Gene variant screening for biomarkers significant for effective ARV therapy with a focus on tenofovir nephrotoxicity

Abstract

Recent South African studies report an increase in hospital admissions due to adverse drug reactions (ADRs), including to tenofovir disoproxil fumarate (TDF). Pharmacogenetic studies conducted in African populations have reported notable differences compared to other populations in variants associated with ADRs, including TDF-induced nephrotoxicity (clinically manifesting as acute kidney injury (AKI)), warranting their further investigation in local populations. The aim of this study was to identify variants in eight TDF implicated ADME genes and to select a subset of SNPs for a genetic association study for TDF-associated nephrotoxicity. Using next generation sequencing (NGS) to screen a cohort of 40 HIV-infected patients of Bantuspeaking origin, 275 variants were identified, including three loss of function and 40 novel variants. Based on allele frequency information (MAF>0.1) and prior association with ADRs, nine polymorphisms within five genes were prioritised for genotyping. This was done in cases presenting with AKI following TDF treatment (n=53) and in controls of similar ethnic origin not presenting with AKI (n=84). The cohort was genotyped using TaqMan® assays. A case-control association study was performed with genotypes, alleles and haplotypes using tests. Suggestive associations were detected for the ABCC2 1249A allele (p=0.02) and ABCC2 haplotypes AAC and AAT (p=0.02 and 0.03 respectively) and TDF induced AKI. The ABCC2 GTT haplotype (p=0.02) appeared to be protective of TDF induced AKI. However, the observed associations were not deemed to be significant following corrections for multiple testing. A limitation of the study was its relatively low power because of the small sample size. Therefore, findings from this work will need to be replicated in more suitably powered cohorts. Despite this, we observed evidence that suggests the potential influence of a subset of ABCC2 variants on TDFinduced AKI.