Genome-wide association and replication study of anti-tuberculosis drugs-induced liver toxicity

Abstract

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.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).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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3078-3) contains supplementary material, which is available to authorized users.

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

“…In addition, variants in AGBL4 and FAM65B were identified as potential risk factors for ATDinduced liver toxicity through GWAS (Petros et al, 2016). In the current study, we did not find genetic variants that passed genome-wide significance level in both the pharmacokineticrelated genes and HLA region.…”

“…Genomewide association studies (GWAS) have identified variant alleles that are associated with an increased risk of developing DIH after treatment intentions with various classes of drugs (Aithal and Grove, 2015;Daly et al, 2009;Urban et al, 2014). Recently, using GWAS in Ethiopian TB patients, we have reported genetic variations in ATP-/GTP-binding proteinlike-4 (AGBL4) and family with sequence similarity 65 member-B (FAM65B) as potential risk factors for developing ATD-induced liver toxicity (Petros et al, 2016).…”

Genome-Wide Association Studies for Idiosyncratic Drug-Induced Hepatotoxicity: Looking Back–Looking Forward to Next-Generation Innovation

“…FAM65B is expressed in the hepatocytes, gall bladder, and bile duct, and a recent study indicated that FAM65B plays roles in liver inflammation (Stoyanov et al, 2015). The GWAS on the antituberculosis drug-induced liver injury also identified a cluster of SNPs in the intron of ATP/GTP-binding protein-like 4 (AGBL4) suggestive of genome-wide significant association (Petros et al, 2016). Although further analysis is required to clarify the functional importance of FAM65B and AGBL4, the study demonstrated the potential of GWASs to discover genetic risk factors that mediate DIH due to antituberculosis drugs.…”

“…To date, a few GWASs have investigated genetic associations with idiosyncratic DIH (Cao et al, 2015;Kindmark et al, 2008;Lucena et al, 2011;Parham et al, 2016;Petros et al, 2016;Singer et al, 2010;Spraggs et al, 2011;Urban et al, 2012). The top associated SNPs are summarized in Table 1.…”

“…Recently, we carried out a GWAS consisting of 48 DIH cases and 354 treatment tolerant Ethiopian tuberculosis patients treated with first-line antituberculosis drugs to identify genetic variants associated with antituberculosis druginduced hepatotoxicity (Petros et al, 2016). It was the first published GWAS for antituberculosis drug-induced hepatotoxicity in an African population.…”