Extensive genetic diversity of CD14 promoter gene (rs2569190) polymorphism is associated with regulation of Plasmodium falciparum parasitemia but not susceptibility to infection

Abstract

Abstract 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. Genetic polymorphisms of the CD14 promoter (rs2569190) has been found to be associated with susceptibility to several diseases. In malaria infection, CD14 gene demonstrates a pathogenic profile in regulating experimental cerebral malaria, with reports of elevated levels of soluble CD14 in serum of malaria patients, with no definitive conclusions. We present a detailed analysis of genetic diversity of CD14 promoter gene polymorphism between a malaria-infected group and uninfected controls, and its association with clinical parameters of disease. Genomic DNA samples obtained from 107 Plasmodium falciparum-infected (microscopy and PCR-confirmed) patients and 380 uninfected controls were subjected to a PCR-RFLP analysis. 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 infected and uninfected controls respectively, with the mutant allele less frequent in infected group. Mean parasitemia (parasites/μl of blood) was significantly regulated based on CD14 genetic profile (19,855 vs 37,041 vs 49,396 for mutants, heterozygotes and wild type alleles respectively), but showed no association with other markers of disease severity (fever, age of patients or anemia). Our results show the mutant variant pushed Th1 cell differentiation resulting in interferon-γ response leading to reduced parasitemia. How this affects disease severity between sub-regional or continental malaria groups deserves elucidation, including extending this results among cerebral malaria patients.