Weighted gene co-expression network analysis and drug-gene interaction bioinformatics uncover key genes associated with various presentations of malaria infection in African children and major drug candidates.

Abstract

Malaria is a fatal parasitic disease with unelucidated pathogenetic mechanism. Herein, we aimed to uncover genes associated with different clinical aspects of malaria based on the GSE1124 dataset that is publicly accessible by using WGCNA. We obtained 16 co-expression modules and their correlations with clinical features. Using the MCODE tool, we identified THEM4, STYX, VPS36, LCOR, KIAA1143, EEA1, RAPGEF6, LOC439994, ZBTB33, PTPN22, ESCO1, and KLF3 as hub genes positively associated with Plasmodium falciparum infection (ASPF). These hub genes were involved in the biological processes of endosomal transport, regulation of natural killer cell proliferation, and KEGG pathways of endocytosis and fatty acid elongation. For the purple module negatively correlated with ASPF, we identified 19 hub genes that were involved in the biological processes of positive regulation of cellular protein catabolic process and KEGG pathways of other glycan degradation. For the salmon module positively correlated with severe malaria anemia (SMA), we identified 17 hub genes that were among those driving the biological processes of positive regulation of erythrocyte differentiation. For the brown module positively correlated with cerebral malaria (CM), we identified eight hub genes and these genes participated in phagolysosome assembly and positive regulation of exosomal secretion, and animal mitophagy pathway. For the tan module negatively correlated with CM, we identified four hub genes that were involved in CD8-positive, alpha-beta T cell differentiation and notching signaling pathway. These findings may provide new insights into the pathogenesis of malaria and help define new diagnostic and therapeutic approaches for malaria patients.