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To assess the hypothesis that nitric oxide is critical in the pathogenesis of cerebral malaria, we analysed genetic variation in the proximal promoter region of NOS2A, the gene encoding inducible nitric oxide synthase. Sequencing 72 Gambian chromosomes revealed 11 single nucleotide polymorphisms in 2.5 kB (theta=8.6 x 10(-4)). Genotyping 104 nuclear families identified six common haplotypes. A single haplotype, uniquely defined by the NOS2A-1659T allele, was associated with cerebral malaria by a transmission disequilibrium test of 334 affected children and their parents (P=0.02). An independent case-control study of 505 different children from the same population replicated the allelic association with cerebral malaria (odds ratio: 1.31, P=0.04). Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria. Despite high linkage disequilibrium across the region studied, this association would not have been detected without the initial construction of a dense marker set for haplotype tagging.

Original publication

DOI

10.1007/s00439-002-0882-4

Type

Journal article

Journal

Human genetics

Publication Date

04/2003

Volume

112

Pages

379 - 386

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX2 7BN, UK.

Keywords

Humans, Malaria, Cerebral, Genetic Predisposition to Disease, Nucleotides, Case-Control Studies, Sequence Analysis, DNA, Microsatellite Repeats, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Genetic, Alleles, African Continental Ancestry Group, Gambia, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Promoter Regions, Genetic, Genetic Variation