Fc Gamma Receptor IIIB (FcγRIIIB) Polymorphisms Are Associated with Clinical Malaria in Ghanaian Children

Abstract

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.

FCGR2C polymorphisms associate with HIV-1 vaccine protection in RV144 trial

“…Aberrant expression or the presence of certain allelic variations of FcγRs is associated with altered functionality that in turn is associated with susceptibility to, or increased severity of, certain autoimmune and infectious diseases and to outcomes of monoclonal Ab cancer treatments (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Besides IgG Abs, IgA Abs also play an important role in humoral immunity.…”

Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression

“…The various FCGR2 and FCGR3 genes show multiple genetic variations including functionally relevant single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs). 2 These SNPs and CNVs have been associated with various autoimmune [3][4][5][6][7][8][9] and infectious diseases, 10,11 and with efficacy of immunotherapy, 12,13 and it is likely that other disease associations will be identified in the future. However, the genetic analysis of this locus is complicated, as it shows a very high degree of homology between the genes.…”

Assessment of HNA alloimmunisation risk in Northeastern Thais, Burmese and Karen

“…These antibodies are responsible for the development of immune-mediated neutrophil destruction in syndromes such as neonatal alloimmune neutropenia (NAIN), autoimmune neutropenia (AIN) and refractoriness to granulocyte transfusions as well as transfusion-related acute lung injury (TRALI) (Bux, 2008). In addition, recent data indicated that HNA polymorphism is not only a risk factor for alloimmune-mediated disorders but also other diseases, including bacterial infection (periodontitis), chronic inflammatory diseases (vasculitis, systemic lupus erythematosus, rheumatoid arthritis) and susceptibility to malaria (Muschter et al, 2011;Adu et al, 2012).…”