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Genetic variations in toll-like receptors and cytokine genes of the innate immune pathways have been implicated in controlling parasite growth and the pathogenesis of  Plasmodium falciparum  mediated malaria. We previously published genetic association of  TLR4  non-synonymous and  TNF-α  promoter polymorphisms with  P.falciparum  blood infection level and here we extend the study considerably by (i) investigating genetic dependence of parasite-load on interleukin-12B polymorphisms, (ii) reconstructing gene-gene interactions among candidate  TLR s and cytokine loci, (iii) exploring genetic and functional impact of epistatic models and (iv) providing mechanistic insights into functionality of disease-associated regulatory polymorphisms. Our data revealed that carriage of AA (P = 0.0001) and AC (P = 0.01) genotypes of  IL12B  3′UTR polymorphism was associated with a significant increase of mean log-parasitemia relative to rare homozygous genotype CC. Presence of  IL12B+1188  polymorphism in five of six multifactor models reinforced its strong genetic impact on malaria phenotype. Elevation of genetic risk in two-component models compared to the corresponding single locus and reduction of  IL12B  (2.2 fold) and lymphotoxin-α (1.7 fold) expressions in patients'peripheral-blood-mononuclear-cells under  TLR4Thr399Ile  risk genotype background substantiated the role of Multifactor Dimensionality Reduction derived models. Marked reduction of promoter activity of  TNF-α  risk haplotype (C-C-G-G) compared to wild-type haplotype (T-C-G-G) with (84%) and without (78%) LPS stimulation and the loss of binding of transcription factors detected  in-silico  supported a causal role of  TNF-1031 . Significantly lower expression of  IL12B+1188  AA (5 fold) and AC (9 fold) genotypes compared to CC and under-representation (P = 0.0048) of allele A in transcripts of patients' PBMCs suggested an Allele-Expression-Imbalance. Allele ( A+1188C ) dependent differential stability (2 fold) of  IL12B -transcripts upon actinomycin-D treatment and observed structural modulation (P = 0.013) of RNA-ensemble were the plausible explanations for AEI. In conclusion, our data provides functional support to the hypothesis that de-regulated receptor-cytokine axis of innate immune pathway influences blood infection level in  P. falciparum  malaria.

Gene-Gene Interaction and Functional Impact of Polymorphisms on Innate Immune Genes in Controlling Plasmodium falciparum Blood Infection Level