A Review of Polymorphisms in the Human Gene for Inducible Nitric Oxide Synthase (NOS2) in Patients with Malaria

Abstract

Significant variability exists in host responses to malaria in different human populations. These epidemiological data have prompted a search for genetic variations that determine host responses to malaria. This review focuses on polymorphisms in the promoter region of inducible nitric oxide synthase (NOS2) as a source of genetic differences in the response of patients to infection with malaria. Nitric oxide (NO), a lipid soluble free radical, mediates host resistance to infectious organisms including parasites. NO is produced by three different NO synthases (NOS) in humans. Research on NO and malaria has focused on the cytokine inducible isoform of NOS (NOS2). The role of NO in host responses to infection and inflammation is likely to be both detrimental and beneficial to the host; this is reflected by the effects of NO on different host tissues and on parasite viability. Therefore, studies of the regulation of NOS2 transcription by different human cell types are important to gain a better understanding of the effects of malaria infection on different host tissues. Several important transcription factor binding sites in the NOS2 promoter region have been identified and represent potential sites of genetic heterogeneity in NOS2 transcription during malaria infection. Furthermore, a variety of studies have been performed to determine the role of NO in the pathogenesis of malaria in humans. Taken together, these studies suggest that high systemic NO production is associated with milder disease and increased parasite clearance while impaired systemic NO production (but increased central nervous system NOS2 expression) is associated with cerebral malaria. There are several possible mechanisms that might explain differences in NO production in malaria patients including functional polymorphisms in the promoter region of NOS2. To date, two NOS2 promoter polymorphisms, G-954C and a CCTTT microsatellite repeat, have been identified, and are associated with disease severity in populations of African patients with malaria. The relationship of these polymorphisms to malaria disease severity in other populations remains controversial and is the subject of ongoing studies. Likewise, the functional significance (relative to NO production) of these polymorphisms in unknown. Therefore, future studies will be necessary to determine whether other polymorphisms in the NOS2 gene are associated with malaria disease severity and to determine the functional effects of these polymorphisms on malaria disease severity and NOS2 transcription.