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TNF as a malaria candidate gene: polymorphism-screening and family-based association analysis of mild malaria attack and parasitemia in Burkina Faso

Genes & Immunity volume 6, pages 472–480 (2005)Cite this article

Abstract

We have previously obtained strong evidence for linkage of mild malaria attack to the MHC region, with a peak close to the tumor necrosis factor (TNF) gene. We screened, for polymorphisms, the entire TNF gene in the same sample of 34 families comprising 197 individuals living in a Plasmodium falciparum endemic area and we found 17 polymorphisms. In a longitudinal study, we investigated whether the 11 most frequent and informative polymorphisms were associated with mild malaria attack and maximum parasitemia, which was the highest parasitemia in each individual over 2 years. Mild malaria attack and maximum parasitemia were positively correlated. Transmission disequilibrium tests showed nominal evidence for association between TNF-1031, TNF-308, TNF851 and TNF1304 polymorphisms, and mild malaria attack on the one hand, and between TNF-238, TNF851 and TNF1304 polymorphisms, and maximum parasitemia on the other hand. After accounting for multiple tests, we confirmed the association of TNF-238 with maximum parasitemia and the association of TNF1304 and TNF851 with maximum parasitemia and mild malaria attack. The association tests with mild malaria attack suggest a moderate effect of TNF-308 polymorphism. In conclusion, our study suggests that several TNF variants may be part of the genetic determinants for maximum parasitemia and/or mild malaria attack.

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References

  1. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 1994; 371: 508–510.

    Article  CAS  PubMed  Google Scholar 

  2. Knight JC, Udalova I, Hill AV et al. A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria. Nat Genet 1999; 22: 145–150.

    Article  CAS  PubMed  Google Scholar 

  3. McGuire W, Knight JC, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D . Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J Infect Dis 1999; 179: 287–290.

    Article  CAS  PubMed  Google Scholar 

  4. Ubalee R, Suzuki F, Kikuchi M et al. Strong association of a tumor necrosis factor-alpha promoter allele with cerebral malaria in Myanmar. Tissue Antigens 2001; 58: 407–410.

    Article  CAS  PubMed  Google Scholar 

  5. Jepson A, Sisay JF, Banya W et al. Genetic linkage of mild malaria to the major histocompatibility complex in Gambian children: study of affected sibling pairs. BMJ 1997; 315: 96–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Flori L, Sawadogo S, Esnault C, Delahaye NF, Fumoux F, Rihet P . Linkage of mild malaria to the major histocompatibility complex in families living in Burkina Faso. Hum Mol Genet 2003; 12: 375–378.

    Article  CAS  PubMed  Google Scholar 

  7. Grau GE, Taylor TE, Molyneux ME et al. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med 1989; 320: 1586–1591.

    Article  CAS  PubMed  Google Scholar 

  8. Kwiatkowski D, Hill AV, Sambou I et al. TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet 1990; 336: 1201–1204.

    Article  CAS  PubMed  Google Scholar 

  9. Kwiatkowski D, Molyneux ME, Stephens S et al. Anti-TNF therapy inhibits fever in cerebral malaria. Q J Med 1993; 86: 91–98.

    CAS  PubMed  Google Scholar 

  10. Kremsner PG, Winkler S, Brandts C et al. Prediction of accelerated cure in Plasmodium falciparum malaria by the elevated capacity of tumor necrosis factor production. Am J Trop Med Hyg 1995; 53: 532–538.

    Article  CAS  PubMed  Google Scholar 

  11. Ferrante A, Kumaratilake L, Rzepczyk CM, Dayer JM . Killing of Plasmodium falciparum by cytokine activated effector cells (neutrophils and macrophages). Immunol Lett 1990; 25: 179–187.

    Article  CAS  PubMed  Google Scholar 

  12. Bouharoun TH, Oeuvray C, Lunel F, Druilhe P . Mechanisms underlying the monocyte-mediated antibody-dependent killing of Plasmodium falciparum asexual blood stages. J Exp Med 1995; 182: 409–418.

    Article  Google Scholar 

  13. Stirnadel HA, Stockle M, Felger I, Smith T, Tanner M, Beck HP . Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania. Trop Med Int Health 1999; 4: 187–193.

    Article  CAS  PubMed  Google Scholar 

  14. Migot-Nabias F, Mombo LE, Luty AJ et al. Human genetic factors related to susceptibility to mild malaria in Gabon. Genes Immun 2000; 1: 435–441.

    Article  CAS  PubMed  Google Scholar 

  15. Mombo LE, Ntoumi F, Bisseye C et al. Human genetic polymorphisms and asymptomatic Plasmodium falciparum malaria in Gabonese schoolchildren. Am J Trop Med Hyg 2003; 68: 186–190.

    Article  CAS  PubMed  Google Scholar 

  16. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  PubMed  Google Scholar 

  17. Sankoh AJ, Huque MF, Dubey SD . Some comments on frequently used multiple endpoint adjustment methods in clinical trials. Stat Med 1997; 16: 2529–2542.

    Article  CAS  PubMed  Google Scholar 

  18. Richardson A, Sisay-Joof F, Ackerman H et al. Nucleotide diversity of the TNF gene region in an African village. Genes Immun 2001; 2: 343–348.

    Article  CAS  PubMed  Google Scholar 

  19. Ackerman H, Usen S, Mott R et al. Haplotypic analysis of the TNF locus by association efficiency and entropy. Genome Biol 2003; 4: R24.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Taverne J, Sheikh N, de SJ, Playfair JH, Probert L, Kollias G . Anaemia and resistance to malaria in transgenic mice expressing human tumour necrosis factor. Immunology 1994; 82: 397–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. May J, Lell B, Luty AJ, Meyer CG, Kremsner PG . Plasma interleukin-10 : tumor necrosis factor (TNF)-alpha ratio is associated with TNF promoter variants and predicts malarial complications. J Infect Dis 2000; 182: 1570–1573.

    Article  CAS  PubMed  Google Scholar 

  22. Drouet C, Shakhov AN, Jongeneel CV . Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. J Immunol 1991; 147: 1694–1700.

    CAS  PubMed  Google Scholar 

  23. Pociot F, D'Alfonso S, Compasso S, Scorza R, Richiardi PM . Functional analysis of a new polymorphism in the human TNF alpha gene promoter. Scand J Immunol 1995; 42: 501–504.

    Article  CAS  PubMed  Google Scholar 

  24. Kaluza W, Reuss E, Grossmann S et al. Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism. J Invest Dermatol 2000; 114: 1180–1183.

    Article  CAS  PubMed  Google Scholar 

  25. Bayley JP, de Rooij H, van den Elsen PJ, Huizinga TW, Verweij CL . Functional analysis of linker-scan mutants spanning the -376, -308, -244, and -238 polymorphic sites of the TNF-alpha promoter. Cytokine 2001; 14: 316–323.

    Article  CAS  PubMed  Google Scholar 

  26. Fong CL, Siddiqui AH, Mark DF . Identification and characterization of a novel repressor site in the human tumor necrosis factor alpha gene. Nucleic Acids Res 1994; 22: 1108–1114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW . Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 1997; 94: 3195–3199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brinkman BM, Zuijdeest D, Kaijzel EL, Breedveld FC, Verweij CL . Relevance of the tumor necrosis factor alpha (TNF alpha) -308 promoter polymorphism in TNF alpha gene regulation. J Inflamm 1995; 46: 32–41.

    PubMed  Google Scholar 

  29. Stuber F, Udalova IA, Book M et al. 308 Tumor necrosis factor (TNF) polymorphism is not associated with survival in severe sepsis and is unrelated to lipopolysaccharide inducibility of the human TNF promoter. J Inflamm 1995; 46: 42–50.

    PubMed  Google Scholar 

  30. Wattavidanage J, Carter R, Perera KL et al. TNFalpha*2 marks high risk of severe disease during Plasmodium falciparum malaria and other infections in Sri Lankans. Clin Exp Immunol 1999; 115: 350–355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Aidoo M, McElroy PD, Kolczak MS et al. Tumor necrosis factor-alpha promoter variant 2 (TNF2) is associated with pre-term delivery, infant mortality, and malaria morbidity in western Kenya: Asembo Bay Cohort Project IX. Genet Epidemiol 2001; 21: 201–211.

    Article  CAS  PubMed  Google Scholar 

  32. Meyer CG, May J, Luty AJ, Lell B, Kremsner PG . TNFalpha-308A associated with shorter intervals of Plasmodium falciparum reinfections. Tissue Antigens 2002; 59: 287–292.

    Article  CAS  PubMed  Google Scholar 

  33. Knight JC, Keating BJ, Rockett KA, Kwiatkowski DP . In vivo characterization of regulatory polymorphisms by allele-specific quantification of RNA polymerase loading. Nat Genet 2003; 33: 469–475.

    Article  CAS  PubMed  Google Scholar 

  34. Rihet P, Abel L, Traore Y, Traore-Leroux T, Aucan C, Fumoux F . Human malaria: segregation analysis of blood infection levels in a suburban area and a rural area in Burkina Faso. Genet Epidemiol 1998; 15: 435–450.

    Article  CAS  PubMed  Google Scholar 

  35. Schellenberg JR, Smith T, Alonso PL, Hayes RJ . What is clinical malaria? Finding case definitions for field research in highly endemic areas. Parasitol Today 1994; 10: 439–442.

    Article  CAS  PubMed  Google Scholar 

  36. Rogier C, Commenges D, Trape JF . Evidence for an age-dependent pyrogenic threshold of Plasmodium falciparum parasitemia in highly endemic populations. Am J Trop Med Hyg 1996; 54: 613–619.

    Article  CAS  PubMed  Google Scholar 

  37. Aucan C, Traore Y, Tall F et al. High immunoglobulin G2 (IgG2) and low IgG4 levels are associated with human resistance to Plasmodium falciparum malaria. Infect Immun 2000; 68: 1252–1258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang L, Cui X, Schmitt K, Hubert R, Navidi W, Arnheim N . Whole genome amplification from a single cell: implications for genetic analysis. Proc Natl Acad Sci USA 1992; 89: 5847–5851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Abecasis GR, Cookson WO . GOLD—Graphical Overview of Linkage Disequilibrium. Bioinformatics 2000; 16: 182–183.

    Article  CAS  PubMed  Google Scholar 

  40. Abecasis GR, Cardon LR, Cookson WO . A general test of association for quantitative traits in nuclear families. Am J Hum Genet 2000; 66: 279–292.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all volunteer families of Bobo-Dioulasso. Assistance from the ‘Genome Variation’ (GenoVarior) core facilities from Marseille-Génopôle was greatly appreciated and we thank Jérôme Belougne for his technical help. This work was supported by the French Ministry of Research and Technology (PAL+ Program), the Fondation pour la Recherche Médicale, the PACA Conseil Régional and the Conseil Général des Bouches du Rhône. LF is supported by a studentship from the Fondation pour la Recherche Médicale and NFD is supported by a studentship from the French Ministry of Research and Technology.

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Authors and Affiliations

  1. Laboratoire d'immunogénétique et de pharmacologie du paludisme-EA 864, Faculté de Pharmacie, Université de la Méditerranée, Marseille, IFR 48, Cedex, France

    L Flori, N F Delahaye, F Fumoux & P Rihet

  2. International Livestock Research Institute, Nairobi, Kenya

    F A Iraqi & M Hernandez-Valladares

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  1. L Flori
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  2. N F Delahaye
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  3. F A Iraqi
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  4. M Hernandez-Valladares
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  5. F Fumoux
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  6. P Rihet
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Correspondence to P Rihet.

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Flori, L., Delahaye, N., Iraqi, F. et al. TNF as a malaria candidate gene: polymorphism-screening and family-based association analysis of mild malaria attack and parasitemia in Burkina Faso. Genes Immun 6, 472–480 (2005). https://doi.org/10.1038/sj.gene.6364231

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