TY - JOUR

T1 - Fc gamma receptor IIIB (Fc gamma RIIIB) polymorphisms are associated with clinical malaria in Ghanaian children

AU - Adu, Bright

AU - Dodoo, Daniel

AU - Adukpo, Selorme

AU - Hedley, Paula L

AU - Arthur, Fareed K N

AU - Gerds, Thomas A

AU - Larsen, Severin O

AU - Christiansen, Michael

AU - Theisen, Michael

PY - 2012

Y1 - 2012

N2 - 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-Fc¿RIIA and Fc¿RIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding Fc¿RIIA and Fc¿RIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding Fc¿RIIA p.H166R and Fc¿RIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. Fc¿RIIA-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 Fc¿RIIA-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 Fc¿RIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p¿=¿0.049). The Fc¿RIIIB-NA2*03 allotype (CTGCGA), a variant of the classical Fc¿RIIIB-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 Fc¿RIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical Fc¿RIIIB 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.

AB - 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-Fc¿RIIA and Fc¿RIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding Fc¿RIIA and Fc¿RIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding Fc¿RIIA p.H166R and Fc¿RIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. Fc¿RIIA-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 Fc¿RIIA-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 Fc¿RIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p¿=¿0.049). The Fc¿RIIIB-NA2*03 allotype (CTGCGA), a variant of the classical Fc¿RIIIB-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 Fc¿RIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical Fc¿RIIIB 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.

U2 - 10.1371/journal.pone.0046197

DO - 10.1371/journal.pone.0046197

M3 - Journal article

C2 - 23049979

VL - 7

SP - e46197

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 9

ER -