Human Genetics

, Volume 131, Issue 2, pp 289–299

Functional haplotypes of Fc gamma (Fcγ) receptor (FcγRIIA and FcγRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children

  • Collins Ouma
  • Gregory C. Davenport
  • Steven Garcia
  • Prakasha Kempaiah
  • Ateefa Chaudhary
  • Tom Were
  • Samuel B. Anyona
  • Evans Raballah
  • Stephen N. Konah
  • James B. Hittner
  • John M. Vulule
  • John M. Ong’echa
  • Douglas J. Perkins
Original Investigation

DOI: 10.1007/s00439-011-1076-8

Cite this article as:
Ouma, C., Davenport, G.C., Garcia, S. et al. Hum Genet (2012) 131: 289. doi:10.1007/s00439-011-1076-8

Abstract

Development of protective immunity against Plasmodium falciparum is partially mediated through binding of malaria-specific IgG to Fc gamma (γ) receptors. Variations in human FcγRIIA-H/R-131 and FcγRIIIB-NA1/NA2 affect differential binding of IgG sub-classes. Since variability in FcγR may play an important role in severe malarial anemia (SMA) pathogenesis by mediating phagocytosis of red blood cells and triggering cytokine production, the relationship between FcγRIIA-H/R131 and FcγRIIIB-NA1/NA2 haplotypes and susceptibility to SMA (Hb < 6.0 g/dL) was investigated in Kenyan children (n = 528) with acute malaria residing in a holoendemic P. falciparum transmission region. In addition, the association between carriage of the haplotypes and repeated episodes of SMA and all-cause mortality were investigated over a 3-year follow-up period. Since variability in FcγR can alter interferon (IFN)-γ production, a mediator of innate and adaptive immune responses, functional associations between the haplotypes and IFN-γ were also explored. During acute malaria, children with SMA had elevated peripheral IFN-γ levels (P = 0.006). Although multivariate logistic regression analyses (controlling for covariates) revealed no associations between the FcγR haplotypes and susceptibility to SMA during acute infection, the FcγRIIA-131H/FcγRIIIB-NA1 haplotype was associated with decreased peripheral IFN-γ (P = 0.046). Longitudinal analyses showed that carriage of the FcγRIIA-131H/FcγRIIIB-NA1 haplotype was associated with reduced risk of SMA (RR 0.65, 95% CI 0.46–0.90; P = 0.012) and all-cause mortality (P = 0.002). In contrast, carriers of the FcγRIIA-131H/FcγRIIIB-NA2 haplotype had increased susceptibility to SMA (RR 1.47, 95% CI 1.06–2.04; P = 0.020). Results here demonstrate that variation in the FcγR gene alters susceptibility to repeated episodes of SMA and mortality, as well as functional changes in IFN-γ production.

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Collins Ouma
    • 1
    • 2
  • Gregory C. Davenport
    • 3
  • Steven Garcia
    • 3
  • Prakasha Kempaiah
    • 3
  • Ateefa Chaudhary
    • 3
  • Tom Were
    • 1
    • 4
  • Samuel B. Anyona
    • 1
  • Evans Raballah
    • 1
  • Stephen N. Konah
    • 1
  • James B. Hittner
    • 5
  • John M. Vulule
    • 6
  • John M. Ong’echa
    • 1
  • Douglas J. Perkins
    • 1
    • 3
  1. 1.Centre for Global Health Research, Kenya Medical Research InstituteUniversity of New Mexico/KEMRI Laboratories of Parasitic and Viral DiseasesKisumuKenya
  2. 2.Department of Biomedical Sciences and TechnologyMaseno UniversityMasenoKenya
  3. 3.Department of Internal Medicine, Center for Global HealthUniversity of New Mexico, Health Sciences CentreAlbuquerqueUSA
  4. 4.Department of PathologyKenyatta UniversityNairobiKenya
  5. 5.Department of PsychologyCollege of CharlestonCharlestonUSA
  6. 6.Centre for Global Health ResearchKenya Medical Research InstituteKisumuKenya

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