THE ROLE OF GENETIC AND EPIGENETIC FACTORS IN ENDOTHELIAL DAMAGE AND REPAIR AMONG GHANAIAN CHILDREN WITH CEREBRAL MALARIA

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.