An investigation into the clinical, biochemical, immunological and epigenetic factors in black South Africa women with preeclampsia and HIV.
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Date
2015
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Abstract
Introduction:
Preeclampsia (PE) and HIV/AIDS contribute significantly to adverse maternal and perinatal outcomes
globally. The treatment of PE remains empiric, however in HIV infection, highly active antiretroviral
therapy (HAART) is used routinely for maternal health and the prevention of vertical transmission in
pregnancy. The relationship between PE and HIV /HAART remains controversial and despite extensive
research, the pathophysiology of both conditions is not fully understood. Contemporary and new
research strategies include immunological and genetic aspects of PE and HIV, and clinical and
biochemical effects associated with HAART.
Aims and Objectives:
The aims of the study were to determine: (1) the association of HIV and HAART with clinical and
biochemical indices in women with PE, (2) the effects of HAART in relation to inflammatory cytokines
in PE and HIV, and (3) the role of gene polymorphisms in preeclamptic women with HIV on HAART.
The specific objectives of the study were to identify significant differences (p>0.05) in the routine
clinical and laboratory indices between the preeclamptic groups, (2) to identify significant changes in
pro-inflammatory cytokines IL2, TNFα, IFNɣ and IL6 in relation to HIV / HAART and preeclampsia,
and (3) to determine the association of single nucleotide polymorphisms (SNP) miRNA 27a (rs
895819T>C) and miRNA 146a ( rs 2910164G>C) with preeclampsia risk and susceptibility to
associated factors.
Materials and Methods:
A prospective cohort study was conducted between July 2013 and September 2014 at Prince Mshiyeni
Memorial Hospital in Durban, South Africa. To maintain ethnographic and anthropometric consistency,
a standard cohort of one hundred and ninety three (193) Black women of Zulu ethnicity comprising 4
groups: i.e. uninfected normotensive (50; 26%), infected normotensive (45; 23%), uninfected
preeclamptic (53; 28%) and infected preeclamptic women (45; 23%) was recruited during pregnancy
after ethical approval and informed consent and followed until delivery. Women with gestational
hypertension, renal disease, diabetes mellitus, chronic hypertension and collagen vascular disease were
excluded. Specific patient characteristics, clinical features, laboratory indices, and complications were
analysed descriptively. Serum levels of pro-inflammatory cytokines TNF-α, IFN- γ, IL2 and IL6 were
determined, using commercially available kits and Cytometric Bead Array (CBA). Genotyping using
PCR and the TaqMan® SNP genotyping assay for single nucleotide polymorphisms miRNA 27a
rs895819T>C and miRNA 146a rs 2910164G>C was performed and analysed in relation to
preeclampsia risk, susceptibility to related clinical features and pro-inflammatory cytokines.
Comparative data was recorded and analysed descriptively.
Results:
Our results indicate that the clinical features, laboratory indices, and complications among HIV infected
preeclamptic women on HAART is similar to uninfected preeclamptic women. However,
gammaglutamyl transferase (GGT), a hepatic enzyme, was markedly elevated (p=0.001) in HIV
infected preeclamptic women on HAART. There were significant decreases in pro-inflammatory
cytokines IL2 (p=0.010), TNF-α (p=0.045), and IL6 (p=0.005), in normotensive women on HAART
compared with uninfected women and significant decreases in IL2 (p=0.000) and TNFα (p=0.000) in
preeclamptic women on HAART compared with uninfected preeclamptic women. In the genotype
analyses, we found that the variant genotypes (GC/CC) in miRNA 146a were significantly associated
with lower severe preeclampsia risk (OR: 0.34, 0.12-0.99; p=0.048), especially in the presence of
HIV/HAART (OR: 0.11; 0.02-0.68, p= 0.018), and the variant genotype (TC/CC) in miRNA 27a was
associated with an elevated BMI in preeclamptic women (32.57 vs 29.25; p= 0.06), especially in the
presence of HIV/HAART (33.47 vs 27.87; p=0.005).
Conclusion:
The effects of HIV and HAART influence biochemical, immunological and genetic aspects in women
with preeclampsia. Gammaglutamyl transferase, a hepatic enzyme, was markedly elevated and
suggests a possible compounding effect on the liver, which is a target organ for preeclampsia and the
side effects of HAART. Current management guidelines remain appropriate, however serial hepatic
function tests are necessary in clinical practice. The prevention of obesity is also necessary to reduce
long term cardiovascular complications associated with these conditions. The immune reconstitutive
effects of HAART include a reduction in pro-inflammatory cytokines in normotensive women as well
as in preeclamptic women, which may have a bearing on the clinical course of preeclampsia in women
on HAART. MiRNA 27a and miRNA 146a are endogenous small RNAs that post transcriptionally
regulate gene expression and are implicated in a plethora of pathophysiological processes related to
preeclampsia and its related features. TC/CC and GC/CC genotype variants in the functional single
nucleotide polymorphisms (SNP) microRNA27a (rs 895819 T>C) and microRNA 146a (rs
2910164G>C were associated with obesity and severe preeclampsia respectively. Obesity is a wellrecognised
risk factor for preeclampsia, and severe preeclampsia is associated with increased morbidity
and mortality. These findings demonstrate the importance of molecular genetics and inflammatory
mediators in preeclampsia, the pathogenesis of which remains multifactorial in origin.
Description
Doctor of Philosophy in Medical Biochemistry. University of KwaZulu-Natal, Medical School 2015.
Keywords
Preeclampsia., Pregnancy -- Complications -- South Africa., Pregnant women -- Genetic aspects., HIV-positive women -- South Africa., Theses -- Medical biochemistry.