ASSOCIATION OF FCγ RECEPTOR IIA (CD32) POLYMORPHISM WITH MALARIAL ANEMIA AND HIGH-DENSITY PARASITEMIA IN INFANTS AND YOUNG CHILDREN

Abstract

Protective immunity against Plasmodium falciparum is partially mediated through binding of malaria-specific IgG antibodies to Fcgamma receptors. Polymorphic variability in Fcgamma RIIa (H/R-131) is associated with differential binding of IgG subtypes and malaria disease outcomes. However, the role of Fcgamma RIIa-131 variability in conditioning susceptibility to severe malarial anemia, the primary manifestation of severe malaria in holoendemic P. falciparum transmission areas, is largely undefined. Thus, Fcgamma RIIa-H131R polymorphism was investigated in 493 children who came to a hospital with acute malaria. Variation in Fcgamma RIIa-131 was not significantly associated with severe malarial anemia (hemoglobin [Hb] < 6.0 g/dL) or malaria anemia (Hb < 8.0 g/dL). However, relative to the heterozygous genotype, homozygotes for the R131 alleles were protected against high-density parasitemia (>or= 10,000 parasites/microL; odds ratio [OR] = 0.58, 95% confidence interval [CI] = 0.37-0.92, P = 0.02), while homozygotes for the H131 alleles were mildly protective (OR = 0.71, 95% CI = 0.45-1.13, P = 0.14). Additional multivariate analyses showed that infection with human immunodeficiency virus type 1 did not influence the associations between FcgammaRIIa-H131R polymorphism and malaria disease outcomes. Genotypic results presented here parallel data illustrating that parasite density is unrelated to the severity of anemia in children with acute malaria. Thus, although homozygosity for the R131 allele protects against high-density parasitemia, FcgammaRIIa-131 polymorphism does not protect against malaria anemia.

The Levels of CD16/Fcγ Receptor IIIA on CD14+CD16+Monocytes Are Higher in Children with SeverePlasmodium falciparumAnemia than in Children with Cerebral or Uncomplicated Malaria

“…While one study found that the H/R genotype is more common in children at risk for severe malaria (50), other studies have shown an association between the H/H genotype or the H allele and severe malaria (10,38). Yet others have found no association (39) or that the H/H genotype is protective (33). The discrepancy in results likely comes from differences in study design, ethnic groups studied, and the pattern of malaria transmission at each study site.…”

Polymorphisms in the Fc Gamma Receptor IIIA and Toll-Like Receptor 9 Are Associated with Protection against Severe Malarial Anemia and Changes in Circulating Gamma Interferon Levels

“…API biochemical galleries (bioMéri-eux, Inc.) and/or serology was used for identification of blood-borne bacterial isolates. The presence of the sickle cell trait (HbAS) was determined by cellulose acetate electrophoresis, while glucose-6-phosphate dehydrogenase (G6PD) deficiency was determined as previously described (47).…”

“…Since previous geneticsbased studies have thoroughly investigated SNPs (41,47) and haplotypes (40,46), we investigated the effect of cross-SNP combinations in conditioning SMA. We examined the associations between Fc␥RIIIA (Ϫ176F/V) and TLR9 (Ϫ1237T/C) promoter-variant combinations and susceptibility to SMA (Hb Ͻ 6.0 g/dl) in children (aged 3 to 36 months) residing in this area of western Kenya where P. falciparum transmission is holoendemic.…”

A Novel Functional Variant in the Stem Cell Growth Factor Promoter Protects against Severe Malarial Anemia

“…To more fully elucidate the potential importance of SCGF in human malaria, variation in the SCGF promoter was explored, a strategy we have previously used in western Kenya to identify immune response genes that condition susceptibility to pediatric SMA (3,35,37,38). Although to date, no studies have described the effect of polymorphic variability in SCGF on any disease, we focused on a single nucleotide polymorphism (SNP) in the promoter region (Ϫ539C/T; rs7246355) based on the allelic distribution in the Yoruba in the Ibadan population in Nigeria examined as part of the HapMap (phase 3) project.…”