Skip to main content

Advertisement

SpringerLink
Log in

Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Plasmodium falciparum malaria is one of the leading global causes of morbidity and mortality with African children bearing the highest disease burden. Among the various severe disease sequelae common to falciparum malaria, severe malarial anemia (SMA) in pediatric populations accounts for the greatest degree of mortality. Although the patho-physiological basis of SMA remains unclear, dysregulation in inflammatory mediators, such as interleukin (IL)-10, appear to play an important role in determining disease outcomes. Since polymorphic variability in innate immune response genes conditions susceptibility to malaria, the relationship between common IL-10 promoter variants (−1,082A/G, −819T/C, and −592A/C), SMA (Hb < 6.0 g/dL), and circulating inflammatory mediator levels (i.e., IL-10, TNF-α, IL-6 and IL-12) were investigated in parasitemic Kenyan children (n = 375) in a holoendemic P. falciparum transmission area. Multivariate logistic regression analyses demonstrated that the −1,082G/−819C/−592C (GCC) haplotype was associated with protection against SMA (OR; 0.68, 95% CI, 0.43–1.05; P = 0.044) and increased IL-10 production (P = 0.029). Although none of the other haplotypes were significantly associated with susceptibility to SMA, individuals with the −1,082A/−819T/−592A (ATA) haplotype had an increased risk of SMA and reduced circulating IL-10 levels (P = 0.042). Additional results revealed that the IL-10:TNF-α ratio was higher in the GCC group (P = 0.024) and lower in individuals with the ATA haplotype (P = 0.034), while the IL-10:IL-12 ratio was higher in ATA haplotype (P = 0.006). Results presented here demonstrate that common IL-10 promoter haplotypes condition susceptibility to SMA and functional changes in circulating IL-10, TNF-α, and IL-12 levels in children with falciparum malaria.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V (2002) Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet 359:1311–1312

    Article  PubMed  CAS  Google Scholar 

  • Awandare GA, Ouma C, Keller CC, Were T, Otieno R, Ouma Y, Davenport GC, Hittner JB, Ong’echa JM, Ferrell R, Perkins DJ (2006) A macrophage migration inhibitory factor promoter polymorphism is associated with high-density parasitemia in children with malaria. Genes Immun 7:568–575

    Article  PubMed  CAS  Google Scholar 

  • Berkley J, Mwarumba S, Bramham K, Lowe B, Marsh K (1999) Bacteraemia complicating severe malaria in children. Trans R Soc Trop Med Hyg 93:283–286

    Article  PubMed  CAS  Google Scholar 

  • Bloland PB, Boriga DA, Ruebush TK, McCormick JB, Roberts JM, Oloo AJ, Hawley W, Lal A, Nahlen B, Campbell CC (1999) Longitudinal cohort study of the epidemiology of malaria infections in an area of intense malaria transmission II. Descriptive epidemiology of malaria infection and disease among children. Am J Trop Med Hyg 60:641–648

    PubMed  CAS  Google Scholar 

  • Breman JG, Egan A, Keusch GT (2001) The intolerable burden of malaria: a new look at the numbers. Am J Trop Med Hyg 64:4–7

    Google Scholar 

  • 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  CAS  Google Scholar 

  • Cai G, Kastelein RA, Hunter CA (1999) IL-10 enhances NK cell proliferation, cytotoxicity and production of IFN-gamma when combined with IL-18. Eur J Immunol 29:2658–2665

    Article  PubMed  CAS  Google Scholar 

  • Carpenter D, Abushama H, Bereczky S, Farnert A, Rooth I, Troye-Blomberg M, Quinnell RJ, Shaw MA (2007) Immunogenetic control of antibody responsiveness in a malaria endemic area. Hum Immunol 68:165–169

    Article  PubMed  CAS  Google Scholar 

  • Clark IA, Chaudhri G (1988) Tumour necrosis factor may contribute to the anaemia of malaria by causing dyserythropoiesis and erythrophagocytosis. Br J Haematol 70:99–103

    Article  PubMed  CAS  Google Scholar 

  • Conti P, Kempuraj D, Kandere K, Di Gioacchino M, Barbacane RC, Castellani ML, Felaco M, Boucher W, Letourneau R, Theoharides TC (2003) IL-10, an inflammatory/inhibitory cytokine, but not always. Immunol Lett 86:123–129

    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 

  • Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P (1999) Polymorphic haplotypes of the interleukin-10 5′ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. Arthritis Rheum 42:1101–1108

    Article  PubMed  CAS  Google Scholar 

  • Eskdale J, Gallagher G (1995) A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics 42:444–445

    Article  PubMed  CAS  Google Scholar 

  • Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW (1998) Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci USA 95:9465–9470

    Article  PubMed  CAS  Google Scholar 

  • Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A (1991) IL-10 inhibits cytokine production by activated macrophages. J Immunol 147:3815–3822

    PubMed  CAS  Google Scholar 

  • Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP (2001) Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol 166:3915–3922

    PubMed  CAS  Google Scholar 

  • Giordani L, Bruzzi P, Lasalandra C, Quaranta M, Schittulli F, Della Ragione F, Iolascon A (2003) Association of breast cancer and polymorphisms of interleukin-10 and tumor necrosis factor-alpha genes. Clin Chem 49:1664–1667

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Ide A, Kawasaki E, Abiru N, Sun F, Takahashi R, Kuwahara H, Fujita N, Kita A, Oshima K, Sakamaki H, Uotani S, Yamasaki H, Yamaguchi Y, Eguchi K (2002) Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age-at-onset. Hum Immunol 63:690–695

    Article  PubMed  CAS  Google Scholar 

  • Jason J, Archibald LK, Nwanyanwu OC, Bell M, Buchanan I, Larned J, Kazembe PN, Dobbie H, Parekh B, Byrd MG, Eick A, Han A, Jarvis WR (2001) Cytokines and malaria parasitemia. Clin Immunol 100:208–218

    Article  PubMed  CAS  Google Scholar 

  • Keijsers V, Verweij CL, Westendorp RG, Breedveld FC, Huizinga T (1997) IL-10 polymorphisms in relation to production and rheumatoid arthritis. Arthritis Rheum 43:120

    Google Scholar 

  • Keller CC, Yamo O, Ouma C, Ong’echa JM, Ounah D, Hittner JB, Vulule JM, Perkins DJ (2006) Acquisition of hemozoin by monocytes down-regulates interleukin-12 p40 (IL-12p40) transcripts and circulating IL-12p70 through an IL-10-dependent mechanism: in vivo and in vitro findings in severe malarial anemia. Infect Immun 74:5249–5260

    Article  PubMed  CAS  Google Scholar 

  • Kube D, Platzer C, von Knethen A, Straub H, Bohlen H, Hafner M, Tesch H (1995) Isolation of the human interleukin 10 promoter. Characterization of the promoter activity in Burkitt’s lymphoma cell lines. Cytokine 7:1–7

    Article  PubMed  CAS  Google Scholar 

  • Kurtis JD, Lanar DE, Opollo M, Duffy PE (1999) Interleukin-10 responses to liver-stage antigen 1 predict human resistance to Plasmodium falciparum. Infect Immun 67:3424–3429

    PubMed  CAS  Google Scholar 

  • Kurtzhals JA, Akanmori BD, Goka BQ, Adabayeri V, Nkrumah FK, Behr C, Hviid L (1999) The cytokine balance in severe malarial anemia. J Infect Dis 180:1753–1755

    Article  PubMed  CAS  Google Scholar 

  • Kwiatkowski DP (2005) How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77:171–192

    Article  PubMed  CAS  Google Scholar 

  • Lalani I, Bhol K, Ahmed AR (1997) Interleukin-10: biology, role in inflammation and autoimmunity. Ann Allergy Asthma Immunol 79:469–483

    Article  PubMed  CAS  Google Scholar 

  • Lee JY, Kim HY, Kim KH, Kim SM, Jang MK, Park JY, Lee JH, Kim JH, Yoo JY (2005) Association of polymorphism of IL-10 and TNF-A genes with gastric cancer in Korea. Cancer Lett 225:207–214

    Article  PubMed  CAS  Google Scholar 

  • Lim S, Crawley E, Woo P, Barnes PJ (1998) Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 352:113

    Article  PubMed  CAS  Google Scholar 

  • Linke A, Kuhn R, Muller W, Honarvar N, Li C, Langhorne J (1996) Plasmodium chabaudi chabaudi: differential susceptibility of gene-targeted mice deficient in IL-10 to an erythrocytic-stage infection. Exp Parasitol 84:253–263

    Article  PubMed  CAS  Google Scholar 

  • Luty AJ, Perkins DJ, Lell B, Schmidt-Ott R, Lehman LG, Luckner D, Greve B, Matousek P, Herbich K, Schmid D, Weinberg JB, Kremsner PG (2000) Low interleukin-12 activity in severe Plasmodium falciparum malaria. Infect Immun 68:3909–3915

    Article  PubMed  CAS  Google Scholar 

  • Mangia A, Santoro R, Piattelli M, Pazienza V, Grifa G, Iacobellis A, Andriulli A (2004) IL-10 haplotypes as possible predictors of spontaneous clearance of HCV infection. Cytokine 25:103–109

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • McDevitt MA, Xie J, Gordeuk V, Bucala R (2004) The anemia of malaria infection: role of inflammatory cytokines. Curr Hematol Rep 3:97–106

    PubMed  Google Scholar 

  • McElroy PD, Lal AA, Hawley WA, Bloland PB, Kuile FO, Oloo AJ, Harlow SD, Lin X, Nahlen BL (1999) Analysis of repeated hemoglobin measures in full-term, normal birth weight Kenyan children between birth and four years of age. III. The Asembo Bay Cohort Project. Am J Trop Med Hyg 61:932–940

    PubMed  CAS  Google Scholar 

  • Meenagh A, Williams F, Ross OA, Patterson C, Gorodezky C, Hammond M, Leheny WA, Middleton D (2002) Frequency of cytokine polymorphisms in populations from western Europe, Africa, Asia, the Middle East and South America. Hum Immunol 63:1055–1061

    Article  PubMed  CAS  Google Scholar 

  • Miller LH, Good MF, Milon G (1994) Malaria pathogenesis. Science 264:1878–1883

    Article  PubMed  CAS  Google Scholar 

  • Ong’echa JM, Keller CC, Were T, Ouma C, Otieno RO, Landis-Lewis Z, Ochiel D, Slingluff JL, Mogere S, Ogonji GA, Orago AS, Vulule JM, Kaplan SS, Day RD, Perkins DJ (2006) Parasitemia, anemia, and malarial anemia in infants and young children in a rural holoendemic Plasmodium falciparum transmission area. Am J Trop Med Hyg 74:376–385

    PubMed  Google Scholar 

  • Ong’echa JM, Remo AM, Kristoff J, Hittner JB, Were T, Ouma C, Otieno RO, Vulule JM, Keller CC, Awandare GA, Perkins DJ (2008) Increased circulating interleukin (IL)-23 in children with malarial anemia: in vivo and in vitro relationship with co-regulatory cytokines IL-12 and IL-10. Clin Immunol 126:211–221

    Article  PubMed  CAS  Google Scholar 

  • Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V (1999) A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis 179:279–282

    Article  PubMed  CAS  Google Scholar 

  • Otieno RO, Ouma C, Ong’echa JM, Keller CC, Were T, Waindi EN, Michaels MG, Day RD, Vulule JM, Perkins DJ (2006) Increased severe anemia in HIV-1-exposed and HIV-1-positive infants and children during acute malaria. Aids 20:275–280

    Article  PubMed  Google Scholar 

  • Ouma C, Keller CC, Opondo DA, Were T, Otieno RO, Otieno MF, Orago AS, Ong’Echa JM, Vulule JM, Ferrell RE, Perkins DJ (2006) Association of Fc gamma receptor IIA (CD32) polymorphism with malarial anemia and high-density parasitemia in infants and young children. Am J Trop Med Hyg 74:573–577

    PubMed  CAS  Google Scholar 

  • Ouma C, Davenport GC, Awandare GA, Keller CC, Were T, Otieno MF, Vulule JM, Martinson J, Ong’echa JM, Ferrell RE, Perkins DJ (2008) Polymorphic variability in the interleukin (IL)-1beta promoter conditions susceptibility to severe malarial anemia and functional changes in IL-1beta production. J Infect Dis 198:1219–1226

    Article  PubMed  CAS  Google Scholar 

  • Perkins DJ, Weinberg JB, Kremsner PG (2000) Reduced interleukin-12 and transforming growth factor-beta1 in severe childhood malaria: relationship of cytokine balance with disease severity. J Infect Dis 182:988–992

    Article  PubMed  CAS  Google Scholar 

  • Prakash D, Fesel C, Jain R, Cazenave PA, Mishra GC, Pied S (2006) Clusters of cytokines determine malaria severity in Plasmodium falciparum-infected patients from endemic areas of Central India. J Infect Dis 194:198–207

    Article  PubMed  CAS  Google Scholar 

  • Scassellati C, Zanardini R, Squitti R, Bocchio-Chiavetto L, Bonvicini C, Binetti G, Zanetti O, Cassetta E, Gennarelli M (2004) Promoter haplotypes of interleukin-10 gene and sporadic Alzheimer’s disease. Neurosci Lett 356:119–122

    Article  PubMed  CAS  Google Scholar 

  • Snow RW, Craig MH, Deichmann U, le Sueur D (1999) A preliminary continental risk map for malaria mortality among African children. Parasitol Today 15:99–104

    Article  PubMed  CAS  Google Scholar 

  • Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8

    PubMed  CAS  Google Scholar 

  • Upperman JS, Pillage G, Siddiqi MQ, Zeevi A, Kelly N, Ford HR, Kammerer C, Spolarics Z (2005) Dominance of high-producing interleukin 6 and low-producing interleukin 10 and interferon gamma alleles in glucose-6-phosphate dehydrogenase-deficient trauma patients. Shock 23:197–201

    PubMed  CAS  Google Scholar 

  • Wilson JN, Rockett K, Jallow M, Pinder M, Sisay-Joof F, Newport M, Newton J, Kwiatkowski D (2005) Analysis of IL10 haplotypic associations with severe malaria. Genes Immun 6:462–466

    Article  PubMed  CAS  Google Scholar 

  • Winkler S, Willheim M, Baier K, Schmid D, Aichelburg A, Graninger W, Kremsner PG (1998) Reciprocal regulation of Th1- and Th2-cytokine-producing T cells during clearance of parasitemia in Plasmodium falciparum malaria. Infect Immun 66:6040–6044

    PubMed  CAS  Google Scholar 

  • WHO (2000) Severe falciparum malaria. Trans R Soc Trop Med Hyg 94(Supplement 1):S1–S90

    Google Scholar 

  • WHO (2005) World Malaria Report 2005. Geneva: World Health Organization/United Nations Children’s Fund; 2005: http://www.rollbackmalaria.org/wmr2005/pdf/WMReport_lr.pdf

  • Wunderink RG, Waterer GW (2003) Genetics of sepsis and pneumonia. Curr Opin Crit Care 9:384–389

    Article  PubMed  Google Scholar 

  • Yao JG, Gao LB, Liu YG, Li J, Pang GF (2008) Genetic variation in interleukin-10 gene and risk of oral cancer. Clin Chim Acta 388:84–88

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to the parents/guardians of the study participants and the children that participated in the study. We are also indebted to the Siaya District Hospital team and the University of New Mexico/KEMRI staff for clinical support. These data are published with the approval of the Director, Kenya Medical Research Institute. This work was supported by grants from the National Institute of Health [AI51305-02 (DJP) and TW05884-02 (DJP)].

Conflict of interest statement

There is no conflict of interest for any of the authors of the manuscript due to commercial or other affiliations.

Author information

Authors and Affiliations

  1. Centre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya

    Collins Ouma, Tom Were, John M. Vulule, John M. Ong’echa & Douglas J. Perkins

  2. Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Gregory C. Davenport & Jeremy Martinson

  3. Department of Pathology, Kenyatta University, Nairobi, Kenya

    Tom Were

  4. Department of Pre-Clinical Sciences, Kenyatta University, Nairobi, Kenya

    Michael F. Otieno

  5. Department of Psychology, College of Charleston, Charleston, SC, USA

    James B. Hittner

  6. Division of Infectious Diseases, University of New Mexico School of Medicine, MSC10-5550, 1 University of New Mexico, Albuquerque, NM, 87131-0001, USA

    John M. Ong’echa & Douglas J. Perkins

  7. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Robert E. Ferrell

Authors
  1. Collins Ouma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregory C. Davenport
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tom Were
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael F. Otieno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. James B. Hittner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John M. Vulule
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeremy Martinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. John M. Ong’echa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert E. Ferrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Douglas J. Perkins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas J. Perkins.

Additional information

The study was approved by the ethical and scientific review committees at the Kenya Medical Research Institute and the institutional review board at the University of Pittsburgh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ouma, C., Davenport, G.C., Were, T. et al. Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production. Hum Genet 124, 515–524 (2008). https://doi.org/10.1007/s00439-008-0578-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-008-0578-5

Keywords

Search

Navigation