Institution: | 1. Durham VA Medical Center, Durham, NC, USA 11. University of Pittsburgh Medical Center, 3500 Terrace St., BST S709, Pittsburgh, PA, 15261, USA 2. Division of Rheumatology and Immunology, Department of Medicine, Duke University, Durham, NC, USA 3. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA 4. Salt Lake VA Medical Center, Salt Lake City, UT, USA 5. Division of Hematology and Oncology, Department of Medicine, Duke University, Durham, NC, USA 6. Hubert Kairuki Memorial University, Dar es Salaam, Tanzania 7. National Institute for Medical Research, Muheza Designated District Hospital, Muheza, Tanga, Tanzania 8. Seattle Biomedical Research Institute, Seattle, WA, USA 10. Division of Medicine, Royal Darwin Hospital, Darwin, NT, Australia 9. International Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia
|
Abstract: | Nitric oxide (NO) mediates host resistance to severe malaria and other infectious diseases. NO production and mononuclear cell expression of the NO producing enzyme-inducible nitric oxide synthase (NOS2) have been associated with protection from severe falciparum malaria. The purpose of this study was to identify single nucleotide polymorphisms (SNPs) and haplotypes in the NOS2 promoter, to identify associations of these haplotypes with malaria severity and to test the effects of these polymorphisms on promoter activity. We identified 34 SNPs in the proximal 7.3 kb region of the NOS2 promoter and inferred NOS2 promoter haplotypes based on genotyping 24 of these SNPs in a population of Tanzanian children with and without cerebral malaria. We identified 71 haplotypes; 24 of these haplotypes comprised 82% of the alleles. We determined whether NOS2 promoter haplotypes were associated with malaria severity in two groups of subjects from Dar es Salaam (N = 185 and N = 250) and in an inception cohort of children from Muheza-Tanga, Tanzania (N = 883). We did not find consistent associations of NOS2 promoter haplotypes with malaria severity or malarial anemia, although interpretation of these results was potentially limited by the sample size of each group. Furthermore, cytokine-induced NOS2 promoter activity determined using luciferase reporter constructs containing the proximal 7.3 kb region of the NOS2 promoter and the G-954C or C-1173T SNPs did not differ from NOS2 promoter constructs that lacked these polymorphisms. Taken together, these studies suggest that the relationship between NOS2 promoter polymorphisms and malaria severity is more complex than previously described. |