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Published on: December 4, 2015
The genetic control of immunity to Plasmodium infection
Audrey V Grant1,2, Christian Roussilhon3,4, Richard Paul5,6
1Unité de la Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, Paris, France. audrey.grant@pasteur.fr.
Insights
Understanding malaria genetics requires studying parasitemia and IgG levels. These immune markers help explain how genetic variations influence malaria severity, guiding future research for new treatments.
Area of Science:
- Genetics
- Immunology
- Infectious Diseases
Background:
- Malaria affects millions globally, particularly children in Africa, with limited vaccine options.
- Genome-wide association studies have identified some genetic factors for severe malaria.
- Understanding host immunity, including parasitemia and IgG levels, is crucial for new malaria interventions.
Purpose of the Study:
- To propose a causal framework for malaria phenotypes.
- To integrate genetic polymorphisms, parasitemia, and IgG levels in malaria progression.
- To highlight the importance of parasitemia and IgG levels in malaria genetic architecture.
Main Methods:
- Developed a global causal framework for malaria progression.
- Reviewed existing knowledge on genetic basis of parasitemia and IgG levels.
- Utilized examples like hemoglobinopathies and FcγRIIa to illustrate causal pathways.
Main Results:
- Genetic polymorphisms can influence malaria at various stages, acting as mediators.
- Immunoglobulin G (IgG) levels can mediate genetic effects by limiting parasitemia.
- Specific genetic variants (e.g., HBB, FCGR2A) show protective effects mediated by parasitemia and IgG levels.
Conclusions:
- Parasitemia and IgG levels are valuable phenotypes for understanding malaria genetics.
- Genome-wide association studies should be applied to parasitemia and IgG levels.
- This approach enhances understanding of the human genetic architecture of malaria.
Background:
Malaria 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.
Results:
We 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.
Conclusions:
We 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.
