UCSF

Since the emergence of the HIV epidemic it has been recognized that complications to HIV infection and variations in drug response and toxicity are influenced by patient genetics. Identification of genetic predictors of HIV infection complications and variation in drug response and toxicity will lead to better treatment options for patients and reduce HIV-related mortality and morbidity. This dissertation contains research that uses candidate gene and genome-wide approaches to identify and characterize novel genetic predictors of nevirapine pharmacokinetics, nucleoside reverse transcriptase inhibitor-induced peripheral neuropathy and HIV-induced peripheral neuropathy. This research demonstrates that nevirapine pharmacokinetic properties are heritable in European and African patients and characterizes the significant effects of CYP2B6 516G>T, CYP2B6 983T>C and ABCC10 rs2125739 on nevirapine Cmin concentrations in a Ugandan HIV+ population. It also highlights the importance of considering all three polymorphisms for prediction of nevirapine Cmin. This dissertation also explores the genetic predictors of NRTI-SN using whole genome and candidate gene approaches in a Ugandan HIV+ population. A polymorphism in VAMP4, rs188298690, was identified in the whole genome study and bioinformatic analyses found that this marker is in an active regulatory region and also a population specific eQTL locus. The candidate gene analysis found that polymorphisms in SLC28A1 and ABCC4 are predictive of the development of NRTI-SN. Finally, this dissertation describes research to identify genetic predictors of HIV-SN. Several polymorphisms in the FOLH1 region were identified in a whole genome study and bioinformatic analyses support a role for these polymorphisms in determining FOLH1 expression. Analysis of the top FOLH1 polymorphism in additional samples showed a trend towards significance and a meta-analysis of the discovery and replication cohorts had improved statistical significance. The research obtained in this dissertation increases the understanding of the role of genetic variation in determining antiviral pharmacokinetics and toxicity and in complications to HIV infection.