title: Genome-Wide Association and Replication Study of Hepatotoxicity Induced by Antiretrovirals Alone or with Concomitant Anti-Tuberculosis Drugs.
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.
authors.affiliation: 1 Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences , Yokohama, Japan .|2 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
authors.forename: Zelalem
authors.initials: Z
authors.lastname: Petros
authors.affiliation: 1 Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences , Yokohama, Japan .
authors.forename: Ming Ta Michael
authors.initials: MT
authors.lastname: Lee
authors.affiliation: 3 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences , Yokohama, Japan .
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takahashi
authors.affiliation: 1 Laboratory for International Alliance on Genomic Research, RIKEN Center for Integrative Medical Sciences , Yokohama, Japan .
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 2 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
authors.forename: Getnet
authors.initials: G
authors.lastname: Yimer
authors.affiliation: 2 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
authors.forename: Abiy
authors.initials: A
authors.lastname: Habtewold
authors.affiliation: 4 Department of Physiology and Pharmacology, Science for Life Laboratory, Karolinska Institutet , Stockholm, Sweden .
authors.forename: Ina
authors.initials: I
authors.lastname: Schuppe-Koistinen
authors.affiliation: 5 Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences , Yokohama, Japan .
authors.forename: Taisei
authors.initials: T
authors.lastname: Mushiroda
authors.affiliation: 2 Department of Pharmacology, School of Medicine, College of Health Sciences, Addis Ababa University , Addis Ababa, Ethiopia .
authors.forename: Eyasu
authors.initials: E
authors.lastname: Makonnen
authors.affiliation: 6 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences , Yokohama, Japan .
authors.forename: Michiaki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: 7 Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge C1:68 , KarolinskaInstitutet, Stockholm, Sweden .
authors.forename: Eleni
authors.initials: E
authors.lastname: Aklillu
mesh_terms: D000328:Adult; D018501:Antirheumatic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D018501:Antirheumatic Agents; D000995:Antitubercular Agents
keywords: Africa; GWAS; OMICS; anti-tuberculosis drugs; antiretroviral drugs; drug-induced hepatotoxicity; genome-wide association study