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-ATDinduced 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.

Genetic Risk Factors in Drug‐Induced Liver Injury Due to Isoniazid‐Containing Antituberculosis Drug Regimens

“…Similar to the findings in two earlier GWAS involving Europeans, 20,21 we failed to detect genomewide significance when we undertook a GWAS in the Indian population. This is in contrast to the recent GWAS performed on a Thai population, where genomewide significance was seen for NAT2 , 19 but is more consistent with a separate GWAS performed in Ethiopians, which also failed to observe genomewide significant signals, 38 although the Ethiopian patients were also undergoing HIV treatments that can cause DILI. In our enlarged European population, which includes the previously studied cases 20,21 as well as eight new cases, 29 we did see one genomewide significant signal in an intronic SNP in ASTN2 .…”

“…to observe genomewide significant signals, 38 although the Ethiopian patients were also undergoing HIV treatments that can cause DILI. In our enlarged European population, which includes the previously studied cases 20,21 as well as eight new cases, 29 we did see one genomewide significant signal in an intronic SNP in ASTN2.…”

Research Progress of Pharmacogenomics in Drug-Induced Liver Injury

“…The slow metabolites of UGT1A6 and UGT1A9 are related to the liver injury induced by tolcapone ( Alfirevic and Pirmohamed, 2012 ), which may be due to the decrease of enzyme activity and the accumulation of toxic substances. In addition, the UGT2B7 rs7439366 allele is associated with an increased risk of diclofenac-induced liver damage ( Daly et al, 2007 ; Petros et al, 2017 ), and the mechanism may be the allelic variation leading to the formation of active diclofenac metabolites that trigger DILI.…”

“…Chinese patients with the nuclear export protein 1 ( XPO1 ) rs4430924 AA genotype were also at significantly higher risk of developing antituberculosis drug-induced hepatotoxicity than those with the GG genotype ( He et al, 2019 ). In antiretroviral therapy, rs199650082 of nucleus signaling-1 ( ERN1 ) is significantly related to DILI, while in antiretroviral therapy combined with anti-tuberculosis therapy, transcriptional variation of synaptotagmin 1 ( Syt1 ) rs4842407 is associated with DILI ( Petros et al, 2017 ). Syt1 is a long intergene non-coding RNAs (lincRNAs) on chromosome 12, which plays a vital role in endocytosis, exocytosis, and the perception of Ca2+ concentration during vesicle transport; a recent experiment has shown that inhibiting its expression can inhibit the invasion and metastasis of liver cancer ( Xu et al, 2020 ).…”

DataRemix: a universal data transformation for optimal inference from gene expression datasets

“…Three downstream genes associated with rs2331413 are likewise endoplasmic reticulum proteins. The ERN1 locus has been associated with several phenotypes in GWAS studies, most notably drug induced hepatotoxicity (Petros et al (2017)).…”