Genetic variants of tumor necrosis factor-α -308G/A (rs1800629) but not Toll-interacting proteins or vitamin D receptor genes enhances susceptibility and severity of malaria infection.

Susceptibility to malaria infection has been associated with host genetic polymorphisms that differs between groups. We hypothesize that Toll-interacting proteins (TOLLIP), vitamin D receptor (VDR) and tumor necrosis factor-α (TNF) genes are significant contributors to susceptibility and disease severity in Plasmodium falciparum (Pf) infection. Our aim is to explore the genomic diversity and haplotype frequency of these genes, as well as extrapolate possible association with markers of severity, between malaria-infected and healthy controls. Genomic DNA samples extracted from the blood of 107 malaria-infected patients and 190 uninfected controls were analyzed, with no difference in genotypic or allelic frequencies of TOLLIP and VDR polymorphisms. However, a significant difference in the genotypic (p = 2.20E-16) and allelic frequencies (p = 2.20E-16) of the TNF-α (snp rs1800629) polymorphism was found. The preponderance of the mutant variant among the malaria-infected show a possible impaired capacity to mount an effective immune response, potentially confirmed by our association results. This result calls for analysis of clearly delineated uncomplicated versus severe disease groups, including serum assays, providing a basis to conclude that susceptibility to malaria infection and potential contribution to disease severity is significantly associated with polymorphisms of the tumor necrosis factor-α but not TOLLIP or VDR genes.

Genetic Diversity of CD14 Promoter Gene Polymorphism (rs2569190) is Associated With Regulation of Malaria Parasitemia and Susceptibility to Plasmodium falciparum Infection.

CD14 is a multifunctional receptor expressed on many cell types and has been shown to mediate immune response resulting in the activation of an inflammatory cascade, with polymorphism of its promoter (rs2569190) found to be associated with susceptibility to several diseases. In malaria infection, the CD14 gene demonstrated a pathogenic profile in regulating experimental cerebral malaria, with reports of elevated levels of soluble CD14 in serum of patients but no definitive conclusion. We present a detailed analysis of genetic diversity of CD14 promoter gene (snp -159 C/T; rs2519190) polymorphism between a malaria-infected group and uninfected controls and its association with clinical parameters of disease. Genomic DNA samples obtained from 106 Plasmodium falciparum malaria-infected patients and 277 uninfected controls were elucidated with a polymerase chain reaction-restriction fragment length polymorphism (RFLP) assay. Our results show a significant diversity (P = 3.32E-06) in the genotypic frequency (3.8% versus 22.4%) of the rs2569190 mutant variant between the malaria-infected group and controls, respectively. The mutant allele had the lowest frequency among the malaria-infected group demonstrating its necessity for infection. Mean parasitemia (parasites/µL of blood) was significantly regulated based on CD14 polymorphic profile (19 855 versus 37 041 versus 49 396 for homozygote mutants, heterozygotes, and homozygote wild type, respectively). Interestingly, we found no association between CD14 genetic variants with fever, age of patients, or anemia. How this affects disease severity between subregional and continental groups deserves further clarification, including extending these studies in a larger group and among severe and asymptomatic patients with malaria.