Mitochondrial Genomics and Antiretroviral Therapy-Associated Metabolic Complications in HIV-Infected Black South Africans: A Pilot Study

Abstract

Studies suggest that mitochondrial DNA (mtDNA) haplogroups are associated with antiretroviral therapy (ART)-related metabolic complications and distal sensory polyneuropathy (DSP), but there have been few studies in persons of African descent. We explored such associations in South African adults. Clinical and laboratory data and DNA specimens from a cross-sectional study were used. Sequencing and Phylotree determined African mtDNA subhaplogroups. Wilcoxon and regression analyses determined associations between mtDNA subhaplogroups and ART-related complications. The 171 participants represented six major haplogroups: L0 (n=78), L1 (n=3), L2 (n=30), L3 (n=53), L4 (n=1), and L5 (n=6). Analyses were restricted to 161 participants representing L0, L2, and L3: 78% were female; the median age was 36 years. All had been exposed to thymidine analogues, 42% were on lopinavir/ritonavir (lopinavir/r), and 58% were on either efavirenz or nevirapine. Median (IQR) ART duration was 22 (14-36) months. Median fasting triglycerides were 1.60 (1.13-1.75) and 1.04 (0.83-1.45) mmol/liter among L3e1 (n=22) and other subhaplogroups, respectively (p=0.003). Subhaplogroup L3e1 [adjusted OR (aOR) 3.16 (95% CI: 1.11-8.96); p=0.03] and exposure to lopinavir/r [aOR 2.98 (95% CI: 1.02-8.96); p=0.05] were independently associated with hypertriglyceridemia, after adjusting for age, sex, and ART duration. There were no significant associations between mtDNA haplogroups and cholesterol, dysglycemia, hyperlactatemia, or lipoatrophy, or DSP. Subhaplogroup L3e1 and lopinavir/r exposure were independently associated with hypertriglyceridemia in black South Africans on ART. This is the first report to link an African mtDNA variant with hypertriglyceridemia. If replicated, these findings may provide new insights into host factors affecting metabolic complications.

Investigating the relationship between mitochondrial genetic variation and cardiovascular-related traits to develop a framework for mitochondrial phenome-wide association studies

“…Three mtSNPs (mt14152, mt15670, mt15942) significantly associated with increased risk of T2D in our population are found on the L3e1 African mitochondrial haplogroup which has previously been associated with hypertriglyceridemia in black South Africans on anti-retroviral therapy [33]. Given that high triglyceride levels are associated with increased risk for T2D, this is consistent with our finding that mtSNPs from the L3e1 haplogroup background are associated with increased risk of T2D.…”

High frequency of mitochondrial DNA mutations in HIV‐infected treatment‐experienced individuals

“…We next investigated whether there was an association between ART‐induced mitochondrial toxicity and mitochondrial haplogroup as reported previously . We found no significant association ( P = 0.58) between mitochondrial toxicity and haplogroup using a multivariate logistic model that incorporated age, gender, duration of HIV infection, duration of ART, CD4 T‐cell count and HIV viral load.…”

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

“…But because not all individuals experience adverse drug reactions when treated with HIV antiretrovirals, there also may be a genetic predisposition to occurrence of side-effects. To date, investigations into genetic risk factors for SN have focused on genes related to mitochondrial function [ 10 , 11 ] and inflammation [ 12 , 13 , 14 ]. However variation in the enzymes responsible for d4T transport and drug metabolism, which may influence susceptibility to d4T adverse reactions, has not yet been investigated.…”