INDUCIBLE NITRIC OXIDE SYNTHASE (NOS2) PROMOTER CCTTT REPEAT POLYMORPHISM: RELATIONSHIP TO IN VIVO NITRIC OXIDE PRODUCTION/NOS ACTIVITY IN AN ASYMPTOMATIC MALARIA-ENDEMIC POPULATION

CRAIG S. BOUTLIS International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by CRAIG S. BOUTLIS in
Current site
Google Scholar
PubMed
Close
,
MAURINE R. HOBBS International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by MAURINE R. HOBBS in
Current site
Google Scholar
PubMed
Close
,
ROBYN L. MARSH International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by ROBYN L. MARSH in
Current site
Google Scholar
PubMed
Close
,
MARY A. MISUKONIS International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by MARY A. MISUKONIS in
Current site
Google Scholar
PubMed
Close
,
ARIANA N. TKACHUK International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by ARIANA N. TKACHUK in
Current site
Google Scholar
PubMed
Close
,
MOSES LAGOG International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by MOSES LAGOG in
Current site
Google Scholar
PubMed
Close
,
JENNIFER BOOTH International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by JENNIFER BOOTH in
Current site
Google Scholar
PubMed
Close
,
DONALD L. GRANGER International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by DONALD L. GRANGER in
Current site
Google Scholar
PubMed
Close
,
MOSES J. BOCKARIE International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by MOSES J. BOCKARIE in
Current site
Google Scholar
PubMed
Close
,
CHARLES S. MGONE International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by CHARLES S. MGONE in
Current site
Google Scholar
PubMed
Close
,
MARC C. LEVESQUE International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by MARC C. LEVESQUE in
Current site
Google Scholar
PubMed
Close
,
J. BRICE WEINBERG International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by J. BRICE WEINBERG in
Current site
Google Scholar
PubMed
Close
, and
NICHOLAS M. ANSTEY International Health Program, Infectious Diseases Division, Menzies School of Health Research, Darwin, Northern Territory, Australia; Northern Territory University, Darwin, Northern Territory, Australia; Division of Infectious Diseases, Department of Internal Medicine, University of Utah and Veterans Administration Medical Centers, Salt Lake City, Utah; Division of Hematology-Oncology, Department of Medicine, Veterans Administration and Duke University Medical Centers, Durham, North Carolina; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea; Papua New Guinea Institute of Medical Research, Goroka, Papua New Guinea; Flinders University, Northern Territory Clinical School, Darwin, Northern Territory, Australia

Search for other papers by NICHOLAS M. ANSTEY in
Current site
Google Scholar
PubMed
Close
Restricted access

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.

Author Notes

  • 1

    Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, Arnelle DR, Hollis D, Mc-Donald MI, Granger DL, 1996. Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. J Exp Med 184 :557–567.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Perkins DJ, Kremsner PG, Schmid D, Misukonis MA, Kelly MA, Weinberg JB, 1999. Blood mononuclear cell nitric oxide production and plasma cytokine levels in healthy gabonese children with prior mild or severe malaria. Infect Immun 67 :4977–4981.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Chiwakata CB, Hemmer CJ, Dietrich M, 2000. High levels of inducible nitric oxide synthase mRNA are associated with increased monocyte counts in blood and have a beneficial role in Plasmodium falciparum malaria. Infect Immun 68 :394–399.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Weinberg JB, Misukonis MA, Shami PJ, Mason SN, Sauls DL, Dittman WA, Wood ER, Smith GK, McDonald B, Bachus KE, 1995. Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages. Blood 86 :1184–1195.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5

    St. Clair EW, Wilkinson WE, Lang T, Sanders L, Misukonis MA, Gilkeson GS, Pisetsky DS, Granger DL, Weinberg JB, 1996. Increased expression of blood mononuclear cell nitric oxide synthase type 2 in rheumatoid arthritis patients. J Exp Med 184 :1173–1178.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Burgner D, Xu W, Rockett K, Gravenor M, Charles IG, Hill AV, Kwiatkowski D, 1998. Inducible nitric oxide synthase polymorphism and fatal cerebral malaria. Lancet 352 :1193–1194.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Kun JF, Mordmuller B, Lell B, Lehman LG, Luckner D, Kremsner PG, 1998. Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria. Lancet 351 :265–266.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Hobbs MR, Udhayakumar V, Levesque MC, Booth J, Roberts JM, Tkachuk AN, Pole A, Coon H, Kariuki S, Nahlen BL, Mwaikambo ED, Lal AL, Granger DL, Anstey NM, Weinberg JB, 2002. A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet 360 :1468–1475.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Burgner D, Usen S, Rockett K, Jallow M, Ackerman H, Cervino A, Pinder M, Kwiatkowski DP, 2003. Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria. Hum Genet 112 :379–386.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Ohashi J, Naka I, Patarapotikul J, Hananantachai H, Looareesuwan S, Tokunaga K, 2002. Significant association of longer forms of CCTTT Microsatellite repeat in the inducible nitric oxide synthase promoter with severe malaria in Thailand. J Infect Dis 186 :578–581.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Levesque MC, Hobbs MR, Anstey NM, Vaughn TN, Chancellor JA, Pole A, Perkins DJ, Misukonis MA, Chanock SJ, Granger DL, Weinberg JB, 1999. Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria. J Infect Dis 180 :1994–2002.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Kun JF, Mordmuller B, Perkins DJ, May J, Mercereau-Puijalon O, Alpers M, Weinberg JB, Kremsner PG, 2001. Nitric oxide synthase 2 (Lambarene) (G-954C), increased nitric oxide production, and protection against malaria. J Infect Dis 184 :330–336.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Warpeha KM, Xu W, Liu L, Charles IG, Patterson CC, Ah-Fat F, Harding S, Hart PM, Chakravarthy U, Hughes AE, 1999. Genotyping and functional analysis of a polymorphic (CCTTT)(n) repeat of NOS2A in diabetic retinopathy. FASEB J 13 :1825–1832.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    De Vera ME, Shapiro RA, Nussler AK, Mudgett JS, Simmons RL, Morris SM Jr, Billiar TR, Geller DA, 1996. Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proc Natl Acad Sci USA 93 :1054–1059.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Boutlis CS, Gowda DC, Naik RS, Maguire GP, Mgone CS, Bockarie MJ, Lagog M, Ibam E, Lorry K, Anstey NM, 2002. Antibodies to Plasmodium falciparum glycosylphosphatidylinositols: inverse association with tolerance of parasitemia in Papua New Guinean children and adults. Infect Immun 70 :5052–5057.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Cattani JA, Tulloch JL, Vrbova H, Jolley D, Gibson FD, Moir JS, Heywood PF, Alpers MP, Stevenson A, Clancy R, 1986. The epidemiology of malaria in a population surrounding Madang, Papua New Guinea. Am J Trop Med Hyg 35 :3–15.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Burkot TR, Graves PM, Cattani JA, Wirtz RA, Gibson FD, 1987. The efficiency of sporozoite transmission in the human malarias, Plasmodium falciparum and P. vivax.Bull World Health Organ 65 :375–380.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Burkot TR, Graves PM, Paru R, Wirtz RA, Heywood PF, 1988. Human malaria transmission studies in the Anopheles punctulatus complex in Papua New Guinea: sporozoite rates, inoculation rates, and sporozoite densities. Am J Trop Med Hyg 39 :135–144.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Cox MJ, Kum DE, Tavul L, Narara A, Raiko A, Baisor M, Alpers MP, Medley GF, Day KP, 1994. Dynamics of malaria parasitaemia associated with febrile illness in children from a rural area of Madang, Papua New Guinea. Trans R Soc Trop Med Hyg 88 :191–197.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Anstey NM, Boutlis CS, Saunders JR, 2002. Systemic nitric oxide production in human malaria. I. Analysis of NO metabolites in biological fluids. Methods Mol Med 72 :461–467.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Boutlis CS, Tjitra E, Maniboey H, Misukonis MA, Saunders JR, Suprianto S, Weinberg JB, Anstey NM, 2003. Nitric oxide production and mononuclear cell nitric oxide synthase activity in malaria-tolerant Papuan adults. Infect Immun 71 :3682–3689.

    • PubMed
    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 71 63 8
Full Text Views 315 3 2
PDF Downloads 104 0 0
 
 
 
 
Affiliate Membership Banner
 
 
Research for Health Information Banner
 
 
CLOCKSS
 
 
 
Society Publishers Coalition Banner
Save