Drug resistance mediating Plasmodium falciparum polymorphisms and clinical presentations of parasitaemic children in Uganda

Abstract

Background Plasmodium falciparum genetic polymorphisms that mediate altered drug sensitivity may impact upon virulence. In a cross-sectional study, Ugandan children with infections mutant at pfcrt K76T, pfmdr1 N86Y, or pfmdr1 D1246Y had about one-fourth the odds of symptomatic malaria compared to those with infections with wild type (WT) sequences. However, results may have been confounded by greater likelihood in those with symptomatic disease of higher density mixed infections and/or recent prior treatment that selected for WT alleles.MethodsPolymorphisms in samples from paired episodes of asymptomatic and symptomatic parasitaemia in 114 subjects aged 4–11 years were followed longitudinally in Tororo District, Uganda. Paired episodes occurred within 3–12 months of each other and had no treatment for malaria in the prior 60 days. The prevalence of WT, mixed, and mutant alleles was determined using multiplex ligase detection reaction-fluorescent microsphere assays.ResultsConsidering paired episodes in the same subject, the odds of symptomatic malaria were lower for infections with mutant compared to WT or mixed sequence at N86Y (OR 0.26, 95% CI 0.09–0.79, p = 0.018), but not K76T or D1246Y. However, symptomatic episodes (which had higher densities) were more likely than asymptomatic to be mixed (for N86Y OR 2.0, 95% CI 1.04–4.0, p = 0.036). Excluding mixed infections, the odds of symptomatic malaria were lower for infections with mutant compared to WT sequence at N86Y (OR 0.33, 95% CI 0.11–0.98, p = 0.046), but not the other alleles. However, if mixed genotypes were grouped with mutants in this analysis or assuming that mixed infections consisted of 50% WT and 50% mutant genotypes, the odds of symptomatic infection did not differ between infections that were mutant or WT at the studied alleles.ConclusionsAlthough infections with only the mutant pfmdr1 86Y genotype were associated with symptomatic infection, this association could primarily be explained by greater parasite densities and therefore greater prevalence of mixed infections in symptomatic children. These results indicate limited association between the tested polymorphisms and risk of symptomatic disease and highlight the value of longitudinal studies for assessing associations between parasite factors and clinical outcomes.

Polymorphism analysis of pfmdr1 gene in Plasmodium falciparum isolates 11 years post-adoption of artemisinin-based combination therapy in Saudi Arabia

“…In addition, the findings of the current study also revealed that the pfmdr1 86 Y mutation and the YF SND haplotype occurred more at low parasitaemia, which is consistent with findings by earlier studies elsewhere 57 – 59 . Although causality cannot be inferred, the association between the pfmdr1 86 Y mutation and the parasitaemia level has been linked to multiplicity of infection and parasite virulence, with parasites with decreased virulence carrying the mutant pfmdr1 86 Y allele 59 , 60 .…”

Genetic Polymorphisms of Pfcrt K76T and Pfmdr1 N86Y among Asymptomatic School Children in Forest Communities of Ekondo Titi Subdivision along the Cameroon-Nigeria Border Area

“…In a region of very high malaria transmission intensity, children harbouring P. falciparum containing mutations associated with resistance to CQ and AQ were less likely to be febrile suggest that wild-type parasites are more capable of causing clinical illness than those with resistance-mediating mutations in pfcrt and pfmdr1 [40]. Our results indicated that, the prevalence of pfcrt was similar among the residence areas, except for pfmdr1whose prevalence was the lowest in Sacred Heart primary school.…”

Polymorphism Analysis of pfmdr1 Gene in Plasmodium falciparum Isolates 11 Years Post-adoption of Artemisinin-based Combination Therapy in Saudi Arabia

“…In addition, the ndings of the current study also revealed that the pfmdr1 86Y mutation and the YFSND haplotype occurred more at low parasitaemia, which is consistent with ndings by earlier studies elsewhere 48,49,50 . Although causality cannot be inferred, the association between the pfmdr1 86Y mutation and the parasitaemia level has been linked to multiplicity of infection and parasite virulence, with parasites with decreased virulence carrying the mutant pfmdr1 86Y allele 50,51 .…”