ABSTRACT
Nitric oxide is an important mediator in the host defence against Plasmodium falciparum malaria. It has antiparasitic effects in vitro. However, its role in clinical disease remains controversial. Polymorphisms in the inducible nitric oxide synthase promoter (iNOS; -954G-->C, -1173C-->T, -2.6 kb CCTTT(n) microsatellite) may influence susceptibility to and severity of malaria. We tested this hypothesis in a case-control study among Ghanaian children with severe malaria (SM) and asymptomatic parasitaemia, respectively, and in healthy controls. In this study, the respective frequencies of iNOS-954G-->C and -1173C-->T did not differ between groups but > or =13 microsatellite copies were associated with SM. -954G-->C and -1173C-->T were in linkage disequilibrium with CCTTT(8) and CCTTT(13), respectively. -954G-->C/CCTTT(8) protected against hyperparasitaemia whereas -1173C-->T/CCTTT(13) increased fatality. These findings suggest that iNOS promoter haplotypes rather than single nucleotide polymorphisms are associated with malaria in Ghanaian children.
Subject(s)
Genetic Predisposition to Disease , Malaria/genetics , Nitric Oxide Synthase/genetics , Promoter Regions, Genetic/genetics , Case-Control Studies , Child , Child, Preschool , Female , Gene Frequency , Genotype , Haplotypes , Humans , Infant , Linkage Disequilibrium , Male , Microsatellite Repeats , Nitric Oxide Synthase Type II , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: The erythrocyte binding antigen-175 (EBA-175) on Plasmodium falciparum merozoites mediates sialic acid dependent binding to glycophorin A on host erythrocytes and, therefore, plays a crucial role in cell invasion. Dimorphic allele segments have been found in its encoding gene with a 342 bp segment present in FCR-3 strains (F-segment) and a 423 bp segment in CAMP strains (C-segment). Possible associations of the dimorphism with severe malaria have been analysed in a case-control study in northern Ghana. METHODS: Blood samples of 289 children with severe malaria and 289 matched parasitaemic but asymptomatic controls were screened for eba-175 F- and C-segments by nested polymerase chain reaction. RESULTS: In children with severe malaria, prevalences of F-, C- and mixed F-/C-segments were 70%, 19%, and 11%, respectively. The C-segment was found more frequently in severe malaria cases whereas mixed infections were more common in controls. Infection with strains harbouring the C-segment significantly increased the risk of fatal outcome. CONCLUSION: The results show that the C-segment is associated with fatal outcome in children with severe malaria in northern Ghana, suggesting that it may contribute to the virulence of the parasite.
