Abstract
BackgroundMalaria remains a major worldwide public health problem with ~207 million cases and ~627,000 deaths per year, mainly affecting children under five years of age in Africa. Recent efforts at elaborating a genetic architecture of malaria have focused on severe malaria, leading to the identification of two new genes and confirmation of previously known variants in HBB, ABO and G6PD, by exploring the whole human genome in genome-wide association (GWA) studies. Molecular pathways controlling phenotypes representing effectiveness of host immunity, notably parasitemia and IgG levels, are of particular interest given the current lack of an efficacious vaccine and the need for new treatment options.ResultsWe propose a global causal framework of malaria phenotypes implicating progression from the initial infection with Plasmodium spp. to the development of the infection through liver and blood-stage multiplication cycles (parasitemia as a quantitative trait), to clinical malaria attack, and finally to severe malaria. Genetic polymorphism may control any of these stages, such that preceding stages act as mediators of subsequent stages. A biomarker of humoral immunity, IgG levels, can also be integrated into the framework, potentially mediating the impact of polymorphism by limiting parasitemia levels. Current knowledge of the genetic basis of parasitemia levels and IgG levels is reviewed through key examples including the hemoglobinopathies, showing that the protective effect of HBB variants on malaria clinical phenotypes may partially be mediated through parasitemia and cytophilic IgG levels. Another example is the IgG receptor FcγRIIa, encoded by FCGR2A, such that H131 homozygotes displayed higher IgG2 levels and were protective against high parasitemia and onset of malaria symptoms as shown in a causal diagram.ConclusionsWe thus underline the value of parasitemia and IgG levels as phenotypes in the understanding of the human genetic architecture of malaria, and the need for applying GWA approaches to these phenotypes.
Highlights
Malaria remains a major worldwide public health problem in spite of numerous international control efforts with ~207 million cases in 2012 and ~627,000 deaths per year, mainly affecting children under five years of age in Africa
We explore the potential of quantitative measures of malaria infection, including parasitemia and the biomarker of humoral host immunity, IgG levels, in the search for human genetic factors impacting on malaria, in this review
For the study of human genetics, it would be optimal to focus on a measure of parasitemia that represents the global effectiveness of anti-malarial host immunity, which would assume factors contributing to malarial parasite pressure to be homogeneous across the study population, including parasite species and strain, and that all other parameters impacting on parasitemia, such as the initial parasite dose, are homogeneous or controlled for
Summary
Malaria remains a major worldwide public health problem in spite of numerous international control efforts with ~207 million cases in 2012 and ~627,000 deaths per year, mainly affecting children under five years of age in Africa (http://www.who.int/en/). We explore the potential of quantitative measures of malaria infection, including parasitemia and the biomarker of humoral host immunity, IgG levels, in the search for human genetic factors impacting on malaria, in this review.
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