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.
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Authors | 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 |
Journal | Human genetics
(Hum Genet)
Vol. 131
Issue 2
Pg. 289-99
(Feb 2012)
ISSN: 1432-1203 [Electronic] Germany |
PMID | 21818580
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- FCGR3B protein, human
- Fc gamma receptor IIA
- GPI-Linked Proteins
- Receptors, IgG
- Interferon-gamma
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Topics |
- Anemia
(complications, genetics)
- Child, Preschool
- GPI-Linked Proteins
(metabolism)
- Genetic Predisposition to Disease
- Haplotypes
- Humans
- Infant
- Infant, Newborn
- Interferon-gamma
(metabolism)
- Kenya
(epidemiology)
- Longitudinal Studies
- Malaria
(genetics, mortality)
- Receptors, IgG
(genetics, metabolism)
- Recurrence
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