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
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 .
OMICS. 2017 Apr;21(4):207-216. doi: 10.1089/omi.2017.0019.
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, 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, 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.
药物性肝毒性（DIH）是一种常见的不良事件，与抗逆转录病毒药物（ARV）和抗结核药物（ATD）均有关联。此外，尽管这两种疾病是撒哈拉以南非洲地区的主要全球健康问题，但非洲人群中导致ARV和ARV-ATD诱导肝毒性的基因变异尚未得到充分研究。我们进行了一项全基因组关联研究（GWAS）和重复研究，以确定与埃塞俄比亚HIV阳性患者仅因ARV药物以及ARV-ATD联合治疗而发生DIH风险相关的基因变异。前瞻性招募了初治的新诊断HIV患者（n = 719），这些患者有或无结核（TB）合并感染，分别接受了基于依非韦伦的ARV治疗，有或无基于利福平的短程ATD治疗。使用Illumina Omni Express Exome Bead Chip基因分型芯片对总共41例DIH患者和452例无DIH患者（治疗耐受者）进行全基因组基因分型，该芯片包含951,117个单核苷酸多态性（SNP）。通过使用由18例DIH患者和208例治疗耐受者组成的独立队列，对p值最低的100个SNP（顶级SNP）进行重复研究。我们在17号染色体上的内质网到细胞核信号传导-1（ERN1）基因中鉴定出一个错义SNP rs199650082（2756G→A，R919Q，p = 1.4×10，优势比[OR] = 18.2，95%置信区间[CI] =
