Important insight into the potential complexity of NO's role in inflammatory disease has also come from studies on malaria in African children (see also INTERSCIENCE).

Children with clinical signs of cerebral malaria that resulted in severe complications or death had significantly lower serum and urine NO levels than did children with uncomplicated malaria or children with no overt malaria. Hobbs and colleagues have shown that increased survival of children with severe malaria is due, in part, to a specific NOS2 promoter polymorphism (C-1173T) that results in increased NO production. The odds of developing clinical malaria in individuals expressing the C/T or T/T genotype was 88% lower than in people who did not have the C-1173T polymorphism. The protective association appeared not only in patients with clinical signs of malaria, but also in control individuals with no overt signs of malaria. In all cases, those with the C/T genotype had higher fasting urine and plasma nitrite metabolites, providing direct evidence that the polymorphism resulted in a physiological increase in NOS activity and NO production. The effect of the increased NO was not likely to be a direct effect of NO's anti-parasitic effect since the frequencies of low or high levels of parasitaemia did not depend on expression of a C-1173T allele. Thus, Hobbs et al concluded that the effect of high NO levels are due to a protective effect of NO beyond simple killing of parasites.

We have begun to ask whether NOS2 promoter polymorphisms can alter the onset and severity of AD. With collaborators from Emory University, Arkansas University School of Medicine and at Duke, we have collected DNA from blood samples of individuals of African descent. We will begin this study by analyzing the frequency of specific NOS2 promoter polymorphisms in de-identified, stored DNA samples from African-American individuals diagnosed with AD, comparing these data to the frequencies observed in African-American age-matched control individuals. To date, over 400 samples have been collected, and analysis is underway.