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

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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.

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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.

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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

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  1. Collins Ouma
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  2. Gregory C. Davenport
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  3. Tom Were
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  4. Michael F. Otieno
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  6. John M. Vulule
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  7. Jeremy Martinson
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  8. John M. Ong’echa
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  9. Robert E. Ferrell
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  10. Douglas J. Perkins
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Correspondence to Douglas J. Perkins.

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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.

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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

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