Discussion
TDF-induced renal toxicity, nephrotoxic, renal tubular dysfunction
RENAL TUBULAR DYSFUNCTION
We characterized genetic associations with renal tubular dysfunction among ART-naive Southern African participants who were randomized to the two dolutegravir arms (plus either TAF and emtricitabine, or TDF and emtricitabine) of the ADVANCE clinical trial. Among 14 polymorphisms that we prioritized based on reported associations with TDF renal toxicity or plasma tenofovir exposure, we found nominal associations with two polymorphisms previously reported – Our primary analyses focused on polymorphisms previously reported to be associated with TDF-related renal toxicity in other populations. Prior studies have implicated multidrug resistance proteins, encoded by In the present study, several To identify novel polymorphisms associated with renal outcomes, we leveraged imputed genome-wide data against the considerable knowledge generated by prior genetic association studies represented in Pharmacogenomics Knowledgebase and the GWAS Catalog. We reasoned that those polymorphisms associated with at least one drug-related phenotype in the Pharmacogenomics Knowledgebase with levels of evidence of 1 or 2 (as described in Methods) or with any trait in the GWAS Catalog at Our study has some limitations. A larger sample size would have increased power to detect associations with modest effect size, or associations with infrequent variants. We did not adjust for concomitant drugs that are potentially nephrotoxic, which may have obscured genetic associations. The study was performed exclusively in Black people living with HIV, who were previously shown to be at lower risk of renal tubular dysfunction [In conclusion, we found associations with two polymorphisms previously reported to be associated with TDF-induced renal toxicity, although in our study the associations did not withstand correction for multiple comparisons and were in the opposite directions than previously reported. We also identified genome-wide significant associations with change in eGFR and polymorphisms in 