Browsing by Author "Makene, Victor Anacletus"

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    Genetic factors associated with malaria severity in children under five years of age from Muheza, Tanzania
    (University of Dar es Salaam, 2011) Makene, Victor Anacletus
    The objective of this study was to answer the question: - Why do some children develop severe forms of malaria or die of malaria, while the vast majorities (> 98 %) survive by experiencing just mild disease? To answer this question DNA samples from 762 Muheza children from a birth cohort with 31/2 years of follow-up were genotyped for 71 single nucleotide polymorphisms (SNPs) including SNPs associated with malaria severity elsewhere. Genotype-malaria outcome associations for 395 children were assessed using generalized estimating equations in R. Protection from WHO defined severe malaria was associated with bednet use (59 %), Sickle cell trait (86 %), IL22+2611: AA (59 %), IL22+708: AT (47 %) and NOS2A: 608Leu/Ser (52 %) while increased risk was associated with IL4-590: CC (3.7 fold). Protection from clinically severe malaria was associated with bednet use (50 %), heterozygous G6PD deficiency (49 %) and IL4R: 503Pro (57 %), while increased risk was associated with NOS2A-1173: CT (2.5 fold). Protection from any severe malaria was associated with bednet use (54 %) and TLR4 heterozygosity: Asp299Gly/399Thr haplotype (51 %) while increased risk was associated with TLR4 homozygosity: Gly299Gly/399Thr haplotype (2.5 fold). Protection from complicated malaria was associated with bednet use (43 %), Sickle cell trait (68 %) and TLR6: 249Ser (51 %) while increased risk was associated with TNF-376: AG (2.6 fold). Protection from hyperparasitemia was associated with bednet use (44 %), IL10-1082: CC (45 %) and CR1: Sl2/2 McCa/a (58 %) while increased risk was associated with IL10+4582: CT (2.3 fold) and NOS2A-954: CG (1.8 fold). Protection from uncomplicated malaria was associated with IL10+4949: AG (79 %) and IL10+4949: GG (85 %). All associations were significant at P < 0.05. Similar failure to detect severe malaria associations with adhesion receptors (CD36, ICAM-1, and CR1) and pro-inflammatory cytokine (TNF), SNPs has been wildely reported. Sickle cell trait was the strongest protective factor against severe and complicated malaria in Muheza children, while IL4-590: CC was the strongest risk factor. Associations with variants of interleukins and nitric oxide synthase genes are complex. GWA studies with multicenter collaborations to achieve sufficient population sizes for detecting small gene effects are recommended.