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Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes

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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.

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References

  • Abraham LJ, Kroeger KM (1999) Impact of the -308 TNF promoter polymorphism on the transcriptional regulation of the TNF gene: relevance to disease. J Leukoc Biol 66:562–566

    PubMed  CAS  Google Scholar 

  • Anstey NM, Weinberg JB, Hassanali MY, Mwaikambo ED, Manyenga D, Misukonis MA, Arnelle DR, Hollis D, McDonald 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

    Article  PubMed  CAS  Google Scholar 

  • Aoki K, Suzuki K, Sugano T, Tasaka T, Nakahara K, Kuge O, Omori A, Kasai M (1995) A novel gene, Translin, encodes a recombination hotspot binding protein associated with chromosomal translocations. Nat Genet 10:167–174

    Article  PubMed  CAS  Google Scholar 

  • Boutlis CS, Hobbs MR, Marsh RL, Misukonis MA, Tkachuk AN, Lagog M, Booth J, Granger DL, Bockarie MJ, Mgone CS, Levesque MC, Weinberg JB, Anstey NM (2003a) Inducible nitric oxide synthase (NOS2) promoter CCTTT repeat polymorphism: relationship to in vivo nitric oxide production/NOS activity in an asymptomatic malaria-endemic population. Am J Trop Med Hyg 69:569–573

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Bredt DS, Snyder SH (1994) Nitric oxide: a physiologic messenger molecule. Annu Rev Biochem 63:175–195

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Burgner D, Rockett K, Ackerman H, Hull J, Usen S, Pinder M, Kwiatkowski DP (2003a) Haplotypic relationship between SNP and microsatellite markers at the NOS2A locus in two populations. Genes Immun 4:506–514

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Chartrain NA, Geller DA, Koty PP, Sitrin NF, Nussler AK, Hoffman EP, Billiar TR, Hutchinson NI, Mudgett JS (1994) Molecular cloning, structure, and chromosomal localization of the human inducible nitric oxide synthase gene. J Biol Chem 269:6765–6772

    PubMed  CAS  Google Scholar 

  • Chu SC, Marks-Konczalik J, Wu HP, Banks TC, Moss J (1998) Analysis of the cytokine-stimulated human inducible nitric oxide synthase (iNOS) gene: characterization of differences between human and mouse iNOS promoters. Biochem Biophys Res Commun 248:871–878

    Article  PubMed  CAS  Google Scholar 

  • Clancy RM, Abramson SB (1995) Nitric oxide: a novel mediator of inflammation. Proc Soc Exp Biol Med 210:93–101

    PubMed  CAS  Google Scholar 

  • Clark IA, Rockett KA (1996) Nitric oxide and parasitic disease. Adv Parasitol 37:1–56

    Article  PubMed  CAS  Google Scholar 

  • Clark AG, Weiss KM, Nickerson DA, Taylor SL, Buchanan A, Stengard J, Salomaa V, Vartiainen E, Perola M, Boerwinkle E, Sing CF (1998) Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am J Hum Genet 63:595–612

    Article  PubMed  CAS  Google Scholar 

  • Coia V, Juliger S, Mordmuller B, Kreidenweis A, Stroh A-L, Ortega C, Vindigni A, Dengjel J, Lukyanov DV, Destro-Bisol G, Fedorov A, Podgornaya OI, Kun JFJ (2005) Analysis of polymorphic sites in the promoter of the nitric oxide synthase 2 gene. Biochem Biophys Res Commun 335:1123–1131

    Article  PubMed  CAS  Google Scholar 

  • Cramer JP, Mockenhaupt FP, Ehrhardt S, Burkhardt J, Otchwemah RN, Dietz E, Gellert S, Bienzle U (2004) iNOS promoter variants and severe malaria in Ghanaian children. Trop Med Int Health 9:1074–1080

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Ewens WJ (1979) Mathematical Population Genetics. Springer, Berlin

    Google Scholar 

  • Fang FC (1997) Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. J Clin Invest 99:2818–2825

    Article  PubMed  CAS  Google Scholar 

  • Ganster RW, Taylor BS, Shao LF, Geller DA (2001) Complex regulation of human inducible nitric oxide synthase gene transcription by Stat 1 and NF-kappa B. Proc Natl Acad Sci USA 98:8638–8643

    Article  PubMed  CAS  Google Scholar 

  • Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, Intaglietta M, van der Heyde HC (2006) Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med 12:1417–1422

    Article  PubMed  CAS  Google Scholar 

  • Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A, Cooper R, Lipshutz R, Chakravarti A (1999) Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet 22:239–247

    Article  PubMed  CAS  Google Scholar 

  • Hobbs MR, Udhayakumar V, Levesque MC, Booth J, Tkachuk AN, Pole A, Roberts JM, Kariuki S, Nahlen BL, Mwaikambo ED, Lal AL, Granger DL, Anstey NM, Weinberg JB (2002) A novel NOS2 promoter polymorphism associated with protection from severe malaria in children from Tanzania and Kenya. Lancet 360:1468–1475

    Article  PubMed  CAS  Google Scholar 

  • Huang X, Miller W (1991) A time-efficient, linear-space local similarity algorithm. Adv Appl Math 12:337–357

    Article  Google Scholar 

  • Hudson RR, Kaplan NL (1985) Statistical properties of the number of recombination events in the history of a sample of DNA sequences. Genetics 111:147–164

    PubMed  CAS  Google Scholar 

  • Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P, Clark TG, Kivinen K (2009) Genome-wide and fine-resolution association analysis of malaria in West Africa. Nature. doi:10.1038/ng.388

  • Jeffreys AJ, Wilson V, Thein SL (1985) Hypervariable ‘minisatellite’ regions in human DNA. Nature 314:67–73

    Article  PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Kauppi L, Neumann R (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29:217–222

    Article  PubMed  CAS  Google Scholar 

  • Jurka J (1998) Repeats in genomic DNA: mining and meaning. Curr Opin Struct Biol 8:333–337

    Article  PubMed  CAS  Google Scholar 

  • Jurka J, Klonowski P, Dagman V, Pelton P (1996) CENSOR–a program for identification and elimination of repetitive elements from DNA sequences. Comput Chem 20:119–121

    Article  PubMed  CAS  Google Scholar 

  • 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 [letter]. Lancet 351:265–266

    Article  PubMed  CAS  Google Scholar 

  • Laubach VE, Zhang CX, Russell SW, Murphy WJ, Sherman PA (1997) Analysis of expression and promoter function of the human inducible nitric oxide synthase gene in DLD-1 cells and monkey hepatocytes. Biochim Biophys Acta 1351:287–295

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Lewontin RC (1964) The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 49:49–67

    PubMed  CAS  Google Scholar 

  • Lewontin RC (1995) The detection of linkage disequilibrium in molecular sequence data. Genetics 140:377–388

    PubMed  CAS  Google Scholar 

  • Li WH (1997) Molecular evolution. Sinauer Associates, Sunderland

    Google Scholar 

  • Li N, Stephens M (2003) Modelling linkage disequilibrium, and identifying recombination hot spots using SNP data. Genetics 165:2213–2233

    PubMed  CAS  Google Scholar 

  • Liang KY, Zeger SL (1986) Longitudinal data analysis using generalized linear models. Biometrika 73:13–22

    Article  Google Scholar 

  • Linn SC, Morelli PJ, Edry I, Cottongim SE, Szabo C, Salzman AL (1997) Transcriptional regulation of human inducible nitric oxide synthase gene in an intestinal epithelial cell line. Am J Physiol 272:G1499–G1508

    PubMed  CAS  Google Scholar 

  • Ludbrook J (1998) Multiple comparison procedures updated. Clin Exp Pharmacol Physiol 25:1032–1037

    Article  PubMed  CAS  Google Scholar 

  • Marks-Konczalik J, Chu SC, Moss J (1998) 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 273:22201–22208

    Article  PubMed  CAS  Google Scholar 

  • Mellott JK, Nick HS, Waters MF, Billiar TR, Geller DA, Chesrown SE (2001) Cytokine-induced changes in chromatin structure and in vivo footprints in the inducible NOS promoter. Am J Physiol Lung Cell Mol Physiol 280:L390–L399

    PubMed  CAS  Google Scholar 

  • Molyneux ME, Taylor TE, Wirima JJ, Borgstein A (1989) Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q J Med 71:441–459

    PubMed  CAS  Google Scholar 

  • Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329:2002–2012

    Article  PubMed  CAS  Google Scholar 

  • Mutabingwa TK, Bolla MC, Li J-L, Domingo GJ, Li X, Fried M, Duffy PE (2005) Maternal malaria and gravidity interact to modify infant susceptibility to malaria. PLoS Med Publ Lib Sci 2:e407

    Google Scholar 

  • Nathan C (1997) Inducible nitric oxide synthase: what difference does it make? J Clin Invest 100:2417–2423

    Article  PubMed  CAS  Google Scholar 

  • Nunokawa Y, Ishida N, Tanaka S (1994) Promoter analysis of human inducible nitric oxide synthase gene associated with cardiovascular homeostasis. Biochem Biophys Res Commun 200:802–807

    Article  PubMed  CAS  Google Scholar 

  • Oates JC, Levesque MC, Hobbs MR, Smith EG, Molano ID, Page GP, Hill BS, Weinberg JB, Cooper GS, Gilkeson GS (2003) Nitric oxide synthase 2 promoter polymorphisms and systemic lupus erythematosus in African-Americans. J Rheumatol 30:60–67

    PubMed  CAS  Google Scholar 

  • Parikh S, Dorsey G, Rosenthal PJ (2004) Host polymorphisms and the incidence of malaria in Ugandan children. Am J Trop Med Hyg 71:750–753

    PubMed  CAS  Google Scholar 

  • 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  CAS  Google Scholar 

  • Reiter LT, Murakami T, Koeuth T, Pentao L, Muzny DM, Gibbs RA, Lupski JR (1996) A recombination hotspot responsible for two inherited peripheral neuropathies is located near a mariner transposon-like element. Nat Genet 12:288–297

    Article  PubMed  CAS  Google Scholar 

  • Robinson LJ, D’Ombrain MC, Stanisic DI, Taraika J, Bernard N, Richards JS, Beeson JG, Tavul L, Michon P, Mueller I, Schofield L (2009) Cellular tumor necrosis factor, gamma interferon, and interleukin-6 responses as correlates of immunity and risk of clinical Plasmodium falciparum malaria in children from Papua New Guinea. Infect Immun 77:3033–3043

    Article  PubMed  CAS  Google Scholar 

  • Sakitani K, Nishizawa M, Inoue K, Masu Y, Okumura T, Ito S (1998) Synergistic regulation of inducible nitric oxide synthase gene by CCAAT/enhancer-binding protein beta and nuclear factor-kappaB in hepatocytes. Genes Cells 3:321–330

    Article  PubMed  CAS  Google Scholar 

  • Schofield L, Grau GE (2005) Immunological processes in malaria pathogenesis. Nat Rev Immunol 5:722–735

    Article  PubMed  CAS  Google Scholar 

  • Sebastiani P, Lazarus R, Weiss ST, Kunkel LM, Kohane IS, Ramoni MF (2003) Minimal haplotype tagging. Proc Natl Acad Sci USA 100:9900–9905

    Article  PubMed  CAS  Google Scholar 

  • Smith GR, Kunes SM, Schultz DW, Taylor A, Triman KL (1981) Structure of chi hotspots of generalized recombination. Cell 24:429–436

    Article  PubMed  CAS  Google Scholar 

  • Spitsin SV, Farber JL, Bertovich M, Moehren G, Koprowski H, Michaels FH (1997) Human- and mouse-inducible nitric oxide synthase promoters require activation of phosphatidylcholine-specific phospholipase C and NF-kappa B. Mol Med 3:315–326

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Donnelly P (2003) A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet 73:1162–1169

    Article  PubMed  CAS  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  • Sunyaev SR, Lathe WC 3rd, Ramensky VE, Bork P (2000) SNP frequencies in human genes an excess of rare alleles and differing modes of selection. Trends Genet 16:335–337

    Article  PubMed  CAS  Google Scholar 

  • Tajima F (1989) Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123:585–595

    PubMed  CAS  Google Scholar 

  • Tatusova TA, Madden TL (1999) BLAST 2 sequences, a new tool for comparing protein and nucleotide sequences. FEMS Microbiol Lett 174:247–250

    Article  PubMed  CAS  Google Scholar 

  • Taylor BS, de Vera ME, Ganster RW, Wang Q, Shapiro RA, Morris SM Jr, Billiar TR, Geller DA (1998) Multiple NF-kappaB enhancer elements regulate cytokine induction of the human inducible nitric oxide synthase gene. J Biol Chem 273:15148–15156

    Article  PubMed  CAS  Google Scholar 

  • Templeton AR, Clark AG, Weiss KM, Nickerson DA, Boerwinkle E, Sing CF (2000) Recombinational and mutational hotspots within the human lipoprotein lipase gene. Am J Hum Genet 66:69–83

    Article  PubMed  CAS  Google Scholar 

  • Wahls WP, Wallace LJ, Moore PD (1990) Hypervariable minisatellite DNA is a hotspot for homologous recombination in human cells. Cell 60:95–103

    Article  PubMed  CAS  Google Scholar 

  • Weinberg JB (1998) Nitric oxide production and nitric oxide synthase type 2 expression by human mononuclear phagocytes: a review. Mol Med 4:557–591

    PubMed  CAS  Google Scholar 

  • Weinberg JB, Lopansri BK, Mwaikambo E, Granger DL (2008) Arginine, nitric oxide, carbon monoxide, and endothelial function in severe malaria. Curr Opin Infect Dis 21:468–475

    Article  PubMed  CAS  Google Scholar 

  • Xu W, Liu L, Emson PC, Harrington CR, Charles IG (1997) Evolution of a homopurine-homopyrimidine pentanucleotide repeat sequence upstream of the human inducible nitric oxide synthase gene. Gene 204:165–170

    Article  PubMed  CAS  Google Scholar 

  • Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, Darcy CJ, Granger DL, Weinberg JB, Lopansri BK, Price RN, Duffull SB, Celermajer DS, Anstey NM (2007) Impaired nitric oxide bioavailability and l-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med 204:2693–2704

    Article  PubMed  CAS  Google Scholar 

  • Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, Price RN, Duffull SB, Celermajer DS, Anstey NM (2008) Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci USA 105:17097–17102

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Institutes of Health (NIAID), and by the Veterans Affairs Research Service. The authors gratefully acknowledge the contributions of Bernard John, R.N., Study Manager, Ann Shambuso, R.N. and Sophia Mbangukira, R.N. at Hubert Kairuki Memorial University, Mikocheni Mission Hospital in Dar es Salaam, Tanzania.

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Authors and Affiliations

  1. Durham VA Medical Center, Durham, NC, USA

    Marc C. Levesque, Charles W. O’Loughlin, Jennifer A. Chancellor, Youwei Chen, Kistie B. Patch, Sallie Allgood, Carolyn A. Fernandez & J. Brice Weinberg

  2. Division of Rheumatology and Immunology, Department of Medicine, Duke University, Durham, NC, USA

    Marc C. Levesque, Charles W. O’Loughlin, Kistie B. Patch, Sallie Allgood & Carolyn A. Fernandez

  3. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA

    Maurine R. Hobbs, Ariana N. Tkachuk, Jennifer Booth, Ann R. Pole & Donald L. Granger

  4. Salt Lake VA Medical Center, Salt Lake City, UT, USA

    Maurine R. Hobbs, Ariana N. Tkachuk, Jennifer Booth, Ann R. Pole & Donald L. Granger

  5. Division of Hematology and Oncology, Department of Medicine, Duke University, Durham, NC, USA

    Jennifer A. Chancellor, Youwei Chen & J. Brice Weinberg

  6. Hubert Kairuki Memorial University, Dar es Salaam, Tanzania

    Esther D. Mwaikambo

  7. National Institute for Medical Research, Muheza Designated District Hospital, Muheza, Tanga, Tanzania

    Theonest K. Mutabingwa

  8. Seattle Biomedical Research Institute, Seattle, WA, USA

    Michal Fried, Bess Sorensen & Patrick E. Duffy

  9. International Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, NT, Australia

    Nicholas M. Anstey

  10. Division of Medicine, Royal Darwin Hospital, Darwin, NT, Australia

    Nicholas M. Anstey

  11. University of Pittsburgh Medical Center, 3500 Terrace St., BST S709, Pittsburgh, PA, 15261, USA

    Marc C. Levesque

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  1. Marc C. Levesque
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  2. Maurine R. Hobbs
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  12. Esther D. Mwaikambo
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  18. Nicholas M. Anstey
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  19. J. Brice Weinberg
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Correspondence to Marc C. Levesque.

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Levesque, M.C., Hobbs, M.R., O’Loughlin, C.W. et al. Malaria severity and human nitric oxide synthase type 2 (NOS2) promoter haplotypes. Hum Genet 127, 163–182 (2010). https://doi.org/10.1007/s00439-009-0753-3

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