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Polymorphisms in the inducible nitric oxide synthase gene (NOS2) promoter have been associated with clinical outcome from malaria. These include a CCTTT repeat (CCTTTn) 2.5 kilobases upstream from the NOS2 transcription start site, and two single nucleotide substitutions: G
C at position -954 (G-954C), and C T at position -1173 (C-1173T). Although hypothesized to influence NO production in vivo, the functional relevance of (CCTTT)n and G-954C is uncertain because disease association studies have yielded inconsistent results. This study found no association between CCTTT repeat number and levels of plasma NO metabolites or peripheral blood mononuclear cell NOS activity in a cohort of asymptomatic malaria-exposed coastal Papua New Guineans 1–60 years old. This suggests that (CCTTT)n does not independently influence NOS2 transcription in vivo. Neither the G-954C nor the C-1173T polymorphisms were identified in this population, indicating the variability and complexity of selection for NOS2 promoter polymorphisms in different malaria-endemic populations.
Received May 13, 2003. Accepted for publication August 8, 2003.
Acknowledgments: We thank the people of Haven and Midiba villages for their participation and assistance; Erwin Ibam, Kerry Lorry, Joseph Slagi, and Ferdinand Baighi for assisting with the field and laboratory work; Andrew Raiko and his staff at the Madang Institute of Medical Research for facilitating the laboratory studies; Joanne Bex and Jocelyn Saunders for assisting with the DNA preparation; Bill St. Clair for designing and undertaking the nitric oxide studies in healthy controls form the United States, and Michael Alpers, Bart Currie, and Ric Price for support.
Financial support: This study was supported by the National Health and Medical Research Council of Australia (a scholarship to Craig S. Boutlis and a fellowship to Nicholas M. Anstey); National Institute of Health grants R01 AI-41764 and 5P30CA43014; Grant no. M01-RR00064 from the National Center for Research Resources to the University of Utah School of Medicine General Clinical Research Center; the Veterans Administration Research Service; the Tudor Foundation; and the Mark Nicholson and Alice Hill Malaria Research Fund.
Authors’ addresses: Craig S. Boutlis, Robyn L. Marsh, and Nicholas M. Anstey, International Health Program, Infectious Diseases Division, Menzies School of Health Research, PO Box 41096, Casuarina, Darwin, Northern Territory, 0811, Australia, Telephone: 61-8-8922-8196, Fax: 61-8-8927-5187, E-mail: anstey{at}menzies.edu.au. Maurine R. Hobbs, Ariana N. Tkachuk, Jennifer Booth, and Donald L. Granger, Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, 30 North 1900 East, Room 4C108, Salt Lake City, UT, 84132-2405, Telephone: 801-585-1677, Fax: 801-585-3377. Mary A. Misukonis, Marc C. Levesque, and J. Brice Weinberg, Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, 508 Fulton Road, Durham, NC, 27705, Telephone: 919-286-6833, Fax: 919-268-6891. Moses Lagog and Moses J. Bockarie, Papua New Guinea Institute of Medical Research, PO Box 378, Madang, 511, Papua New Guinea, Teelphone: 675-852-2909, Fax: 675-852-3289. Charles S. Mgone, African Malaria Network Trust, PO Box 33207, Dar es Salaam, Tanzania, Telephone: 255-22-270-0018 ext. 104, Fax: 255-22-270-0380.
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  C. S. Boutlis, J. B. Weinberg, J. Baker, M. J. Bockarie, C. S. Mgone, Q. Cheng, and N. M. Anstey Nitric Oxide Production and Nitric Oxide Synthase Activity in Malaria-Exposed Papua New Guinean Children and Adults Show Longitudinal Stability and No Association with Parasitemia Infect. Immun., December 1, 2004; 72(12): 6932 - 6938. [Abstract] [Full Text] [PDF]
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