Pharmacogenetic variation influences sensory neuropathy occurrence in Southern Africans treated with stavudine-containing antiretroviral therapy

Abstract

BackgroundThe use of the HIV antiretroviral drug stavudine (d4T), a thymidine analogue, is associated with the development of mitochondrial toxicities such as sensory neuropathy (SN). Genetic variation in genes relating to d4T transport and metabolism, as well as genetic variation in the thymidine synthesis pathway, could influence occurrence of d4T-related toxicity.MethodsWe examined this hypothesis in a cohort of HIV-positive South African adults exposed to d4T, including 143 cases with SN and 120 controls without SN. Ten SNPs in four genes associated with stavudine transport, and 16 SNPs in seven genes of the thymidine synthesis / phosphorylation pathway were genotyped using Agena mass spectrometry methods. Associations between sensory neuropathy and genetic variants were evaluated using PLINK by univariate and multivariable analyses.ResultsAge and height were significantly associated with SN occurrence. Using logistic regression with age and height as covariates, and uncorrected empirical p-values, genetic variation in SLC28A1, SAMHD1, MTHFR and RRM2B was associated with SN in South Africans using d4T.ConclusionVariation in genes relating to d4T transport and metabolism, as well as genetic variation in the thymidine synthesis pathway may influence occurrence of d4T-related SN. These data contribute to the characterisation of African pharmacogenetic variation and its role in adverse response to antiretroviral therapy.

Human immunodeficiency virus–related peripheral neuropathy: A systematic review and meta‐analysis

“…Moketla and colleagues performed a study in subjects taking stavudine therapy, in which the authors hypothesised that genetic variation in genes involved in stavudine transport and metabolism as well as thymidine synthesis pathways may be implicated as risk factors for development of NRTI‐associated sensory neuropathy [67]. Genetic variants of the SLC28A1 , SAMHD1 , MTHFR and RRM2B were significantly associated with sensory neuropathy in the stavudine‐using population.…”

Inferior Colliculus Transcriptome After Status Epilepticus in the Genetically Audiogenic Seizure-Prone Hamster GASH/Sal

“…The two families of nucleoside transporters SLC28 and SLC29 have several members that participates in modulating neurotransmission, vascular tone, immune responses and other physiological processes (Mulinta et al, 2017). The Slc28a1 gene stands out as the protein-coding gene for Solute Carrier Family 28 Member 1 (Pastor-Anglada et al, 2005), and has been related to some pathologies such as cancer (Wang and Buolamwini, 2019), atrial fibrillation (Lin et al, 2016), and antiretroviral therapy absorption (Moketla et al, 2018), but not to epilepsy. Thus, Slc28a1 overexpression in the IC of GASH/Sal animals in comparison with their controls may result from a process of physiological compensation whereby Slc28a1 overexpression increases nucleic acid synthesis toward activating molecular processes to attenuate cellular stress, and consequently, contributing to epileptogenesis in the GASH/Sal.…”

Epidemiology of HIV-associated peripheral neuropathy in people living with human immunodeficiency virus infection in Greece

“…18 Different genetic backgrounds of study populations also seem to be responsible for the occurrence and progression of various diseases, including DSPN, as well as susceptibility to drug-induced toxicity. [19][20][21][22][23][24] The investigation of various risk factors for the development of PN in people living with HIV throughout international literature has diachronically yielded contradictory or at least inconclusive findings. The major finding of the studies regarding PN-association with aggravating factors during the "pre-HAART" era was patients' high viral load and low CD4 T-cell countand therefore AIDS staging or severity.…”