Fc γ receptor IIIB (FcγRIIIB) polymorphisms are associated with clinical malaria in Ghanaian children

Plasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from clini...

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Bibliographic Details
Published in:PloS one 2012-09, Vol.7 (9), p.e46197-e46197
Main Authors: Adu, Bright, Dodoo, Daniel, Adukpo, Selorme, Hedley, Paula L, Arthur, Fareed K N, Gerds, Thomas A, Larsen, Severin O, Christiansen, Michael, Theisen, Michael
Format: Article
Language:English
Subjects:
Alleles
Allotypes
Anemia
Antibodies
Antigens
Arthritis
Biochemistry
Biology
Child
Child, Preschool
Children
Epidemiology
Exons - genetics
Fc receptors
Female
Genetic aspects
Genetic polymorphisms
Genetic Predisposition to Disease
Ghana
GPI-Linked Proteins - genetics
Haplotypes
Heredity
Humans
Immunoglobulin G
Immunology
Infant
Infectious diseases
Leukocytes (neutrophilic)
Ligands
Malaria
Malaria - genetics
Malaria vaccines
Male
Medical research
Medicine
Neutrophils
Parasitology
Plasmodium falciparum
Polymerase chain reaction
Polymorphism
Polymorphism, Genetic - genetics
Population
Receptors
Receptors, IgG - genetics
Regression analysis
Respiratory burst
Studies
Vaccines
Vector-borne diseases
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Summary:Plasmodium falciparum malaria kills nearly a million people annually. Over 90% of these deaths occur in children under five years of age in sub-Saharan Africa. A neutrophil mediated mechanism, the antibody dependent respiratory burst (ADRB), was recently shown to correlate with protection from clinical malaria. Human neutrophils constitutively express Fc gamma receptor-FcγRIIA and FcγRIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding FcγRIIA and FcγRIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding FcγRIIA p.H166R and FcγRIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. FcγRIIA-p.166H/R was genotyped by gene specific polymerase chain reaction followed by allele specific restriction enzyme digestion. FCGR3B-exon 3 was sequenced in 585 children, aged 1 to 12 years living in a malaria endemic region of Ghana. Multivariate logistic regression analysis found no association between FcγRIIA-166H/R polymorphism and clinical malaria. The A-allele of FCGR3B-c.233C>A (rs5030738) was significantly associated with protection from clinical malaria under two out of three genetic models (additive: p=0.0061; recessive: p=0.097; dominant: p=0.0076) of inheritance. The FcγRIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p=0.049). The FcγRIIIB-NA2*03 allotype (CTGCGA), a variant of the classical FcγRIIIB-NA2 (CTGCAA) was associated with susceptibility to clinical malaria (p=0.0092). The present study is the first to report an association between a variant of FcγRIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical FcγRIIIB allotypes. This would be crucial to the improvement of neutrophil mediated functional assays such as the ADRB assay aimed at assessing the functionality of antibodies induced by candidate malaria vaccines.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0046197