| Human genes that protect against malaria |
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| Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005 77(2):171-92. PMID: 16001361 |
| Common erythrocyte variants that affect resistance to malaria |
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| Gene |
Protein |
Function |
Reported Genetic Associations with Malaria |
| FY |
Duffy antigen |
Chemokine receptor |
FYO allele completely protects against P. vivax infection. |
| DARC |
Duffy antigen (DBP) |
receptor for chemokines |
selective exposure of the DBP binding site within DARC is key to the preferential binding of DBP to immature reticulocytes, which is the potential mechanism underlying the preferential infection of a reticulocyte subset by P vivax. |
| G6PD |
Glucose-6-phosphatase dehydogenase |
Enzyme that protects against oxidative stress |
increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. |
| PK |
Pyruvate kinase |
an enzyme of glycolysis |
Protects against invasion |
| GYPA |
Glycophorin A |
Sialoglycoprotein |
GYPA-deficient erythrocytes are resistant to invasion by P. falciparum. |
| GYPB |
Glycophorin B |
Sialoglycoprotein |
GYPB-deficient erythrocytes are resistant to invasion by P. falciparum. |
| GYPC |
Glycophorin C |
Sialoglycoprotein |
GYPC-deficient erythrocytes are resistant to invasion by P. falciparum. |
| Dantu+ (NE type) |
DUP4 |
Hybrid GYPA (extracellular)+GYPB (intracellular) |
the GYPB-A hybrid proteins seen in DUP4 could potentially affect both receptor-ligand interactions and the physical properties of the red blood cell membrane. |
| HBA |
a-Globin |
Component of hemoglobin |
a+ Thalassemia protects against severe malaria but appears to enhance mild malaria episodes in some environments. |
| HBB |
b-Globin |
Component of hemoglobin |
HbS and HbC alleles protect against severe malaria. HbE allele reduces parasite invasion. |
| HP |
Haptoglobin |
Hemoglobin-binding protein present in plasma (not erythrocyte) |
Haptoglobin 1-1 genotype is associated with susceptibility to severe malaria in Sudan and Ghana. |
| SCL4A1 |
CD233, erythrocyte band 3 protein |
Chloride/bicarbonate exchanger |
Deletion causes ovalocytosis but protects against cerebral malaria. |
| ATP2B4 |
RBC membrane calcium transporter |
calcium transporter |
alteration of its structure or expression may disturb the homeostasis of intra-erythrocytic Ca2+ concentrations |
| ABCB6 |
ATP-binding cassette transporter |
transport porphyrin in nucleated cells, but its physiologic role in enucleated erythrocytes is unknown |
encode the Langereis (Lan) blood group antigen. Lan null individuals are asymptomatic |
| ABO |
glycosyltransferase |
determines ABO blood group |
Non-O haplotypes inherited from mothers, but not fathers, are significantly associated with severe malaria |
| CD40LG |
CD40 ligand |
a glycoprotein involved in B cell proliferation, antigen presenting cell activation, and Ig class switching |
homozygotes showed significantly reduced risk of severe malaria in The Gambia |
| HbS |
Sickle hemoglobin |
the most common type of abnormal hemoglobin and the basis of both sickle cell trait and sickle cell anemia. |
HbS confers a remarkably fixed level of protection against cerebral malaria and severe malarial anemia, with heterozygotes showing 89% reduced risk |
| HbC |
hemoglobin C |
abnormal hemoglobin wher E6K substitution occurs in b-globin |
HbC confers protection against severe malaria |
| PIEZO1 |
mechanosensitive ion channel |
Mechanosensitive channels respond to membrane tension by altering their conformation between an open state and a closed state. |
Variable reduction of P. falciparum growth in vitro. Some studies suggest RBC dehydration, but others find no association. Also associated with reduced var2csa expression |
| CD55 |
RBC invasion receptor |
CD55 prevents formation of C3 and C5 convertases in the complement system |
CD55-null erythrocytes from two Inab individuals were resistant to invasion by all P. falciparum strains tested, demonstrating that this protein is an essential host factor |
| CD44 |
RBC invasion receptor |
CD44 was validated as host factors required for efficient invasion of RBCs by P. falciparum |
Validated by by performing invasion assays using wild type and knockdown cRBCs in vitro |
| EPP |
Host cell ferrochelatase |
final enzyme in the heme biosynthetic pathway |
Malarial parasite growth is impeded in erythropoietic protoporphyric erythrocytes because of decreased host cell ferrochelatase activity. |
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| Host molecules that mediate cytoadherence by infected erythrocytes and that have been reported to show association with resistance or susceptibility to malaria |
| Gene |
Protein |
Interaction with Parasitized Erythrocyte |
Reported Genetic Associations with Malaria |
| CD36 |
CD36 antigen, thrombospondin receptor |
PE-binding receptor on endothelium and dendritic cells |
CD36 polymorphisms show variable associations with severe malaria in the Gambia, Kenya, Thailand, and India. |
| CR1 |
CR1, complement receptor 1 |
PE-binding receptor on erythrocytes |
CR1 polymorphisms show variable associations with severe malaria in the Gambia, Thailand, Papua New Guinea and India |
| ESEL |
E-selectin |
transmembrane glycoprotein expressed on activated endothelium and as soluble protein in plasma |
ESEL polymorphisms show association wih cerebral malaria and enhanced risk of disease in Nigeria and India |
| ICAM1 |
CD54, intercellular adhesion molecule-1 |
PE-binding receptor on endothelium |
ICAM1 polymorphisms show variable associations with severe malaria in Kenya, Gabon, the Gambia and India |
| PECAM1 |
CD31, platelet-endothelial cell–adhesion molecule |
PE-binding receptor on endothelium PECAM1 |
polymorphisms show variable associations with severe malaria in Thailand, Kenya, Papua New Guinea and India. |
| TLR1 |
Toll-like receptor 1 |
a member of the toll-like receptor family (TLR) of pattern recognition receptors of the innate immune system. |
enetic variation in TLR1 has effects on the host response to Plasmodium falciparum malaria in Asian populations. |
| TLR4 |
Toll-like receptor 4 |
a member of the toll-like receptor family (TLR) of pattern recognition receptors of the innate immune system. |
TLR4 signalling is important for the generation of the severe inflammatory response involved in placental malaria pathogenesis. |
| CSF2 |
CSF2 (5q31.1) |
is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya |
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| PE parasitized erythrocyte. |
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| Immune genes reported to be associated with different malaria phenotypes |
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| Gene |
Protein |
Function |
Reported Genetic Associations with Malaria |
| APOBEC3B |
(deoxy)cytidine deaminase family protein |
Innate immunity |
Association of the 29.5 kb APOBEC3b gene deletion polymorphism with susceptibility to malaria in India |
| FCGR2A |
CD32, low affinity receptor for Fc fragment of IgG |
Clearance of antigen-antibody complexes |
Association with severe malaria in the Gambia and India |
| HLA-B |
HLA-B, a component of MHC class I |
Antigen presentation that leads to cytotoxic T cells |
HLA-B53 association with severe malaria in the Gambia |
| HLA-DR |
HLA-DR, a component of MHC class II |
Antigen presentation that leads to antibody production |
HLA-DRB1 association with severe malaria in the Gambia |
| CTL4 |
cytotoxic T-lymphocyte-associated protein 4 |
a protein receptor that, functioning as an immune checkpoint, downregulates immune responses. |
association between alleles of CTL4 gene with malaria displayed a significant association with reduced risk for clinical malaria |
| IFNAR1 |
Interferon a receptor component |
Cytokine receptor |
Association with severe malaria in the Gambia and as risk factors for malaria in India |
| IFNG |
Interferon g |
Cytokine with antiparasitic and proinflammatory properties |
Weak associations with severe malaria in the Gambia; strong association of haplotype containing short CA repeat with severe malaria in India |
| IFNGR1 |
Interferon g receptor component |
Cytokine receptor |
Association with severe malaria in Mandinka people of the Gambia |
| IL1A/IL1B |
Interleukin-1a and -1b |
Proinflammatory cytokines |
Marginal associations with severe malaria in the Gambia |
| IL10 |
Interleukin-10 |
Anti-inflammatory cytokine |
Haplotypic association with severe malaria in the Gambia |
| IL12B |
Interleukin-12 b subunit |
Promotes development of Th1 cells |
Association with severe malaria in Tanzania |
| IL4 |
Interleukin-4 |
Promotes antibody-producing B cells |
Association with antimalarial antibody levels in Fulani people of Burkina Faso; Children homozygous for IL4 VNTR allele 2 had a lower SM risk as well as lower IL-4 plasma levels. |
| MBL2 |
Mannose-binding protein |
Activates classic complement |
Association with severe malaria in Gabon |
| NOS2A |
Inducible NO synthase |
Generates NO, a free radical |
Various associations with severe malaria in Gabon, the Gambia, Tanzania, and India |
| TNF |
Tumor necrosis factor |
Cytokine with antiparasitic and proinflammatory properties |
Various associations with severe malaria and reinfection risk in the Gambia, Kenya, Gabon, Sri Lanka, and India |
| TNFSF5 |
CD40 ligand |
T cell–B cell interactions leading to immunoglobulin class switching |
Association with severe malaria in the Gambia |
| Updates related to the situation in India contributed by Saman Habib |
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