The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations.

Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.

A replication study of the association between the IL12B promoter allele CTCTAA and susceptibility to cerebral malaria in Thai population.

BACKGROUND: Interleukin-12 (IL-12), a heterodimeric cytokine composed of p35 and p40 subunits, has been thought to play an important role in the pathogenesis of malaria. The IL-12p40 subunit is encoded by the IL12B gene. An IL12B promoter allele, CTCTAA, at rs17860508 has been reported to be associated with susceptibility to cerebral malaria in African populations. However, this association has not so far been replicated in non-African populations. METHODS: To examine whether the CTCTAA allele is associated with susceptibility to cerebral malaria in Asian populations, 303 Thai patients with Plasmodium falciparum malaria (109 cerebral malaria and 194 mild malaria patients) were genotyped for rs17860508 by PCR-direct sequencing. RESULTS: The CTCTAA allele showed a significant association with susceptibility to cerebral malaria in the Thai population (allelic OR = 1.37; one sided P-value = 0.030). CONCLUSIONS: The existence of a significant association between the CTCTAA allele and susceptibility to cerebral malaria was confirmed in Southeast Asian population, which was previously reported in African populations.

A complement receptor-1 polymorphism with high frequency in malaria endemic regions of Asia but not Africa.

Complement receptor-1 (CR1) is a ligand for rosette formation, a phenomenon associated with cerebral malaria (CM). Binding is dependent on erythrocyte CR1 copy number. In Caucasians, low CR1 expressors have two linked mutations. We determined the Q981H and HindIII RFLP distribution in differing population groups to ascertain a possible role in adaptive evolution. We examined 194 Caucasians, 180 Choctaw Indians, 93 Chinese-Taiwanese, 304 Cambodians, 89 Papua New Guineans (PNG) and 366 Africans. PCR/RFLP used HindIII for CR1 expression and BstNI for the Q981H mutation. DNA sequencing and pyrosequencing were performed to resolve inconclusive results. Gene frequencies for the L allele were 0.15 in Africans, 0.16 in Choctaws, 0.18 in Caucasians, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.58 in PNG. Allelic frequency for 981H were 0.07 in Africans, 0.15 in Caucasians, 0.18 in Choctaws, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.54 in PNG. The Q981H polymorphism correlates with the HindIII RFLP in most groups except West Africans and appears to be part of a low CR1 expression haplotype. The gene frequency for the haplotype is highest in the malaria-endemic areas of Asia, suggesting that this haplotype may have evolved because it protects from rosetting and CM.

Thrombocytopenia and Plasmodium falciparum malaria in children with different exposures.

We studied thrombocytopenia during acute Plasmodium falciparum malaria in 64 traveller children from Paris (France), 85 children from Dakar (Senegal) with an intermittent exposure (69 with severe attack or cerebral malaria), and 81 children from Libreville (Gabon) with a perennial exposure (43 with severe attack or cerebral malaria). Initial thrombocytopenia was present in 43-58% of children with P falciparum malaria but was not more frequent in severe outcome or cerebral malaria. Low parasitaemia may lead to the misdiagnosis of malaria and delayed treatment when there is associated thrombocytopenia

Effects of early cerebral malaria on cognitive ability in Senegalese children.

Twenty-nine Senegalese children with a history of cerebral malaria (CM) performed more poorly on the Kaufman Assessment Battery for Children (K-ABC) Simultaneous Processing domain and on the Test of Variables of Attention (TOVA) attention capacity indicators in comparison with a matched control group. Thus, CM can disrupt neuropsychological integration during critical developmental periods, impacting on global neurological integrity, attentional vigilance, perceptual acuity, and subsequent development of visual-spatial processing and memory foundational to global cognitive ability. A subsequent structural equation model confirmed that rural children are at greater risk for CM, subsequent attention deficits, and other developmental risk factors in addition to the CM impact on K-ABC performance. We document CM as one of a host of developmental risk factors within the complex web of poverty in sub-Saharan Africa, which limit children's ability to achieve their full intellectual potential and, thus, extend the human cost of the disease beyond general measures of mortality and morbidity.

Severe malaria in children at Port Moresby General Hospital, Papua New Guinea.

The demographic and clinical features of severe malaria in children on the south coast of Papua New Guinea have never been clearly documented. This prospective study sought to define the associations between ethnic origin, domain, age, nutritional status and severe malaria in this group and to assess significant clinical features, evaluate the use of a coma score as a prognostic indicator in cerebral malaria and to determine the ultimate outcome. Twenty patients with severe malaria (17 cerebral malaria and 3 severe anaemia) were studied. Their mean age of 4.96 years was significantly greater than that of matched controls with uncomplicated. Plasmodium falciparum infection with mean age 3.79 years (0.02 < p < 0.05). Nutritional status was not a significant independent risk factor when controlled against inpatients with other diagnoses. Low coma scores (Adelaide scale 4/14 or less) sensitively predicted the risk of dying vs survival. The mortality of 18% was comparable with other series. Current standard treatment with quinine and Fansidar was effective and no early recrudescence was encountered in the survivors. The degree of intermarriage and migration between regions precluded firm conclusions from being drawn as to the relevance of ethnic and geographical factors in the epidemiology of severe malaria in this region.