MalariaGEN's process for developing a GWA data-release policy.

<p>MalariaGEN's process for developing a GWA data-release policy.</p

Data application process.

<p>Data application process.</p

Association tests of <i>PROCR</i> haplotypes with severe malaria, cerebral malaria, and severe malaria anemia.

<p>Aff, affected individuals; unaff, unaffected individuals.</p>a<p>Refers to SNP number as designated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115770#pone-0115770-t002" target="_blank">Table 2</a>.</p>b<p>Results of haplotypic-specific score tests adjusted for gender, age, and ethnicity assuming an additive mode of inheritance.</p>c<p>Simulation p-values are computed based on a permuted re-ordering of the trait and covariates in Haplo Stats <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115770#pone.0115770-Schaid1" target="_blank">[29]</a>.</p><p>Association tests of <i>PROCR</i> haplotypes with severe malaria, cerebral malaria, and severe malaria anemia.</p

PROCR rare variant analyses including SNPs with MAF ≤1%.

<p>CMC, combined and multivariate collapsing; WSS, weighted sum statistic; VT, variable thresholds methods.</p>a<p>Adjusted for age, gender, and ethnic group.</p><p>PROCR rare variant analyses including SNPs with MAF ≤1%.</p

Endothelial Protein C Receptor Gene Variants Not Associated with Severe Malaria in Ghanaian Children

<div><p>Background</p><p>Two recent reports have identified the Endothelial Protein C Receptor (EPCR) as a key molecule implicated in severe malaria pathology. First, it was shown that EPCR in the human microvasculature mediates sequestration of <i>Plasmodium falciparum</i>-infected erythrocytes. Second, microvascular thrombosis, one of the major processes causing cerebral malaria, was linked to a reduction in EPCR expression in cerebral endothelial layers. It was speculated that genetic variation affecting EPCR functionality could influence susceptibility to severe malaria phenotypes, rendering <i>PROCR</i>, the gene encoding EPCR, a promising candidate for an association study.</p><p>Methods</p><p>Here, we performed an association study including high-resolution variant discovery of rare and frequent genetic variants in the <i>PROCR</i> gene. The study group, which previously has proven to be a valuable tool for studying the genetics of malaria, comprised 1,905 severe malaria cases aged 1–156 months and 1,866 apparently healthy children aged 2–161 months from the Ashanti Region in Ghana, West Africa, where malaria is highly endemic. Association of genetic variation with severe malaria phenotypes was examined on the basis of single variants, reconstructed haplotypes, and rare variant analyses.</p><p>Results</p><p>A total of 41 genetic variants were detected in regulatory and coding regions of <i>PROCR</i>, 17 of which were previously unknown genetic variants. In association tests, none of the single variants, haplotypes or rare variants showed evidence for an association with severe malaria, cerebral malaria, or severe malaria anemia.</p><p>Conclusion</p><p>Here we present the first analysis of genetic variation in the <i>PROCR</i> gene in the context of severe malaria in African subjects and show that genetic variation in the <i>PROCR</i> gene in our study population does not influence susceptibility to major severe malaria phenotypes.</p></div

Predictors for early, middle, late death in African children with severe falciparum malaria and stratified by country.

<p>Abbreviations: CI = confidence interval; OR = odds ratio; P = P-value.</p

Boxplot analysis showing time to death by site representing median (line), interquartile range(box).

<p>Boxplot analysis showing time to death by site representing median (line), interquartile range(box).</p

Observed and Population Predicted Concentrations (Solid Black Line) of DHA (Semilogarithmic Scale; ng/ml) versus Time post Dose (h)

<div><p>Study site: filled circle, Bangkok; open square, Ghana; filled triangle, Mae-Sot; open circle, Malawi; asterisk, South Africa.</p> <p>The population predicted concentrations are calculated for a dose of 10 mg/kg.</p></div

Relationship of Estimated Probability of Requiring Rescue Treatment and V/F of DHA (l/kg)

<p>Derived from a multiple logistic regression model with adjustment for the confounders: baseline parasitaemia, baseline PCV, age, and gender.</p

Residual (log_e Units) versus Population Predicted Concentrations of DHA (log_e Units)

<p>Residual = observed − population predicted concentration of DHA.</p