Genetic variation influencing mitochondrial DNA copy number and the development of sensory neuropathy in HIV-positive patients exposed to stavudine

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dc.contributor.authorMarutha, Tebogo Rector
dc.date.accessioned2018-03-12T07:10:59Z
dc.date.available2018-03-12T07:10:59Z
dc.date.issued2017
dc.descriptionA dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree in Master of Science in the School of Molecular and Cell Biology August 2017en_ZA
dc.description.abstractAntiretroviral therapy (ART) drugs such as stavudine (d4T) are known to have off-target side-effects, including the inhibition of DNA polymerase gamma which replicates mitochondrial DNA (mtDNA). ART-induced depletion of mtDNA copy number may cause mitochondrial toxicities such as sensory neuropathy (SN). Genetic variation in DNA polymerase gamma or in other nuclear genes influencing mtDNA replication and mtDNA copy number may therefore contribute to susceptibility to d4T-induced SN. DNA samples from 263 HIV-positive South African adults exposed to d4T were classified as cases with SN (n = 143) and controls without SN (n = 120). A total of 28 single nucleotide polymorphism (SNPs) were chosen in nuclear genes from the mtDNA replication pathway and from a GWAS paper examining SNP association with ART-induced SN (Leger et al. 2014). Genotyping was performed using Sequenom Mass Spectrometry. MtDNA copy number was determined using a qPCR assay. Associations between SN and genetic variants, between genetic variants and mtDNA copy number, and between mtDNA copy number and SN were evaluated in univariate and multivariate models using Plink v1.07 and GraphPad v7. Age and height were significantly different in the cases with SN vs controls without SN. In univariate analyses, three SNPs and two haplotypes were significantly associated with SN, three SNPs were associated with pain intensity and three haplotypes were significantly associated with mtDNA copy number. However, there were no significant associations with SN, pain intensity or mtDNA copy number after correction for multiple SNP testing. No significant difference in mtDNA copy number in cases vs. controls was observed. In conclusion variation in nuclear-encoded mitochondrial genes examined in the current study do not play a role in ART-related mitochondrial complications such as changes in mtDNA copy number, or occurrence of SN.en_ZA
dc.description.librarianMT2018en_ZA
dc.format.extentOnline resource (xv, 152 leaves)
dc.identifier.citationMarutha, Tebogo Rector (2017) Genetic variation influencing mitochondrial DNA copy number and the development of sensory neuropathy in HIV-positive patients exposed to stavudine, University of the Witwatersrand, Johannesburg, <http://hdl.handle.net/10539/24162>
dc.identifier.urihttps://hdl.handle.net/10539/24162
dc.language.isoenen_ZA
dc.subject.lcsh
dc.subject.lcshHighly active antiretroviral therapy
dc.subject.lcshHIV-positive persons--South Africa
dc.subject.lcshMitichondrial DNA
dc.subject.lcshNeuropathy
dc.titleGenetic variation influencing mitochondrial DNA copy number and the development of sensory neuropathy in HIV-positive patients exposed to stavudineen_ZA
dc.typeThesisen_ZA
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