Heritability of P. falciparum and P. vivax Malaria in a Karen Population in Thailand

The majority of studies concerning malaria host genetics have focused on individual genes that confer protection against rather than susceptibility to malaria. Establishing the relative impact of genetic versus non-genetic factors on malaria infection and disease is essential to focus effort on key determinant factors. This relative contribution has rarely been evaluated for Plasmodium falciparum and almost never for Plasmodium vivax. We conducted a longitudinal cohort study in a Karen population of 3,484 individuals in a region of mesoendemic malaria, Thailand from 1998 to 2005. The number of P. falciparum and P. vivax clinical cases and the parasite density per person were determined. Statistical analyses were performed to account for the influence of environmental factors and the genetic heritability of the phenotypes was calculated using the pedigree-based variance components model. The genetic contribution to the number of clinical episodes resulting from P. falciparum and P. vivax were 10% and 19% respectively. There was also moderate genetic contribution to the maximum and overall parasite trophozoite density phenotypes for both P. falciparum (16%&16%) and P. vivax (15%&13%). These values, for P. falciparum, were similar to those previously observed in a region of much higher transmission intensity in Senegal, West Africa. Although environmental factors play an important role in acquiring an infection, genetics plays a determinant role in the outcome of an infection with either malaria parasite species prior to the development of immunity

Positively Selected G6PD-Mahidol Mutation Reduces Plasmodium vivax Density in Southeast Asians

International audienceGlucose-6-phosphate dehydrogenase (G6PD) deficiency—the most common known enzymopathy—is associated with neonatal jaundice and hemolytic anemia usually after exposure to certain infections, foods, or medications. Although G6PD-deficient alleles appear to confer a protective effect against malaria, the link with clinical protection from Plasmodium infection remains unclear. We investigated the effect of a common G6PD deficiency variant in Southeast Asia—the G6PD-Mahidol487A variant—on human survival related to vivax and falciparum malaria. Our results show that strong and recent positive selection has targeted the Mahidol variant over the past 1500 years. We found that the G6PD-Mahidol487A variant reduces vivax, but not falciparum, parasite density in humans, which indicates that Plasmodium vivax has been a driving force behind the strong selective advantage conferred by this mutation

Number of pairs of individuals as defined by genetic relationship (phi2) and household relationship.

<p>Number of pairs of individuals as defined by genetic relationship (phi2) and household relationship.</p

Contribution (%) of genetic (heritability, h²) and house (c²) effects to variability in malaria and non-malaria clinical and biological phenotypes of <i>P. falciparum</i> (Pf) and <i>P. vivax</i> (Pv).

<p>h², variance due to genetics, c², variance due to house effect, S.E. the standard error; NS, not significant (<i>p-value</i>>0.05); NE, not estimated.</p>a<p>Retained because of marginal significance.</p

Summary of samples used in epidemiological and genetic analyses.

<p>For epidemiological analyses, presented are the number of data points (observations and calculated mean/max values) analyzed for each phenotype category, the corresponding number of individuals implicated and hence residual values generated. For genetic analyses, presented are the number of these individuals for whom pedigree information was available and thus the number of independent families and relative pairs count for each phenotype in the heritability analyses. In parentheses, the number belonging to the large complex family.</p

Percentage of variation in <i>P. falciparum</i> (Pf) and <i>P. vivax</i> (Pv) phenotypes explained by environmental factors (and their interactions) in the statistical analyses.

<p>In parentheses, <i>p</i> is the <i>p-value</i>; in bold, <i>p-value</i><10⁻³.</p>a<p>Retained because of significant interaction with Age.</p

Proportions of variation explained by genetic heritability, house and environmental factors found to have a significant effect on the phenotype measured (Table 3&6).

<p>(A) Number of clinical episodes of <i>P. falciparum</i> (PFA); (B) Number of clinical episodes of <i>P. vivax</i> (PVA); (C) Number of non-malaria clinical episodes (NMF); (D) Maximum <i>P. falciparum</i> parasite density (mx-PFD); (E) Overall <i>P. falciparum</i> parasite density (PFD); (F) Maximum <i>P. vivax</i> parasite density (mx-PVD); (G) Overall <i>P. vivax</i> parasite density (PVD). Values of 1% or less not indicated numerically in the figure.</p

Pair-wise correlation between phenotypes studied.

<p>PFA, Number of visits Pf+; NMF, Number of non-malaria fever visits; PVA, Number of visits Pv+; mx-PFD, Pf max parasite density; PFD, Overall Pf parasite densities; mx-PVD, Pv max parasite density; PVD, Overall Pv parasite densities. In bold, highly significant p value (≤10⁻⁴); in italic, significant p value that becomes not significant after Bonferroni correction for multiple testing (21 hypotheses tested).</p

Family statistics.

<p>Family statistics.</p