title: Functional haplotypes of Fc gamma (Fcγ) receptor (FcγRIIA and FcγRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children.
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.
authors.affiliation: Centre for Global Health Research, Kenya Medical Research Institute, University of New Mexico/KEMRI Laboratories of Parasitic and Viral Diseases, Kisumu, Kenya.
authors.forename: Collins
authors.initials: C
authors.lastname: Ouma
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Davenport
authors.forename: Steven
authors.initials: S
authors.lastname: Garcia
authors.forename: Prakasha
authors.initials: P
authors.lastname: Kempaiah
authors.forename: Ateefa
authors.initials: A
authors.lastname: Chaudhary
authors.forename: Tom
authors.initials: T
authors.lastname: Were
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Anyona
authors.forename: Evans
authors.initials: E
authors.lastname: Raballah
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Konah
authors.forename: James B
authors.initials: JB
authors.lastname: Hittner
authors.forename: John M
authors.initials: JM
authors.lastname: Vulule
authors.forename: John M
authors.initials: JM
authors.lastname: Ong'echa
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Perkins
mesh_terms: D000740:Anemia / Q000150:complications* / Q000235:genetics*; D002675:Child, Preschool; D058851:GPI-Linked Proteins / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007371:Interferon-gamma / Q000378:metabolism*; D007630:Kenya / Q000453:epidemiology; D008137:Longitudinal Studies; D008288:Malaria / Q000235:genetics* / Q000401:mortality*; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism*; D012008:Recurrence
chemical_list: C428200:FCGR3B protein, human; C080568:Fc gamma receptor IIA; D058851:GPI-Linked Proteins; D017452:Receptors, IgG; D007371:Interferon-gamma