Previous epidemiological studies have demonstrated a protective association between the NOS2G-954C (NOS2Lambaréné) polymorphism in inducible nitric oxide (NO) 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 NO during episodes of malaria. Forty-seven boys with uncomplicated malaria received an infusion of 15N-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, of whom 6 were NOS2G-954C heterozygotes. Heterozygotes had higher urinary 15N nitrate enrichments, 2.3 ± 0.6 versus 1.4 ± 0.5 atoms percent excess (p= 0.001) and higher ratios of 15N between urine nitrate and plasma arginine (87 ± 11 versus 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 versus 0.83 ± 0.50 umol/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.
- nitric oxide
- Plasmodium falciparum
- nitric oxide synthase
- Copyright © 2010, American Journal of Physiology - Regulatory, Integrative and Comparative Physiology