetic variants that are putatively associated with DIH due to ARV drugs alone and ARV-ATD co-treatment establish a foundation for future personalized medicine in people with HIV and TB and call for larger studies in independent populations.

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