| dc.description.abstract | Plasmodium falciparum, the most virulent and lethal human malaria parasite, IS
responsible for most malaria-related morbidity and mortality in sub-Saharan Africa. It
manifests mainly as severe malarial anaemia (SMA) in children in malaria holoendemic
areas such as western Kenya. So far, few studies have investigated genetic
polymorphism in cytokines, which are important determinants of immune response
regulation. Since previous studies have suggested that interleukin-4 (IL-4) and IL-6
production and their interactions seem to playa significant role in the pathogenesis of
severe malaria, this study investigated the fuctional effects of IL-4 -589T/C and IL-6 -
636G/C gene promoter single nucleotide polymorphisms (SNPs) on IL-4 and IL-6
cytokine production and their associations with SMA and high-density parasitaemia
(HDP) during malaria infections. This was a cross-sectional study based at Siaya District
Hospital (SDH) and a total of 618 and 602 study participants were studied for IL-4 -
589T/C and IL-6 -636G/C SNPs, respectively. The study participants were grouped as
aparasitaemic controls (AC), low density parasitaemia (LDP), HDP, SMA and nonsevere
malarial anaemia (Non-SMA). This was after the study participants had met the
inclusion criteria which considered their natural exposure to P. falciparum, prior
hospitalisation, intended relocation, being P. falciparum positive or negative and signing
of the consent forms by parents/guardians, amongst others. Three millilitres of venous
blood samples were collected (in ethylene diamine tetracetic acid (EDT A) vacutainer
tubes and tubes without anticoagulants) from aparasitaemic children and malaria
parasitemic children presenting at SDH and were used for clinical, immunological, and
molecular evaluations, including haemogl~ electrophoresis, genotyping, full
haemogram and cytokine profile anal~es. The IL-4 -589T/C and IL-6 -636G/C
genotyping was carried out using a Taqman S' allelic discrimination by real time PCR.
Human Cytokine Twenty-Five Plex Antibody Bead Kit and a haematological analyzer
were used to determine the cytokine levels and blood cell indices, respectively. The data
were analysed by SPSS software. Kruskal Wallis test and the Marin-Whitney U tests
were used for across group and pairwise comparisons, respectively. Proportionality was
tested by X2 tests, while multivariate logistic regression analysis was used for determining
the associations between the genotypes and malaria clinical outcomes, in a model
controlling for the confounders (age, gender, sickle-cell trait, bacteremia and HIV status).
Results showed that IL-4 -589T/C SNP was significantly associated with increased
susceptibility to HDP (OR; 1.64, 95%CI; 1.01-2.65, P=0.044); however, the IL-6 -
636G/C SNP was not associated with any malaria disease outcome. In addition, the IL-4
-589T/C and IL-6 -636G/C SNPs were not functionally associated with circulating IL-4
and IL-6 levels, respectively. The significant departure from the Hardy-Weinberg
equilibrium (HWE) shown by the IL-4 -589T/C and IL-6 -636G/C genotypic
distributions, implicate the action of evolutionary forces on the genes, possibly through
the exposure of the population to malaria. In conclusion, the variation in the IL-4
promoter region as found in this tudy seems to be conditioning the clinical outcomes of
fa1ciparum malaria and as a result, should be useful in the development of novel
interventions for the control and management of severe malaria. The results of IL-6 -
636G/C SNP from this study, .on the other hand; has shown that the polymorphism
neither conditions malaria disease outcomes nor circulating IL-6 levels in this population,
thus necessitating studies on additional IL-6 SNPs. | en_US |
