Genetic diversity of pharmacogenes in a Bantu-speaking cohort and evaluation of variants associated with tenofovir-induced nephrotoxicity
E. Sibongile Tshabalala1, Ananyo Choudhury2, Natasha Beeton-Kempen1, Faheem Seedat3 and Ebrahim Variava3, Neil Martinson4, Michèle Ramsay2, 5 and Dalu Mancama1
1CSIR, Biosciences Unit, South Africa: 2Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, South Africa; 3Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; 4Perinatal HIV Research Unit, Baragwanath Hospital and Faculty of Health Sciences, University of the Witwatersrand, South Africa; 5Division of Human Genetics, National Health Laboratory Service, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, South Africa
Recent South African studies report an increase in hospital admissions due to adverse drug reactions (ADRs), including to tenofovir disoproxil fumarate (TDF). Growing evidence suggests a genetic contribution to TDF-related ADRs. Given the high genetic diversity observed in African populations, the aim of this study was to elucidate the pharmacological implications of such diversity by identifying and characterizing known and novel pharmacogenetic variants and evaluating their possible association with TDF-induced nephrotoxicity. Using targeted next generation sequencing to screen 40 Bantu-speaking individuals for variants in 65 genes, 1687 variants were identified; including 129 novel and 22 potential loss-of-function variants. Based on allele frequency (MAF>0.1) and prior association with ADRs, nine SNPs within five genes were prioritised for a genetic association study for TDF-induced nephrotoxicity (clinically manifesting as acute kidney injury (AKI)). A total of 137 HIV positive patients on TDF treatment were subsequently genotyped using TaqMan® assays, 53 of whom presented with AKI. Association analysis was performed with alleles, genotypes and haplotypes using χ2 tests. The ABCC2 1249A allele and ABCC2 haplotypes AAC and AAT displayed associations with TDF-induced AKI (p≤0.05). The ABCC2 GTT haplotype (p=0.02) appeared to be protective against TDF-induced AKI. However, the associations were not significant following corrections for multiple testing. Further evaluation of these ABCC2 variants in larger cohorts is warranted to establish their role, if any, in TDF-induced AKI.
