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

The original publication is available at http://www.plosone.orgPlasmodium 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-FcɣRIIA and FcɣRIIIB by which they interact with immunoglobulin (Ig) G (IgG)-subclass antibodies. Polymorphisms in exon 4 of FCGR2A and exon 3 of FCGR3B genes encoding FcɣRIIA and FcɣRIIIB respectively have been described to alter the affinities of both receptors for IgG. Here, associations between specific polymorphisms, encoding FcɣRIIA p.H166R and FcɣRIIIB-NA1/NA2/SH variants with clinical malaria were investigated in a longitudinal malaria cohort study. FcɣRIIA-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 FcɣRIIA-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 FcɣRIIIB-SH allotype (CTGAAA) containing the 233A-allele (in bold) was associated with protection from malaria (p = 0.049). The FcɣRIIIB-NA2*03 allotype (CTGCGA), a variant of the classical FcɣRIIIB-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 FcɣRIIIB-NA2 and susceptibility to clinical malaria and provides justification for further functional characterization of variants of the classical FcɣRIIIB 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.European and Developing Countries Clinical Trials Partnership (www.edctp.org) (TA.2007.40200.012)European Vaccine Initiative (www.euvaccine.eu) (08-2007)African Malaria Network Trust (www.amanet-trust.org) (008/2008AIA)Publisher's versio

Polymorphisms in the RNASE3 Gene Are Associated with Susceptibility to Cerebral Malaria in Ghanaian Children

BACKGROUND: Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM. METHODOLOGY/PRINCIPAL FINDINGS: The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n=45) and SA (n=56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n=105). The 371G allele was significantly associated with CM (p=0.00945, OR=2.29, 95% CI=1.22-4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p=0.000913, OR=4.14, 95% CI=1.79-9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection. CONCLUSIONS/SIGNIFICANCE: The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis

Measurement Of Activity Concentrations Of 226Ra, 232Th, 40K And 137Cs In Some Common Spices Consumed By Inhabitants In Accra Metropolis, Ghana

A spice is a vegetable substance of indigenous or exotic origin which is or has a hot, pigment taste, used to enhance taste of foods or to add to them the stimulant ingredients contained in them. Knowledge of radioactivity levels in human diet is of particular concern for the estimation of possible radiological hazards to human health. In this study, the radioactivity concentrations of 226Ra, 232Th, 40K and 137Cs in some selected natural and processed spices of different brands in the Madina District of Accra Metropolis were determined and the ingested doses via food consumption were also assessed using gamma spectrometry. The average activity concentration of 226Ra, 232Th, 40K and 137Cs in the natural spices were 0.81 ± 0.2 BqKg-1, 0.98 ± 0.4 BqKg-1, 2.19 ± 0.9 BqKg-1 and 0.06 ± 0.01 BqKg-1 respectively. For the processed spices, the average activity concentration of 226Ra, 232Th, 40K and 137Cs were 0.18 ± 0.1 BqKg-1, 0.3 ± 0.1 BqKg-1, 1.3 ± 0.8 BqKg-1 and 0.02 ± 0.01 BqKg-1 respectively. The levels of 137Cs observed in the samples are within the range of ‘background’ concentrations. The estimated total annual effective dose received from 226Ra, 232Th and 137Cs, due to consumption of natural (fresh) and processed spices by the inhabitants of Madina in the Accra metropolis was 8.47 μSvy-1 and this is far below the average radiation dose of 0.29 mSvy-1 received per caput worldwide due to ingestion of natural radionuclides provided in UNSCEAR (2000) report. The results indicate insignificant radiological health hazard to the public due to the consumption of spices via foods

Determination of Radionuclides in Underground Water Sources Within the Environments of University of Cape Coast

Abstract: Preliminary studies on groundwater samples from selected wells in University of Cape Coast and its surroundings in the Central region of Ghana have been carried out to determine the annual effective dose from intake of naturally occurring radionuclides. Measurements were carried out using gamma spectrometry. The average annual effective doses obtained in this study were 0.15±0.04 mSv for Apewosika, 0.17±0.03 mSv for Amamoma, 0.14±0.01 mSv for Kokoado and 0.17±0.03 mSv for Kwaprow respectively. The values calculated were about 1.7 times higher than WHO guidance levels of 0.1 mSv/y from intake of radionuclides in water. 232 Th and 40 K levels are lower than the world average values whilst 238 U levels are slightly higher. The total annual effective dose in the study area is lower than the ICRP recommended public dose limit of 1 mSv per year

Apresentação do Programa de Avaliação Externa da Qualidade / INSA IP

<div><p><em>Plasmodium falciparum</em> 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 <em>FCGR2A</em> and exon 3 of <em>FCGR3B</em> 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. <em>FCGR3B</em>-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 <em>FCGR3B</em>-c.233C>A (rs5030738) was significantly associated with protection from clinical malaria under two out of three genetic models (additive: <em>p</em> = 0.0061; recessive: <em>p</em> = 0.097; dominant: <em>p</em> = 0.0076) of inheritance. The FcγRIIIB-SH allotype (CTG<b>A</b>AA) containing the 233A-allele (in bold) was associated with protection from malaria (<em>p</em> = 0.049). The FcγRIIIB-NA2*03 allotype (CTGCGA), a variant of the classical FcγRIIIB-NA2 (CTGCAA) was associated with susceptibility to clinical malaria (<em>p</em> = 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.</p> </div

<i>FCGR3B</i> allele frequencies and Hardy-Weinberg (HW) estimations in protected individuals.

*<p>Allele and amino acid numberings refer to positions in <i>FCGR3B</i> transcript ENST00000367964.</p>a<p>HW estimations based on children (n = 267) who had diploid copies of <i>FCGR3B</i>, were the first sibling in a family and were not susceptible to clinical malaria in the observation period.</p

Studied SNPs in the <i>FCGR3B</i> gene, linkage disequilibrium (LD) patterns and haplotype association analysis.

<p><b>A</b>) A schematic of exon 3 <i>FCGR3B</i> gene (<b>NM_000570.4</b>) and LD plot of the respective SNPs visualised using Haploview v4.2. The LD plot shows pairwise r² values (×100) given in the squares for each comparison between the SNPs. White squares represent r² values equal to 0. Different shades of grey represent r² values between 0 and 1. <b>B</b>) Haplotype associations with susceptibility to clinical malaria compared to clinically protected individuals. Odds ratio (OR) and 95% confidence intervals (CI) were determined using multivariate logistic regression controlling for age, gender, ethnicity, sickle-cell status, <i>FCGR3B</i> copy number, blood group and use of bed net. The haplotype with the highest frequency in the study population was considered the reference group in the multivariate logistic regression analyses. ^ŦVariant first reported in this study, the associated gene for NA1*06 is <i>FCGR3B*01A194G, G316A</i>; ^Ψ Variants first reported by Matsuo et al, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046197#pone.0046197-Matsuo1" target="_blank">[28]</a>, the associated genes for NA1*02, NA2*02 and NA2*03 are <i>FCGR3B*01G316A</i>, <i>FCGR3B*02G194A</i> and <i>FCGR3B*02A244G</i> respectively.</p

Single marker association of <i>FCGR3B</i> alleles with clinical malaria.

<p>Odds ratio (OR) and 95% confidence intervals (CI) were determined using multivariate logistic regression controlling for age, gender, ethnicity, sickle-cell status, <i>FCGR3B</i> copy number, blood group, family structure and use of bed net. MAF: minor allele frequency.</p>Ŧ<p>All individuals who never had malaria despite parasitaemia at any time point (monthly blood slide) during the study, plus all individuals who never had malaria but without detectable parasitaemia by microscopy.</p