The Role of Genetic and Epigenetic Factors in Endothelial Damage and Repair among Ghanaian Children with Cerebral Malaria
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Date
2019-03
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Publisher
University of Ghana
Abstract
The declining malaria burden in endemic regions is predicted to increase the proportion
of malaria infections that progress to cerebral malaria (CM). This epidemiologic
scenario appears ominous against the backdrop of a poor understanding of CM
pathogenesis, lack of effective adjunctive therapies, and poor prognosis after onset.
Thus, the need to better understand the pathogenesis of CM has become
more apparent. To better understand the pathogenesis of CM, this study explored both
genetic and epigenetic aspects of the emerging malaria pathophysiologic paradigm,
which pivots on imbalances in endothelial damage and repair in cerebral
microvasculature during P. falciparum infections.
The Sequenom MassARRA Y platform (iPLEX) was used to genotype a focused panel
of 27 single nucleotide polymorphisms (SNPs) in a cross-sectional study involving 221
children. In silico techniques were used to characterize the epigenetic context of SNPs
and assess their potential effect on microRNAs and transcription factors. Immune cells
and angiogenic factors were measured with Human Magnetic Luminex Assay and flow
cytometry, respectively.
A striking find of this study was the association of a CDH5 SNP (rs2304527) and an
MMP9 SNP (rs3918256) with CM and endothelial integrity respectively. CDH5 SNP
(rs2304527) offered protection from CM under the over-dominant inheritance model
assumption and children with the heterozygote T/G genotype were approximately three
times less likely to have CM relative to their colleagues with the IT -GG genotype. On
the other hand, MMP9 SNP (rs3918256) was a risk factor for endothelial damage.
Relative to the reference genotype (GG), children with the AA genotype ofrs3918256
were approximately 4 times more likely to be classified as ProDamage under the
recessive inheritance model. These two SNPs were subsequently found to disrupt the
binding sites of several transcription factors involved in the angiopoietin and tie
signalling pathway. Several other SNPs were found to influence the binding affinity of
transcription factors but only two (rs3918211 and rs20544) affected micro RNA target
sites.
Receiver operating characteristic (ROC) analysis to test the ability of angiogenic factors
to discriminate between malaria and endothelial integrity phenotypes gave middling
results. The best performing angiogenic factor for discriminating eM from UM was
NGRI which had only a 66% chance of accurately discriminating eM from UM.
Similarly, all angiogenic factors performed poorly in discriminating endothelial
integrity phenotypes.
This is the first study to implicate rs2304527 and rs3918256 in the pathogenesis of eM.
Although in silico analysis suggests some epigenetic roles for these SNPs, future studies
may want to further explore their functional roles. Unfortunately, the prospects of using
angiogenic factors considered in this study to discriminate between malaria and
endothelial integrity phenotypes appear dim. Taken together, this study provides
valuable insights on the genetic and epigenetic aspects of endothelial damage and repair
during a P. falciparum malaria in Ghanaian children.
Description
PhD - Public Health
Keywords
Genetic, Epigenetic, Endothelial Damage, Cerebral Malaria, Ghana