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<h4>Background</h4>Mitochondrial toxicity, particularly symptomatic hyperlactataemia or lactic acidosis (SHL/LA), has been attributed to the use of nucleoside reverse transcriptase inhibitors (NRTIs), possibly because of their capacity to impede human mitochondrial DNA polymerase-γ (POLG), which is responsible for the replication of mitochondrial DNA.<h4>Objective</h4>To determine whether known monogenic POLG1 polymorphisms could be linked with the unexpectedly high incidence of SHL/LA observed in HIV-infected Zulu-speaking patients exposed to the NRTIs stavudine or zidovudine in their antiretroviral therapy.<h4>Methods</h4>One hundred and sixteen patients from Edendale Hospital, Pietermaritzburg, South Africa, participated in the study between March and August 2014. Fifty-nine symptomatic cases were compared with 57 non-symptomatic controls on stavudine for ≥24 months. Among the symptomatic patients, 13 had SHL with measured lactate between 3.0 and 4.99 mmol/L, and 46 had LA with a lactate level ≥5 mmol/L. Genomic DNA from 113 samples was used for subsequent allelic discrimination polymerase chain reaction screening for the R964C and E1143G single-nucleotide polymorphisms of POLG1. Sequencing was performed for 40/113 randomly selected samples for confirmation of the genotyping results.<h4>Results</h4>Neither of the two known POLG1 mutations was observed. The cases presented with SHL/LA between 4 and 18 months on stavudine. Females (70.4%) were significantly (p&lt;0.001) more likely to be cases (adjusted odds ratio 24.24, 95% CI 5.14 - 114.25) compared with males.<h4>Conclusion</h4>This study has shown that our sample of the Zulu-speaking population does not exhibit a genetic predisposition to SHL/LA associated with known monogenic POLG1 mutations, indicating another possible predisposing factor for increased risk of SHL/LA.

Original publication

DOI

10.7196/samj.2016.v106.i12.10818

Type

Journal

South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde

Publication Date

12/2016

Volume

106

Pages

1254 - 1259

Addresses

Discipline of Genetics and Microbiology, School of Life Sciences, College of Agriculture, Engineering and Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa; Discipline of Clinical Genetics, School of Clinical Medicine, College of Health Sciences, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa. dtyachieng@hotmail.com.