title: Nitric oxide generation in children with malaria and the NOS2G-954C promoter polymorphism.
abstract: Previous epidemiological studies have demonstrated a protective association between the NOS2G-954C (NOS2(Lambaréné)) polymorphism in inducible nitric oxide synthase and severe malaria. The polymorphism is commoner in children with uncomplicated compared with severe malaria. We now show that the likely mechanism for such protection is increased flux of nitrogen from arginine to nitric oxide (NO) during episodes of malaria. Forty-seven boys with uncomplicated malaria received an infusion of (15)N-arginine to measure directly whole body in vivo NO production. The NOS2G-954C genotype previously associated with reduced risk of severe malaria in Gabon was also assessed. Evaluable data were obtained from 40 boys, of whom 6 were NOS2G-954C heterozygotes. Heterozygotes had higher urinary (15)N nitrate enrichments, 2.3 ± 0.6 vs. 1.4 ± 0.5 atoms percent excess (P = 0.001) and higher ratios of (15)N between urine nitrate and plasma arginine (87 ± 11 vs. 57 ± 18%, P = 0.001) consistent with accelerated NO production. We also derived total NO production rates, combining data with total urine production rate and nitrate concentration; these showed no difference by genotype (0.62 ± 0.36, n = 6 vs. 0.83 ± 0.50 μmol/kg·h, n = 16; P = 0.36), but data were confounded by very high variability in measurements of urine output and nitrate concentrations. This study supports the idea that NOS2 genotype protects against severe malaria by increasing NO production during episodes of uncomplicated malaria.
authors.affiliation: Centre for Infection, St. George's Hospital Medical School, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Planche
authors.forename: Derek C
authors.initials: DC
authors.lastname: Macallan
authors.forename: Toni
authors.initials: T
authors.lastname: Sobande
authors.forename: Steffen
authors.initials: S
authors.lastname: Borrmann
authors.forename: Jürgen F J
authors.initials: JF
authors.lastname: Kun
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Krishna
authors.forename: Peter G
authors.initials: PG
authors.lastname: Kremsner
mesh_terms: D001120:Arginine / Q000008:administration & dosage / Q000031:analogs & derivatives; D002648:Child; D002675:Child, Preschool; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D008288:Malaria / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D009587:Nitrogen Isotopes; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D009587:Nitrogen Isotopes; D009569:Nitric Oxide; D001120:Arginine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II