Table 1.

Novel alleles associated with strong protection from severe malaria.

Gene	Protective variant	Malaria phenotype in vivoa	Possible protective mechanisms	Other associated phenotypes	Geographic distribution of allele frequency	References
ATP2B4/PMC4a (calcium channel)	Haplotype with >50 variants, including one disrupting a GATA binding site	23-35% protection against severe malaria and placental malaria	Reduction of parasitemia in vivo; reduction of P. falciparum growth in vitro; RBC dehydration; additional pleiotropic effects	Decreased transcript and protein expression; decreased calcium export; increased MCHCb; increased HGBC; decreased RDWd; decreased reticulocytes	African: 35% European: 11% South Asian: 15% East Asian: 3% Admixed American: 11% (chr1:20368 4896-T-G)	[7,11–15,43,79,80]
PIEZO1 (mechanose nsitive ion channel)	E756del	50% protection against severe malaria in a Gabonese population	Variable reduction of P. falciparum growth in vitro. Some studies suggest RBC dehydration, but others find no association. Also associated with reduced var2csa expression	Macrophage-mediated iron overload; increased jumping performance	African: 17% European: <0.06% South Asian: <0.2% East Asian: <0.08% Admixed American: 1.5% (chr16:8873 3964-GTCC-G)	[6,15,17–19,27,28,79,79]
GYPA/GYPB hybrid (RBC membrane sialoglycoprotein)	Haplotype of a duplicated chimeric protein known as the Dantu antigen	33-40% protection against severe malaria	Significant reduction of P. falciparum invasion and growth in vitro; partially mediated by increased RBC membrane tension	Reduced MCVe and MCHf in hetero zygotes and especially homozygotes; substantial changes to expression of RBC membrane proteome	Absent from most of Africa and the rest of the world, but present at 2-13% frequency in parts of East Africa	[22–24,80]

^aBased on odds ratio for the broadest category of severe malaria in an additive or recessive association model with one copy of the allele.

^bmean corpuscular hemoglobin concentration (g/dL red blood cells)

^chemoglobin (g/dL whole blood)

^dred blood cell distribution width (% coefficient of variation)

^emean corpuscular volume of red blood cells (fL)

^fmean cell hemoglobin of red blood cells (pg)