GENETIC SUSCEPTIBILITY TO CEREBRAL MALARIA: A GWAS STUDY

Abstract

Cerebral malaria is a life-threatening neurological complication of Plasmodium falciparum infection, predominantly affecting children in sub-Saharan Africa. While many individuals are exposed to the parasite, only a subset develops cerebral malaria, suggesting a pivotal role for host genetic susceptibility. This study aimed to identify genetic variants associated with susceptibility to cerebral malaria using a genome-wide association study (GWAS) approach. A total of 1,000 children (500 cases with cerebral malaria and 500 controls with uncomplicated malaria) were genotyped using high-density SNP arrays. Rigorous quality control procedures were applied, and population stratification was corrected using principal component analysis. To assess the SNPs and illness link, a logistic regression method was applied while also considering age, sex and ancestry.  After looking at replication results in a Ghanaian cohort, we used gene ontology enrichment to determine the significance of the genes. Several, but specifically ten, DNA variations were discovered by the GWAS on chromosomes 6, 9 and 11 and these variations were found to play important roles in immune stimulation and endothelial health.  Because the odds ratios ranged from 1.4 to 2.5, it was clear that these SNPs might become genetic markers of risk.  In other locations, evidence of a connection was also uncovered (p < 1 x 10⁻⁵).  Nominal significance was seen in four SNPs, whereas seven SNPs were confirmed to be associated by the replication study in Ghana.  In gene ontology analysis, significant details were found in pathways involving leukocyte adhesion, cytokine behavior and barrier breakdown for the brain, all of which are related to the symptoms of cerebral malaria.  After principal component analysis, we found only little population substructure bias and this did not affect the performance of the logistic regression models.  Apart from explaining molecular pathways related to severe malaria, this research proposes genes that put people at risk of cerebral malaria and suggests areas for consideration in risk assessment and treatment.