Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso

Genes & Immunity volume 12, pages 481–489 (2011)Cite this article

Subjects

Abstract

Hemoglobin C (HbC) has been recently associated with protection against Plasmodium falciparum malaria. It is thought that HbC influences the development of immune responses against malaria, suggesting that the variation at the HbC locus (rs33930165) may interact with polymorphic sites in immune genes. We investigated, in 198 individuals belonging to 34 families living in Burkina Faso, statistical interactions between HbC and 11 polymorphisms within interleukin-4 (IL4), IL12B, NCR3, tumor necrosis factor (TNF) and lymphotoxin-α (LTA), which have been previously associated with malaria-related phenotypes. We searched for multilocus interactions by using the pedigree-based generalized multifactor dimensionality reduction approach. We detected 29 multilocus interactions for mild malaria, maximum parasitemia or asymptomatic parasitemia after correcting for multiple tests. All the single-nucleotide polymorphisms studied are included in several multilocus models. Nevertheless, most of the significant multilocus models included IL12B 3′ untranslated region, IL12Bpro or LTA+80, suggesting that those polymorphisms play a particular role in the interactions detected. Moreover, we identified six multilocus models involving NCR3 that encodes the activating natural killer (NK) receptor NKp30, suggesting an interaction between HbC and genes involved in the activation of NK cells. More generally, our findings suggest an interaction between HbC and genes influencing the activation of effector cells for phenotypes related to mild malaria.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Allison AC . Genetic control of resistance to human malaria. Curr Opin Immunol 2009; 21: 499–505.

    Article  CAS  PubMed  Google Scholar 

  2. Agarwal A, Guindo A, Cissoko Y, Taylor JG, Coulibaly D, Kone A et al. Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood 2000; 96: 2358–2363.

    CAS  PubMed  Google Scholar 

  3. Mockenhaupt FP, Ehrhardt S, Cramer JP, Otchwemah RN, Anemana SD, Goltz K et al. Hemoglobin C and resistance to severe malaria in Ghanaian children. J Infect Dis 2004; 190: 1006–1009.

    Article  CAS  PubMed  Google Scholar 

  4. Modiano D, Luoni G, Sirima BS, Simpore J, Verra F, Konate A et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature 2001; 414: 305–308.

    Article  CAS  PubMed  Google Scholar 

  5. Gilles HM, Fletcher KA, Hendrickse RG, Lindner R, Reddy S, Allan N . Glucose-6-phosphate-dehydrogenase deficiency, sickling, and malaria in African children in South Western Nigeria. Lancet 1967; 1: 138–140.

    Article  CAS  PubMed  Google Scholar 

  6. Guinet F, Diallo DA, Minta D, Dicko A, Sissoko MS, Keita MM et al. A comparison of the incidence of severe malaria in Malian children with normal and C-trait hemoglobin profiles. Acta Trop 1997; 68: 175–182.

    Article  CAS  PubMed  Google Scholar 

  7. Rihet P, Flori L, Tall F, Traore AS, Fumoux F . Hemoglobin C is associated with reduced Plasmodium falciparum parasitemia and low risk of mild malaria attack. Hum Mol Genet 2004; 13: 1–6.

    Article  CAS  PubMed  Google Scholar 

  8. Kreuels B, Kreuzberg C, Kobbe R, Ayim-Akonor M, Apiah-Thompson P, Thompson B et al. Differing effects of HbS and HbC traits on uncomplicated falciparum malaria, anemia, and child growth. Blood 2010; 115: 4551–4558.

    Article  CAS  PubMed  Google Scholar 

  9. Modiano D, Bancone G, Ciminelli BM, Pompei F, Blot I, Simpore J et al. Haemoglobin S and haemoglobin C: ‘quick but costly’ versus ‘slow but gratis’ genetic adaptations to Plasmodium falciparum malaria. Hum Mol Genet 2008; 17: 789–799.

    Article  CAS  PubMed  Google Scholar 

  10. Wood ET, Stover DA, Slatkin M, Nachman MW, Hammer MF . The beta-globin recombinational hotspot reduces the effects of strong selection around HbC, a recently arisen mutation providing resistance to malaria. Am J Hum Genet 2005; 77: 637–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fairhurst RM, Baruch DI, Brittain NJ, Ostera GR, Wallach JS, Hoang HL et al. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature 2005; 435: 1117–1121.

    Article  CAS  PubMed  Google Scholar 

  12. Fairhurst RM, Fujioka H, Hayton K, Collins KF, Wellems TE . Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state. Blood 2003; 101: 3309–3315.

    Article  CAS  PubMed  Google Scholar 

  13. Friedman MJ, Roth EF, Nagel RL, Trager W . The role of hemoglobins C, S, and Nbalt in the inhibition of malaria parasite development in vitro. Am J Trop Med Hyg 1979; 28: 777–780.

    Article  CAS  PubMed  Google Scholar 

  14. Olson JA, Nagel RL . Synchronized cultures of P falciparum in abnormal red cells: the mechanism of the inhibition of growth in HbCC cells. Blood 1986; 67: 997–1001.

    CAS  PubMed  Google Scholar 

  15. Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, Diakite SA, Arie T et al. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc Natl Acad Sci USA 2008; 105: 991–996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Storey J, Fleming AF, Cornille-Brogger R, Molineaux L, Matsushima T, Kagan I . Abnormal haemoglobins in the Sudan savanna of Nigeria. IV. Malaria, immunoglobulins and antimalarial antibodies in haemoglobin AC individuals. Ann Trop Med Parasitol 1979; 73: 311–315.

    Article  CAS  PubMed  Google Scholar 

  17. Verra F, Simpore J, Warimwe GM, Tetteh KK, Howard T, Osier FH et al. Haemoglobin C and S role in acquired immunity against Plasmodium falciparum malaria. PLoS One 2007; 2: e978.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mavoungou E, Held J, Mewono L, Kremsner PG . A Duffy binding-like domain is involved in the NKp30-mediated recognition of Plasmodium falciparum-parasitized erythrocytes by natural killer cells. J Infect Dis 2007; 195: 1521–1531.

    Article  CAS  PubMed  Google Scholar 

  19. Flori L, Kumulungui B, Aucan C, Esnault C, Traore AS, Fumoux F et al. Linkage and association between Plasmodium falciparum blood infection levels and chromosome 5q31-q33. Genes Immun 2003; 4: 265–268.

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Rihet P, Traore Y, Abel L, Aucan C, Traore-Leroux T, Fumoux F . Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33. Am J Hum Genet 1998; 63: 498–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Barbier M, Delahaye NF, Fumoux F, Rihet P . Family-based association of a low producing lymphotoxin-alpha allele with reduced Plasmodium falciparum parasitemia. Microbes Infect 2008; 10: 673–679.

    Article  CAS  PubMed  Google Scholar 

  23. Delahaye NF, Barbier M, Fumoux F, Rihet P . Association analyses of NCR3 polymorphisms with P. falciparum mild malaria. Microbes Infect 2007; 9: 160–166.

    Article  CAS  PubMed  Google Scholar 

  24. Flori L, Delahaye NF, Iraqi FA, Hernandez-Valladares M, Fumoux F, Rihet P . TNF as a malaria candidate gene: polymorphism-screening and family-based association analysis of mild malaria attack and parasitemia in Burkina Faso. Genes Immun 2005; 6: 472–480.

    Article  CAS  PubMed  Google Scholar 

  25. Lou XY, Chen GB, Yan L, Ma JZ, Mangold JE, Zhu J et al. A combinatorial approach to detecting gene-gene and gene-environment interactions in family studies. Am J Hum Genet 2008; 83: 457–467.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Barbier M, Atkinson A, Fumoux F, Rihet P . IL12B polymorphisms are linked but not associated with Plasmodium falciparum parasitemia: a familial study in Burkina Faso. Genes Immun 2008; 9: 405–411.

    Article  CAS  PubMed  Google Scholar 

  27. Hananantachai H, Patarapotikul J, Ohashi J, Naka I, Krudsood S, Looareesuwan S et al. Significant association between TNF-alpha (TNF) promoter allele (−1031C, −863C, and −857C) and cerebral malaria in Thailand. Tissue Antigens 2007; 69: 277–280.

    Article  CAS  PubMed  Google Scholar 

  28. Marquet S, Doumbo O, Cabantous S, Poudiougou B, Argiro L, Safeukui I et al. A functional promoter variant in IL12B predisposes to cerebral malaria. Hum Mol Genet 2008; 17: 2190–2195.

    Article  CAS  PubMed  Google Scholar 

  29. Morahan G, Boutlis CS, Huang D, Pain A, Saunders JR, Hobbs MR et al. A promoter polymorphism in the gene encoding interleukin-12 p40 (IL12B) is associated with mortality from cerebral malaria and with reduced nitric oxide production. Genes Immun 2002; 3: 414–418.

    Article  CAS  PubMed  Google Scholar 

  30. Phawong C, Ouma C, Tangteerawatana P, Thongshoob J, Were T, Mahakunkijcharoen Y et al. Haplotypes of IL12B promoter polymorphisms condition susceptibility to severe malaria and functional changes in cytokine levels in Thai adults. Immunogenetics 2010; 62: 345–356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tangteerawatana P, Perlmann H, Hayano M, Kalambaheti T, Troye-Blomberg M, Khusmith S . IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria. Malar J 2009; 8: 286.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tangteerawatana P, Pichyangkul S, Hayano M, Kalambaheti T, Looareesuwan S, Troye-Blomberg M et al. Relative levels of IL4 and IFN-gamma in complicated malaria: association with IL4 polymorphism and peripheral parasitemia. Acta Trop 2007; 101: 258–265.

    Article  CAS  PubMed  Google Scholar 

  33. Roetynck S, Baratin M, Johansson S, Lemmers C, Vivier E, Ugolini S . Natural killer cells and malaria. Immunol Rev 2006; 214: 251–263.

    Article  CAS  PubMed  Google Scholar 

  34. Korbel DS, Finney OC, Riley EM . Natural killer cells and innate immunity to protozoan pathogens. Int J Parasitol 2004; 34: 1517–1528.

    Article  CAS  PubMed  Google Scholar 

  35. Artavanis-Tsakonas K, Eleme K, McQueen KL, Cheng NW, Parham P, Davis DM et al. Activation of a subset of human NK cells upon contact with Plasmodium falciparum-infected erythrocytes. J Immunol 2003; 171: 5396–5405.

    Article  CAS  PubMed  Google Scholar 

  36. Baratin M, Roetynck S, Pouvelle B, Lemmers C, Viebig NK, Johansson S et al. Dissection of the role of PfEMP1 and ICAM-1 in the sensing of Plasmodium-falciparum-infected erythrocytes by natural killer cells. PLoS One 2007; 2: e228.

    Article  PubMed  PubMed Central  Google Scholar 

  37. D’Ombrain MC, Voss TS, Maier AG, Pearce JA, Hansen DS, Cowman AF et al. Plasmodium falciparum erythrocyte membrane protein-1 specifically suppresses early production of host interferon-gamma. Cell Host Microbe 2007; 2: 130–138.

    Article  PubMed  Google Scholar 

  38. Agaugue S, Marcenaro E, Ferranti B, Moretta L, Moretta A . Human natural killer cells exposed to IL-2, IL-12, IL-18, or IL-4 differently modulate priming of naive T cells by monocyte-derived dendritic cells. Blood 2008; 112: 1776–1783.

    Article  CAS  PubMed  Google Scholar 

  39. Marcenaro E, Dondero A, Moretta A . Multi-directional cross-regulation of NK cell function during innate immune responses. Transpl Immunol 2006; 17: 16–19.

    Article  CAS  PubMed  Google Scholar 

  40. Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56 (bright) subset. Blood 2001; 97: 3146–3151.

    Article  CAS  PubMed  Google Scholar 

  41. Iversen AC, Norris PS, Ware CF, Benedict CA . Human NK cells inhibit cytomegalovirus replication through a noncytolytic mechanism involving lymphotoxin-dependent induction of IFN-beta. J Immunol 2005; 175: 7568–7574.

    Article  CAS  PubMed  Google Scholar 

  42. Marcenaro E, Della Chiesa M, Bellora F, Parolini S, Millo R, Moretta L et al. IL-12 or IL-4 prime human NK cells to mediate functionally divergent interactions with dendritic cells or tumors. J Immunol 2005; 174: 3992–3998.

    Article  CAS  PubMed  Google Scholar 

  43. Hunt NH, Grau GE . Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol 2003; 24: 491–499.

    Article  CAS  PubMed  Google Scholar 

  44. Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P, Clark TG et al. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet 2009; 41: 657–665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cabrera G, Cot M, Migot-Nabias F, Kremsner PG, Deloron P, Luty AJ . The sickle cell trait is associated with enhanced immunoglobulin G antibody responses to Plasmodium falciparum variant surface antigens. J Infect Dis 2005; 191: 1631–1638.

    Article  CAS  PubMed  Google Scholar 

  46. Ntoumi F, Flori L, Mayengue PI, Matondo Maya DW, Issifou S, Deloron P et al. Influence of carriage of hemoglobin AS and the Fc gamma receptor IIa-R131 allele on levels of immunoglobulin G2 antibodies to Plasmodium falciparum merozoite antigens in Gabonese children. J Infect Dis 2005; 192: 1975–1980.

    Article  CAS  PubMed  Google Scholar 

  47. Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S et al. An immune basis for malaria protection by the sickle cell trait. PLoS Med 2005; 2: e128.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 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 

  49. Traore Y, Rihet P, Traore-Leroux T, Aucan C, Gazin P, Coosemans M et al. Analysis of the genetic factors controlling malarial infection in man. Sante 1999; 9: 53–59.

    CAS  PubMed  Google Scholar 

  50. 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 

  51. Walley AJ, Cookson WO . Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy. J Med Genet 1996; 33: 689–692.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Laird NM, Horvath S, Xu X . Implementing a unified approach to family-based tests of association. Genet Epidemiol 2000; 19 (Suppl 1): S36–S42.

    Article  PubMed  Google Scholar 

  53. 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 

  54. 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 

  55. Sinha S, Mishra SK, Sharma S, Patibandla PK, Mallick PK, Sharma SK et al. Polymorphisms of TNF-enhancer and gene for FcgammaRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population. Malar J 2008; 7: 13.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Ubalee R, Suzuki F, Kikuchi M, Tasanor O, Wattanagoon Y, Ruangweerayut R 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 

  57. Vafa M, Maiga B, Israelsson E, Dolo A, Doumbo OK, Troye-Blomberg M . Impact of the IL-4 -590 C/T transition on the levels of Plasmodium falciparum specific IgE, IgG, IgG subclasses and total IgE in two sympatric ethnic groups living in Mali. Microbes Infect 2009; 11: 779–784.

    Article  CAS  PubMed  Google Scholar 

  58. Ritchie MD, Hahn LW, Roodi N, Bailey LR, Dupont WD, Parl FF et al. Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer. Am J Hum Genet 2001; 69: 138–147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lou XY, Chen GB, Yan L, Ma JZ, Zhu J, Elston RC et al. A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence. Am J Hum Genet 2007; 80: 1125–1137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I . Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001; 125: 279–284.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all volunteer families of Bobo Dioulasso. AA and MB were supported by a studentship from the French Ministry of Research and Technology. This work was supported by INSERM.

Author information

Authors and Affiliations

  1. INSERM, UMR928-TAGC, Marseille, France

    A Atkinson, S Afridi & P Rihet

  2. Aix-Marseille Université, INSERM U928-TAGC, Université de la Méditerranée, Marseille, France

    A Atkinson, S Afridi, F Fumoux & P Rihet

  3. INSERM, UMR745, Paris, France

    M Barbier

  4. UMR-MD3, IFR 48, Marseille, France

    F Fumoux

Authors
  1. A Atkinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Barbier
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Afridi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F Fumoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P Rihet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Rihet.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Atkinson, A., Barbier, M., Afridi, S. et al. Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso. Genes Immun 12, 481–489 (2011). https://doi.org/10.1038/gene.2011.19

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2011.19

Keywords

This article is cited by

Search

Advanced search

Quick links