Associations of Single Nucleotide Polymorphisms in IL-18 Gene with Plasmodium falciparum-Associated Malaria

Abstract

Introduction: Interleukin-18 (IL-18) is a pro-inflammatory cytokine, reported to be involved in the initial immune responses against malaria. Genetic variations in the host are an important factor that influences the etiology of malaria at several disease levels. Polymorphisms within the IL-18 gene are associated with susceptibility and clinical outcome of several diseases. Methods: We genotyped single nucleotide polymorphisms (SNPs) in IL-18 of patients infected with Plasmodium falciparum with varying extent of parasitemia and different age groups. Results: SNPs rs5744292 (OR = 70.446; 95% CI = 4.318-1149.323; p<0.0001) and rs544354 (OR = 1.498; 95% CI = 1.088-2.063; p=0.013) were found to be significantly associated with parasitemia in P. falciparum-infected patients when compared with healthy control subjects. SNP rs5744292 (OR = 7.597; 95% CI=1.028-56.156; p=0.019) was associated with increased parasite density in infected patients. SNPs rs544354 (OR 0.407; 95% CI=0.204-0.812; p = 0.009) and rs360714 (OR of 0.256; 95% CI=0.119-0.554; p = 0.001) were significantly associated with parasite density in an age-dependent manner, with the risk alleles present more frequently among the younger (1-9 years) patients. Several haplotypes were found to have a significant association with parasitemia. In-vitro expression analysis using luciferase reporter assay showed that SNPs rs1946518 and rs187238 in the IL-18 gene promoter region and rs360728 and rs5744292 in the 3ʹ-untranslated region of the IL-18 gene were associated with enhanced transcriptional activity. Conclusion:Our results suggest that polymorphisms within the IL-18 gene are associated with the susceptibility to P. falciparum infection and related parasitemia among groups with different parasite density and across various age groups.