Home LiteratureArticle Details
PMID: 12552317 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Nucleotide and haplotypic diversity of the NOS2A promoter region and its relationship to cerebral malaria.

Human genetics ·Vol. 112 ·No. 4 ·2003-04-00 ·Pages 379-86

Burgner D, Usen S, Rockett K, Jallow M, Ackerman H, Cervino A, Pinder M, Kwiatkowski DP

Abstract

To assess the hypothesis that nitric oxide is critical in the pathogenesis of cerebral malaria, we analysed genetic variation in the proximal promoter region of NOS2A, the gene encoding inducible nitric oxide synthase. Sequencing 72 Gambian chromosomes revealed 11 single nucleotide polymorphisms in 2.5 kB (theta=8.6 x 10(-4)). Genotyping 104 nuclear families identified six common haplotypes. A single haplotype, uniquely defined by the NOS2A-1659T allele, was associated with cerebral malaria by a transmission disequilibrium test of 334 affected children and their parents (P=0.02). An independent case-control study of 505 different children from the same population replicated the allelic association with cerebral malaria (odds ratio: 1.31, P=0.04). Taken together these data indicate a weak but significant association of the NOS2A locus with susceptibility to cerebral malaria. Despite high linkage disequilibrium across the region studied, this association would not have been detected without the initial construction of a dense marker set for haplotype tagging.

MeSH Terms
Alleles Blacks/genetics Case-Control Studies Gambia/ethnology Genetic Predisposition to Disease/genetics Genetic Variation/genetics Genotype Haplotypes/genetics Humans Linkage Disequilibrium Malaria, Cerebral/genetics Microsatellite Repeats Nitric Oxide Synthase/genetics Nitric Oxide Synthase Type II Nucleotides/genetics Polymorphism, Genetic Promoter Regions, Genetic/genetics Sequence Analysis, DNA
Chemicals
Nucleotides NOS2 protein, human Nitric Oxide Synthase Nitric Oxide Synthase Type II
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Burgner David
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX2 7BN, UK.
Usen Stanley
Rockett Kirk
Jallow Muminatou
Ackerman Hans
Cervino Alessandra
Pinder Margaret
Kwiatkowski Dominic P
References (40)
40 references, click to expand
  1. Inducible nitric oxide synthase: what difference does it make?
    J Clin Invest. 1997 Nov 15;100(10):2417-23 PMID: 9366554
  2. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children.
    Q J Med. 1989 May;71(265):441-59 PMID: 2690177
  3. Killing of Plasmodium falciparum in vitro by nitric oxide derivatives.
    Infect Immun. 1991 Sep;59(9):3280-3 PMID: 1879941
  4. Hybridization of synthetic oligodeoxyribonucleotides to phi chi 174 DNA: the effect of single base pair mismatch.
    Nucleic Acids Res. 1979 Aug 10;6(11):3543-57 PMID: 158748
  5. Measuring nitric oxide production in human clinical studies.
    Methods Enzymol. 1999;301:49-61 PMID: 9919553
  6. Association of the ICAM-1Kilifi mutation with protection against severe malaria in Lambaréné, Gabon.
    Am J Trop Med Hyg. 1999 Nov;61(5):776-9 PMID: 10586911
  7. TRANSFAC: an integrated system for gene expression regulation.
    Nucleic Acids Res. 2000 Jan 1;28(1):316-9 PMID: 10592259
  8. Functional consequences of a polymorphism affecting NF-kappaB p50-p50 binding to the TNF promoter region.
    Mol Cell Biol. 2000 Dec;20(24):9113-9 PMID: 11094063
  9. Nitric oxide and parasitic disease.
    Adv Parasitol. 1996;37:1-56 PMID: 8881597
  10. Dissociation kinetics of 19 base paired oligonucleotide-DNA duplexes containing different single mismatched base pairs.
    Nucleic Acids Res. 1987 Jan 26;15(2):797-811 PMID: 3822815
  11. Possible central role of nitric oxide in conditions clinically similar to cerebral malaria.
    Lancet. 1992 Oct 10;340(8824):894-6 PMID: 1383658
  12. Nitric oxide synthase type 2 promoter polymorphisms, nitric oxide production, and disease severity in Tanzanian children with malaria.
    J Infect Dis. 1999 Dec;180(6):1994-2002 PMID: 10558957
  13. Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus.
    Am J Hum Genet. 2001 Aug;69(2):413-9 PMID: 11431705
  14. Inducible nitric oxide synthase polymorphism and fatal cerebral malaria.
    Lancet. 1998 Oct 10;352(9135):1193-4 PMID: 9777841
  15. Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter.
    Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1054-9 PMID: 8577713
  16. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).
    Am J Hum Genet. 1993 Mar;52(3):506-16 PMID: 8447318
  17. 1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line.
    Infect Immun. 1998 Nov;66(11):5314-21 PMID: 9784538
  18. Residual neurologic sequelae after childhood cerebral malaria.
    J Pediatr. 1997 Jul;131(1 Pt 1):125-9 PMID: 9255203
  19. Nitric oxide synthase 2(Lambaréné) (G-954C), increased nitric oxide production, and protection against malaria.
    J Infect Dis. 2001 Aug 1;184(3):330-6 PMID: 11443559
  20. The HUGO Gene Nomenclature Committee (HGNC).
    Hum Genet. 2001 Dec;109(6):678-80 PMID: 11810281
  21. A repressor in the proximal human inducible nitric oxide synthase promoter modulates transcriptional activation.
    FASEB J. 2002 Apr;16(6):631-3 PMID: 11919177
  22. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase.
    Am J Hum Genet. 1998 Aug;63(2):595-612 PMID: 9683608
  23. Prospects for whole-genome linkage disequilibrium mapping of common disease genes.
    Nat Genet. 1999 Jun;22(2):139-44 PMID: 10369254
  24. High plasma levels of nitrogen oxides are associated with severe disease and correlate with rapid parasitological and clinical cure in Plasmodium falciparum malaria.
    Trans R Soc Trop Med Hyg. 1996 Jan-Feb;90(1):44-7 PMID: 8730311
  25. General score tests for associations of genetic markers with disease using cases and their parents.
    Genet Epidemiol. 1996;13(5):423-49 PMID: 8905391
  26. Evolution of a homopurine-homopyrimidine pentanucleotide repeat sequence upstream of the human inducible nitric oxide synthase gene.
    Gene. 1997 Dec 19;204(1-2):165-70 PMID: 9434180
  27. Transcriptional regulation of human inducible nitric oxide synthase gene in an intestinal epithelial cell line.
    Am J Physiol. 1997 Jun;272(6 Pt 1):G1499-508 PMID: 9227487
  28. Association between serum levels of reactive nitrogen intermediates and coma in children with cerebral malaria in Papua New Guinea.
    Trans R Soc Trop Med Hyg. 1996 May-Jun;90(3):270-3 PMID: 8758073
  29. A generalization of the transmission/disequilibrium test for uncertain-haplotype transmission.
    Am J Hum Genet. 1999 Oct;65(4):1170-7 PMID: 10486336
  30. Polymorphism in promoter region of inducible nitric oxide synthase gene and protection against malaria.
    Lancet. 1998 Jan 24;351(9098):265-6 PMID: 9457101
  31. Characterization of single-nucleotide polymorphisms in coding regions of human genes.
    Nat Genet. 1999 Jul;22(3):231-8 PMID: 10391209
  32. Common west African HLA antigens are associated with protection from severe malaria.
    Nature. 1991 Aug 15;352(6336):595-600 PMID: 1865923
  33. Cytokine-mediated transcriptional induction of the human inducible nitric oxide synthase gene requires both activator protein 1 and nuclear factor kappaB-binding sites.
    J Biol Chem. 1998 Aug 28;273(35):22201-8 PMID: 9712833
  34. A 27-bp region of the inducible nitric oxide synthase promoter regulates expression in glial cells.
    J Neurochem. 2001 Jul;78(1):129-40 PMID: 11432980
  35. 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. 1996 Aug 1;184(2):557-67 PMID: 8760809
  36. Characterization and functional analysis of the human inducible nitric oxide synthase gene promoter.
    Mol Med. 1996 Mar;2(2):226-35 PMID: 8726465
  37. High-resolution haplotype structure in the human genome.
    Nat Genet. 2001 Oct;29(2):229-32 PMID: 11586305
  38. Association of a functional inducible nitric oxide synthase promoter variant with complications in type 2 diabetes.
    J Mol Med (Berl). 2002 Feb;80(2):96-104 PMID: 11907646
  39. Haplotype tagging for the identification of common disease genes.
    Nat Genet. 2001 Oct;29(2):233-7 PMID: 11586306
  40. Nitric oxide and infection: another view.
    Clin Infect Dis. 1995 Oct;21 Suppl 2:S152-7 PMID: 8845443
Article Info
Journal
Human genetics
Abbr.
Hum Genet
ISSN
0340-6717
DOI
10.1007/s00439-002-0882-4
Published
2003-04-00
Epub
2003-00-28
Pages
379-86
Language
English
Region
Germany
NLM ID
7613873
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1007/s00439-002-0882-4 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2