RBCC Red Blood Cell Collection

GYPC (GLPC, GPC) [Confidence: high (a blood group or CD marker)]
Glycophorin-C (Glycoconnectin; Glycophorin-D; GPD; Glycoprotein beta; PAS-2'; Sialoglycoprotein D; CD236)

hRBCD IPI00026299
IPI00026299 Splice isoform Glycophorin C of P04921 Glycophorin C Splice isoform Glycophorin C of P04921 Glycophorin C membrane n/a n/a 1 2 2 n/a n/a n/a 5 n/a 1 1 n/a n/a n/a n/a n/a 3 1 n/a integral membrane protein also splice isoform Glycophorin D found at its expected molecular weight found at molecular weight

BGMUT gerbich
262 gerbich GYPC GYPC GYPC +2+3+4 reference reference Ge:2,3,4 (Ge+) ~100% 2416746 M36284 Colin et al. 2008-09-23 20:56:12.977 NA

Comments
Isoform P04921-2 was detected.

UniProt P04921
ID GLPC_HUMAN Reviewed; 128 AA.
AC P04921; B2R522; Q53SV9; Q92642;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 13-AUG-1987, sequence version 1.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=Glycophorin-C;
DE AltName: Full=Glycoconnectin;
DE AltName: Full=Glycophorin-D;
DE Short=GPD;
DE AltName: Full=Glycoprotein beta;
DE AltName: Full=PAS-2';
DE AltName: Full=Sialoglycoprotein D;
DE AltName: CD_antigen=CD236;
GN Name=GYPC; Synonyms=GLPC, GPC;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GLYCOPHORIN-C).
RX PubMed=2416746;
RA Colin Y., Rahuel C., London J., Romeo P.-H., D'Auriol L., Galibert F.,
RA Cartron J.-P.;
RT "Isolation of cDNA clones and complete amino acid sequence of human
RT erythrocyte glycophorin C.";
RL J. Biol. Chem. 261:229-233(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GLYCOPHORIN-C).
RX PubMed=3606576;
RA High S., Tanner M.J.A.;
RT "Human erythrocyte membrane sialoglycoprotein beta. The cDNA sequence
RT suggests the absence of a cleaved N-terminal signal sequence.";
RL Biochem. J. 243:277-280(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GLYCOPHORIN-C).
RX PubMed=3544149; DOI=10.1016/S0338-4535(86)80020-4;
RA Cartron J.-P., Colin Y., le van Kim C., Rahuel C., Blanchard D.,
RA Bloy C., London J.;
RT "Structure of human erythrocyte glycophorin C deduced from cDNA
RT analysis.";
RL Rev. Fr. Transfus. Immunohematol. 29:267-285(1986).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM GLYCOPHORIN-C).
RC TISSUE=Liver;
RX PubMed=3595602; DOI=10.1111/j.1432-1033.1987.tb11478.x;
RA le van Kim C., Colin Y., Blanchard D., Dahr W., London J.,
RA Cartron J.-P.;
RT "Gerbich blood group deficiency of the Ge:-1,-2,-3 and Ge:-1,-2,3
RT types. Immunochemical study and genomic analysis with cDNA probes.";
RL Eur. J. Biochem. 165:571-579(1987).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GLYCOPHORIN-C).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLU-124.
RG SeattleSNPs variation discovery resource;
RL Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM GLYCOPHORIN-C).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP PROTEIN SEQUENCE OF 49-88.
RX PubMed=3571235;
RA Blanchard D., Dahr W., Hummel M., Latron F., Beyreuther K.,
RA Cartron J.-P.;
RT "Glycophorins B and C from human erythrocyte membranes. Purification
RT and sequence analysis.";
RL J. Biol. Chem. 262:5808-5811(1987).
RN [10]
RP PROTEIN SEQUENCE OF 1-87.
RC TISSUE=Blood;
RA Dahr W., Humel M., Blanchard D., Beyreuther K., Cartron J.-P.;
RT "Isolation and structural analysis of glycophorin C.";
RL Biol. Chem. Hoppe-Seyler 366:777-778(1985).
RN [11]
RP PROTEIN SEQUENCE OF 1-48.
RC TISSUE=Blood;
RX PubMed=4074499;
RA Dahr W., Beyreuther K.;
RT "A revision of the N-terminal structure of sialoglycoprotein D
RT (glycophorin C) from human erythrocyte membranes.";
RL Biol. Chem. Hoppe-Seyler 366:1067-1070(1985).
RN [12]
RP PRELIMINARY PROTEIN SEQUENCE OF 1-48, AND GLYCOSYLATION AT SER-3;
RP THR-4; SER-6; ASN-8; SER-9; THR-10; SER-15; SER-24; SER-26; THR-27;
RP THR-28; THR-31; THR-32; THR-33 AND SER-42.
RC TISSUE=Blood;
RX PubMed=7106126; DOI=10.1111/j.1432-1033.1982.tb06650.x;
RA Dahr W., Beyreuther K., Kordowicz M., Krueger J.;
RT "N-terminal amino acid sequence of sialoglycoprotein D (glycophorin C)
RT from human erythrocyte membranes.";
RL Eur. J. Biochem. 125:57-62(1982).
RN [13]
RP PROTEIN SEQUENCE OF 30-91.
RX PubMed=2776757; DOI=10.1111/j.1432-1033.1989.tb21093.x;
RA El-Maliki B., Blanchard D., Dahr W., Beyreuther K., Cartron J.-P.;
RT "Structural homology between glycophorins C and D of human
RT erythrocytes.";
RL Eur. J. Biochem. 183:639-643(1989).
RN [14]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-22 AND 42-128.
RC TISSUE=Spleen;
RX PubMed=2349119; DOI=10.1093/nar/18.10.3076;
RA le van Kim C., Mitjavila M.T., Clerget M., Cartron J.-P., Colin Y.;
RT "An ubiquitous isoform of glycophorin C is produced by alternative
RT splicing.";
RL Nucleic Acids Res. 18:3076-3076(1990).
RN [15]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-16.
RX PubMed=2584223;
RA le van Kim C., Colin Y., Mitjavila M.T., Clerget M., Dubart A.,
RA Nakazawa M., Vainchenker W., Cartron J.-P.;
RT "Structure of the promoter region and tissue specificity of the human
RT glycophorin C gene.";
RL J. Biol. Chem. 264:20407-20414(1989).
RN [16]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 17-128.
RX PubMed=2818576;
RA High S., Tanner M.J.A., Macdonald E.N., Anstee D.J.;
RT "Rearrangements of the red-cell membrane glycophorin C
RT (sialoglycoprotein beta) gene. A further study of alterations in the
RT glycophorin C gene.";
RL Biochem. J. 262:47-54(1989).
RN [17]
RP GENE STRUCTURE.
RX PubMed=2917976;
RA Colin Y., le van Kim C., Tsapis A., Clerget M., D'Auriol L.,
RA London J., Galibert F., Cartron J.-P.;
RT "Human erythrocyte glycophorin C. Gene structure and rearrangement in
RT genetic variants.";
RL J. Biol. Chem. 264:3773-3780(1989).
RN [18]
RP POLYMORPHISM, AND INVOLVEMENT IN PROTECTION AGAINST MALARIA.
RX PubMed=12469115; DOI=10.1038/nm807;
RA Maier A.G., Duraisingh M.T., Reeder J.C., Patel S.S., Kazura J.W.,
RA Zimmerman P.A., Cowman A.F.;
RT "Plasmodium falciparum erythrocyte invasion through glycophorin C and
RT selection for Gerbich negativity in human populations.";
RL Nat. Med. 9:87-92(2003).
RN [19]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-104, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [20]
RP GLYCOSYLATION AT SER-42, STRUCTURE OF CARBOHYDRATES, AND MASS
RP SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.M111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of
RT N-and O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [21]
RP VARIANT BLOOD GROUP ANTIGEN WB.
RX PubMed=1991173;
RA Chang S., Reid M.E., Conboy J., Kan Y.W., Mohandas N.;
RT "Molecular characterization of erythrocyte glycophorin C variants.";
RL Blood 77:644-648(1991).
RN [22]
RP VARIANT BLOOD GROUP ANTIGEN DH(A).
RX PubMed=1413665; DOI=10.1111/j.1423-0410.1992.tb01220.x;
RA King M.J., Avent N.D., Mallinson G., Reid M.E.;
RT "Point mutation in the glycophorin C gene results in the expression of
RT the blood group antigen Dha.";
RL Vox Sang. 63:56-58(1992).
RN [23]
RP VARIANT BLOOD GROUP ANTIGEN AN(A).
RX PubMed=8219208;
RA Daniels G., King M.J., Avent N.D., Khalid G., Reid M.E., Mallinson G.,
RA Symthe J., Cedergren B.;
RT "A point mutation in the GYPC gene results in the expression of the
RT blood group Ana antigen on glycophorin D but not on glycophorin C:
RT further evidence that glycophorin D is a product of the GYPC gene.";
RL Blood 82:3198-3203(1993).
CC -!- FUNCTION: This protein is a minor sialoglycoprotein in human
CC erythrocyte membranes. The blood group Gerbich antigens and
CC receptors for Plasmodium falciparum merozoites are most likely
CC located within the extracellular domain. Glycophorin-C plays an
CC important role in regulating the stability of red cells.
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type III membrane
CC protein. Note=Linked to the membrane via band 4.1.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Glycophorin-C;
CC IsoId=P04921-1; Sequence=Displayed;
CC Name=Glycophorin-D;
CC IsoId=P04921-2; Sequence=VSP_001777;
CC -!- TISSUE SPECIFICITY: Glycophorin-C is expressed in erythrocytes.
CC Glycophorin-D is ubiquitous.
CC -!- PTM: O-glycosylated with core 1 or possibly core 8 glycans.
CC -!- POLYMORPHISM: GYPC is responsible for the Gerbich blood group
CC system. Deletion of exon 3 in GYPC changes the serologic phenotype
CC of the Gerbich blood group system, resulting in Ge negativity. Ge
CC negative individuals are protected against severe malaria due to
CC erythrocytes resistance to Plasmodium falciparum invasion
CC [MIM:611162].
CC -!- SIMILARITY: Belongs to the glycophorin-C family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA32093.1; Type=Frameshift; Positions=35;
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene
CC mutation database;
CC URL="http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system;=gerbich";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Glycophorin C entry;
CC URL="http://en.wikipedia.org/wiki/Glycophorin_C";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/gypc/";
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DR EMBL; M11802; AAA60023.1; -; mRNA.
DR EMBL; M36284; AAA52625.1; -; mRNA.
DR EMBL; X12496; CAA31016.1; -; mRNA.
DR EMBL; X51973; CAA36235.1; -; mRNA.
DR EMBL; M28335; AAA52574.1; -; mRNA.
DR EMBL; AK312032; BAG34969.1; -; mRNA.
DR EMBL; AY838876; AAV80423.1; -; Genomic_DNA.
DR EMBL; AC013474; AAY14660.1; -; Genomic_DNA.
DR EMBL; BC106051; AAI06052.1; -; mRNA.
DR EMBL; BC104246; AAI04247.1; -; mRNA.
DR EMBL; BC104247; AAI04248.1; -; mRNA.
DR EMBL; X14242; CAA32458.1; -; Genomic_DNA.
DR EMBL; M29662; AAA52626.1; -; Genomic_DNA.
DR EMBL; X13890; CAA32093.1; ALT_FRAME; Genomic_DNA.
DR EMBL; X13892; CAA32093.1; JOINED; Genomic_DNA.
DR EMBL; X13893; CAA32093.1; JOINED; Genomic_DNA.
DR PIR; A92573; GFHUC.
DR RefSeq; NP_001243513.1; NM_001256584.1.
DR RefSeq; NP_002092.1; NM_002101.4.
DR RefSeq; NP_058131.1; NM_016815.3.
DR UniGene; Hs.59138; -.
DR PDB; 2EJY; NMR; -; B=117-128.
DR PDBsum; 2EJY; -.
DR ProteinModelPortal; P04921; -.
DR IntAct; P04921; 1.
DR MINT; MINT-1527497; -.
DR STRING; 9606.ENSP00000259254; -.
DR PhosphoSite; P04921; -.
DR DMDM; 121407; -.
DR PaxDb; P04921; -.
DR PRIDE; P04921; -.
DR Ensembl; ENST00000259254; ENSP00000259254; ENSG00000136732.
DR Ensembl; ENST00000356887; ENSP00000349354; ENSG00000136732.
DR Ensembl; ENST00000409836; ENSP00000386904; ENSG00000136732.
DR GeneID; 2995; -.
DR KEGG; hsa:2995; -.
DR UCSC; uc002tnq.4; human.
DR CTD; 2995; -.
DR GeneCards; GC02P127413; -.
DR HGNC; HGNC:4704; GYPC.
DR HPA; CAB009445; -.
DR HPA; HPA008965; -.
DR MIM; 110750; gene+phenotype.
DR MIM; 611162; phenotype.
DR neXtProt; NX_P04921; -.
DR PharmGKB; PA29082; -.
DR eggNOG; NOG146330; -.
DR HOGENOM; HOG000112742; -.
DR HOVERGEN; HBG094619; -.
DR InParanoid; P04921; -.
DR KO; K06576; -.
DR OMA; ASTTMHT; -.
DR OrthoDB; EOG7VDXSF; -.
DR PhylomeDB; P04921; -.
DR EvolutionaryTrace; P04921; -.
DR GenomeRNAi; 2995; -.
DR NextBio; 11870; -.
DR PRO; PR:P04921; -.
DR ArrayExpress; P04921; -.
DR Bgee; P04921; -.
DR CleanEx; HS_GYPC; -.
DR Genevestigator; P04921; -.
DR GO; GO:0030863; C:cortical cytoskeleton; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR InterPro; IPR003585; Neurexin-like.
DR SMART; SM00294; 4.1m; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Blood group antigen;
KW Cell membrane; Complete proteome; Direct protein sequencing;
KW Glycoprotein; Membrane; Phosphoprotein; Polymorphism;
KW Reference proteome; Sialic acid; Transmembrane; Transmembrane helix.
FT CHAIN 1 128 Glycophorin-C.
FT /FTId=PRO_0000149050.
FT TOPO_DOM 1 57 Extracellular.
FT TRANSMEM 58 81 Helical; Signal-anchor for type III
FT membrane protein.
FT TOPO_DOM 82 128 Cytoplasmic.
FT SITE 8 8 Not glycosylated; in variant Webb
FT antigen.
FT MOD_RES 104 104 Phosphoserine.
FT CARBOHYD 3 3 O-linked (GalNAc...).
FT CARBOHYD 4 4 O-linked (GalNAc...).
FT CARBOHYD 6 6 O-linked (GalNAc...).
FT CARBOHYD 8 8 N-linked (GlcNAc...).
FT CARBOHYD 9 9 O-linked (GalNAc...).
FT CARBOHYD 10 10 O-linked (GalNAc...).
FT CARBOHYD 15 15 O-linked (GalNAc...).
FT CARBOHYD 24 24 O-linked (GalNAc...).
FT CARBOHYD 26 26 O-linked (GalNAc...).
FT CARBOHYD 27 27 O-linked (GalNAc...).
FT CARBOHYD 28 28 O-linked (GalNAc...).
FT CARBOHYD 31 31 O-linked (GalNAc...).
FT CARBOHYD 32 32 O-linked (GalNAc...).
FT CARBOHYD 33 33 O-linked (GalNAc...).
FT CARBOHYD 42 42 O-linked (GalNAc...).
FT VAR_SEQ 1 21 Missing (in isoform Glycophorin-D).
FT /FTId=VSP_001777.
FT VARIANT 8 8 N -> S (in Webb (WB) antigen).
FT /FTId=VAR_003193.
FT VARIANT 14 14 L -> F (in Duch (DH(a)) antigen).
FT /FTId=VAR_003194.
FT VARIANT 23 23 A -> S (in Ahonen (AN(a)) antigen).
FT /FTId=VAR_003195.
FT VARIANT 124 124 K -> E (in dbSNP:rs28370000).
FT /FTId=VAR_021342.
SQ SEQUENCE 128 AA; 13811 MW; C9C654009A5642D5 CRC64;
MWSTRSPNST AWPLSLEPDP GMASASTTMH TTTIAEPDPG MSGWPDGRME TSTPTIMDIV
VIAGVIAAVA IVLVSLLFVM LRYMYRHKGT YHTNEAKGTE FAESADAALQ GDPALQDAGD
SSRKEYFI
//

MIM 110750
*RECORD*
*FIELD* NO
110750
*FIELD* TI
+110750 BLOOD GROUP--GERBICH; Ge
GLYCOPHORIN C, INCLUDED; GYPC, INCLUDED; GPC, INCLUDED;;
read moreGLYCOPHORIN D, INCLUDED; GYPD, INCLUDED; GPD, INCLUDED;;
DUCH BLOOD GROUP, INCLUDED;;
DH BLOOD GROUP, INCLUDED
*FIELD* TX
Antibody demonstrating this antigen was found in cases of fetomaternal
incompatibility (Barnes and Lewis, 1961). Independence from ABO, MNS, P,
Rh, Kell, Duffy, and Kidd systems has been demonstrated (Race and
Sanger, 1975). Anstee et al. (1984) studied the red cells of 2 unrelated
persons who lacked Ge blood group substance and 3 minor
sialoglycoproteins that are associated with the cytoskeleton of normal
red cells. About 10% of red cells in each subject were 'frankly
elliptocytic.' In Melanesia there are more Gerbich-negative persons than
in any other part of the world (Booth and McLoughlin, 1972). Since
Gerbich-negative red cells lack beta- and gamma-sialoglycoproteins, it
is reasonable to presume that Gerbich antigens are located on these
proteins, also called glycophorin C. Glycophorin C is a minor red cell
membrane component, representing about 4% of the membrane
sialoglycoproteins. It is a putative receptor for the merozoites of
Plasmodium falciparum (Pasvol et al., 1984). The occurrence of
elliptocytosis and Gerbich-negative red cells in Melanesia may be
related to the function of glycophorin C in relation to Plasmodium
falciparum. However, the primary defect in the Malaysian-Melanesian type
of elliptocytosis resides in the band 3 protein of the red cell membrane
(109270.0002). Glycophorin C has a role in the maintenance of red cell
shape (Bennett, 1985).

Colin et al. (1986) isolated cDNA clones for red cell glycophorin C and
deduced its complete amino acid sequence. It is a single polypeptide
chain of 128 amino acids showing very little homology with the major red
cell membrane glycophorins A and B, which carry the blood group MN
(111300) and Ss (111740) antigens, respectively, and are closely related
proteins. Mattei et al. (1986) used a cDNA clone for GYPC in studies by
in situ hybridization to assign the GYPC locus to 2q14-q21. Some rare
individuals with the Gerbich-negative phenotype lack certain minor
erythrocyte sialoglycoproteins. Anderson et al. (1986) reported such an
individual whose erythrocytes lacked beta- and gamma-sialoglycoproteins
in SDS-PAGE but had 2 additional abnormal sialoglycoproteins. Analysis
using SDS-PAGE of erythrocyte membranes from his 2 children failed to
reveal any similar abnormal sialoglycoproteins. This led to the
suggestion by Anderson et al. (1986) that in this instance the
Gerbich-negative phenotype may have resulted from other mechanisms,
possibly defective glycosylation, rather than from a crossover involving
the gene coding for the primary protein structure of the
sialoglycoproteins. Glycophorin C carries Gerbich determinants; Ge
antigens are also present on glycophorin D. Using a cDNA prepared from
the mRNA of glycophorin C, Le Van Kim et al. (1987) found that the
Ge-negative condition in donors with nonelliptocytic red cells is
associated with a 3-kb deletion in the glycophorin C gene. Their
findings also suggested that the same gene codes for glycophorin D. Reid
et al. (1987) obtained unequivocal evidence of the autosomal codominant
nature of the Ge alleles by means of protein immunoblotting using
monoclonal antibodies against what they termed the beta and gamma
sialoglycoproteins (SGPs). El-Maliki et al. (1989) concluded from the
sequence data that glycophorin D is an abridged version of glycophorin
C. Glycophorin C is a single polypeptide chain of 128 amino acid
residues. GYPD is smaller than GYPC (24 kD vs 32 kD). Amino acid
sequence showed identity of GYPD with residues of 30 to 126 of GYPC. The
mechanism generating GYPC and GYPD from the same gene may involve
translation of the same mRNA to in-phase AUGs by leaky translation
(Cartron et al., 1990). Available sequencing information on GYPD was
consistent with this model. From studies of the molecular basis of the
rare blood group An(a) antigen, Daniels et al. (1993) obtained further
evidence that glycophorin D is a product of the GYPC gene.

Winardi et al. (1993) characterized the deficiency of glycophorins C and
D in erythrocytes of the Leach phenotype. They found that the deficiency
was the consequence of deletion or marked alteration of exons 3 and 4 of
the GYPC gene. The mutant gene encoded an mRNA stable enough to be
detected in circulating reticulocytes. The protein encoded by this mRNA
would not be expected to be expressed in the cell membrane because it
would lack the transmembrane and cytoplasmic domains.

Data on gene frequencies of allelic variants were tabulated by
Roychoudhury and Nei (1988).

*FIELD* AV
.0001
GLYCOPHORIN C, YUS VARIANT
GYPC, EX2DEL

Immunochemical and serologic studies identified a number of glycophorin
C variants that include the Yus, Gerbich, and Webb phenotypes. In the
Yus phenotype, Chang et al. (1991) demonstrated a 57-bp deletion that
corresponds to exon 2 of the glycophorin C gene.

.0002
GLYCOPHORIN C, GERBICH VARIANT
MALARIA, RESISTANCE TO
GYPC, EX3DEL

In the Gerbich phenotype, Chang et al. (1991) identified deletion of the
84-bp exon 3 of the glycophorin C gene.

Deletion of exon 3 in the GYPC gene has been found in Melanesians; this
alteration changes the serologic phenotype of the Gerbich (Ge) blood
group system, resulting in Ge negativity (Booth and McLoughlin, 1972;
Serjeantson et al., 1994). The GYPC ex3del allele reaches a high
frequency (46.5%) in coastal areas of Papua New Guinea where malaria
(611162) is hyperendemic (Patel et al., 2001). The Plasmodium falciparum
erythrocyte-binding antigen 140 (EBA140, also known as BAEBL) binds with
high affinity to the surface of human erythrocytes. Maier et al. (2003)
showed that the receptor for EBA140 is glycophorin C and that this
interaction mediates a principal P. falciparum invasion pathway into
human erythrocytes. EBA140 does not bind to GYPC in Ge-negative
erythrocytes, nor can P. falciparum invade such cells using this
invasion pathway. This provides compelling evidence that Ge negativity
has arisen in Melanesian populations through natural selection by severe
malaria.

.0003
GLYCOPHORIN D, WEBB VARIANT
BLOOD GROUP--WEBB ANTIGEN WB
GYPD, ASN8SER

The Webb antigen was first described by Simmons and Albrey (1963) in
Australia. It is a very rare antigen. Bloomfield et al. (1986) found 8
examples of Wb-positive antigen, 2 in the same family, among 10,117
random blood donors in South Wales. Family studies confirmed autosomal
dominant inheritance. The Webb antigen segregated independently of ABO,
Rh, MNSs, Jk, and Lu; furthermore, it was not X-linked or Y-linked.
Whereas the cDNA generated from mRNA in the Yus and Gerbich phenotypes
is shorter than normal, that from the Webb phenotype is of normal size.
Chang et al. (1991) demonstrated an A-to-G transition at nucleotide 23
of the coding sequence, resulting in substitution of asparagine by
serine. This modification accounted for the altered glycosylation of
glycophorin seen with the Webb phenotype. Telen et al. (1991) likewise
found a point mutation resulting in substitution of serine for
asparagine at amino acid position 8.

.0004
GLYCOPHORIN D, DUCH VARIANT
BLOOD GROUP DH
GYPD, LEU14PHE

Duch, Dh(a), an exceedingly rare red cell antigen, is recognized by an
antibody found in Aarhus, Denmark, in 1968 (Jorgensen et al., 1982). The
antigen was found in 5 persons in 3 generations and segregated
independently of Rh, MNSs and Kidd.

Spring (1991) detected the Duch antigen on a variant of glycophorin C
that had the same apparent molecular mass as normal GPC. The location of
Dh(a) on GPC was tentatively assigned to the sequence between residues 1
and 47. Since the Dh(a) antigen was not detected on GPD but was present
on GPC, it was presumed to reside within residues 1-21 at the N-terminal
domain of GPC. By sequencing PCR-amplified DNA, King et al. (1992)
demonstrated a C-to-T transition at nucleotide 40 responsible for a
substitution of leucine by phenylalanine at amino acid residue 14.

*FIELD* SA
Reid (1972); Sondag et al. (1987)
*FIELD* RF
1. Anderson, S. E.; McKenzie, J. L.; McLoughlin, K.; Beard, M. E.
J.; Hart, D. N. J.: The inheritance of abnormal sialoglycoproteins
found in a Gerbich negative individual. Pathology 18: 407-412, 1986.

2. Anstee, D. J.; Parsons, S. F.; Ridgwell, K.; Tanner, M. J. A.;
Merry, A. H.; Thomson, E. E.; Judson, P. A.; Johnson, P.; Bates, S.;
Fraser, I. D.: Two individuals with elliptocytic red cells apparently
lack three minor erythrocyte membrane sialoglycoproteins. Biochem.
J. 218: 615-619, 1984.

3. Barnes, R.; Lewis, T. L. T.: A rare antibody (anti-Ge) causing
hemolytic disease of the newborn. Lancet 278: 1285-1286, 1961. Note:
Originally Volume II.

4. Bennett, V.: The membrane skeleton of human erythrocytes and its
implications for more complex cells. Annu. Rev. Biochem. 54: 273-304,
1985.

5. Bloomfield, L.; Rowe, G. P.; Green, C.: The Webb (Wb) antigen
in South Wales donors. Hum. Hered. 36: 352-356, 1986.

6. Booth, P. B.; McLoughlin, K.: The Gerbich blood group system,
especially in Melanesians. Vox Sang. 22: 73-84, 1972.

7. Cartron, J.-P.; Colin, Y.; Kudo, S.; Fukuda, M.: Molecular genetics
of human erythrocyte sialoglycoproteins A, B, C, and D.In: Harris,
J. R.: Erythroid Cells. Blood Cell Biochemistry. New York: Plenum
Press (pub.) 1: 1990. Pp. 299-335.

8. Chang, S.; Reid, M. E.; Conboy, J.; Kan, Y. W.; Mohandas, N.:
Molecular characterization of erythrocyte glycophorin C variants. Blood 77:
644-648, 1991.

9. Colin, Y.; Rahuel, C.; London, J.; Romeo, P. H.; d'Auriol, L.;
Galibert, F.; Cartron, J.-P.: Isolation of cDNA clones and complete
amino acid sequence of human erythrocyte glycophorin C. J. Biol.
Chem. 261: 229-233, 1986.

10. Daniels, G.; King, M.-J.; Avent, N. D.; Khalid, G.; Reid, M.;
Mallinson, G.; Symthe, J.; Cedergren, B.: A point mutation in the
GYPC gene results in the expression of the blood group An(a) antigen
on glycophorin D but not on glycophorin C: further evidence that glycophorin
D is a product of the GYPC gene. Blood 82: 3198-3203, 1993.

11. El-Maliki, B.; Blanchard, D.; Dahr, W.; Beyreuther, K.; Cartron,
J.-P.: Structural homology between glycophorins C and D of human
erythrocytes. Europ. J. Biochem. 183: 639-643, 1989.

12. Jorgensen, J.; Drachmann, O.; Gavin, J.: Duch, Dh(a), a low frequency
red cell antigen. Hum. Hered. 32: 73-75, 1982.

13. King, M. J.; Avent, N. D.; Mallinson, G.; Reid, M. E.: Point
mutation in the glycophorin C gene results in the expression of the
blood group antigen Dh(a). Vox Sang. 63: 56-58, 1992.

14. Le Van Kim, C.; Colin, Y.; Blanchard, D.; Dahr, W.; London, J.;
Cartron, J.-P.: Gerbich blood group deficiency of the Ge:-1,-2,-3
and Ge:-1,-2,3 types: immunochemical study and genomic analysis with
cDNA probes. Europ. J. Biochem. 165: 571-579, 1987.

15. Maier, A. G.; Duraisingh, M. T.; Reeder, J. C.; Patel, S. S.;
Kazura, J. W.; Zimmerman, P. A.; Cowman, A. F.: Plasmodium falciparum
erythrocyte invasion through glycophorin C and selection for Gerbich
negativity in human populations. Nature Med. 9: 87-92, 2003.

16. Mattei, M. G.; Colin, Y.; Le Van Kim, C.; Mattei, J. F.; Cartron,
J. P.: Localization of the gene for human erythrocyte glycophorin
C to chromosome 2, q14-q21. Hum. Genet. 74: 420-422, 1986.

17. Pasvol, G.; Anstee, D. J.; Tanner, M. J. A.: Glycophorin C and
the invasion of red cells by Plasmodium falciparum. Lancet 329:
907-908, 1984. Note: Originally Volume I.

18. Patel, S. S.; Mehlotra, R. K.; Kastens, W.; Mgone, C. S.; Kazura,
J. W.; Zimmerman, P. A.: The association of the glycophorin C exon
3 deletion with ovalocytosis and malaria susceptibility in the Wosera,
Papua New Guinea. Blood 98: 3489-3491, 2001.

19. Race, R. R.; Sanger, R.: Blood Groups in Man. Oxford: Blackwell
Sci. Publ. (pub.) (6th ed.): 1975. Pp. 416-421.

20. Reid, M. E.: The Gerbich blood group antigens: a review. Med.
Lab. Sci. 43: 177-182, 1972.

21. Reid, M. E.; Sullivan, C.; Taylor, M.; Anstee, D. J.: Inheritance
of human-erythrocyte Gerbich blood group antigens. Am. J. Hum. Genet. 41:
1117-1123, 1987.

22. Roychoudhury, A. K.; Nei, M.: Human Polymorphic Genes: World
Distribution. New York: Oxford Univ. Press (pub.) 1988.

23. Serjeantson, S. W.; White, B. S.; Bhatia, K.; Trent, R. J.: A
3.5 kb deletion in the glycophorin C gene accounts for the Gerbich-negative
blood group in Melanesians. Immun. Cell Biol. 72: 23-27, 1994.

24. Simmons, R. T.; Albrey, J. A.: A 'new' blood group antigen Webb
(Wb) of low frequency found in two Australian families. Med. J. Aust. I:
8-10, 1963.

25. Sondag, D.; Alloisio, N.; Blanchard, D.; Ducluzeau, M.-T.; Colonna,
P.; Bachir, D.; Bloy, C.; Cartron, J.-P.; Delaunay, J.: Gerbich reactivity
in 4.1(-) hereditary elliptocytosis and protein 4.1 level in blood
group Gerbich deficiency. Brit. J. Haemat. 65: 43-50, 1987.

26. Spring, F. A.: Immunochemical characterisation of the low-incidence
antigen, Dh(a). Vox Sang. 61: 65-68, 1991.

27. Telen, M. J.; Le Van Kim, C.; Guizzo, M. L.; Cartron, J.-P.; Colin,
Y.: Erythrocyte Webb-type glycophorin C variant lacks N-glycosylation
due to an asparagine to serine substitution. Am. J. Hemat. 37: 51-52,
1991.

28. Winardi, R.; Reid, M.; Conboy, J.; Mohandas, N.: Molecular analysis
of glycophorin C deficiency in human erythrocytes. Blood 81: 2799-2803,
1993.

*FIELD* CN
Victor A. McKusick - updated: 12/10/2002

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
terry: 01/08/2009
mgross: 7/5/2007
joanna: 11/5/2004
alopez: 11/5/2003
terry: 5/16/2003
alopez: 1/9/2003
alopez: 12/11/2002
alopez: 12/10/2002
terry: 12/10/2002
terry: 7/24/1998
davew: 8/18/1994
mimadm: 4/19/1994
pfoster: 3/31/1994
carol: 3/19/1994
carol: 10/21/1993
carol: 10/20/1993

MIM 611162
*RECORD*
*FIELD* NO
611162
*FIELD* TI
#611162 MALARIA, SUSCEPTIBILITY TO
MALARIA, RESISTANCE TO, INCLUDED;;
MALARIA, SEVERE, SUSCEPTIBILITY TO, INCLUDED;;
read moreMALARIA, SEVERE, RESISTANCE TO, INCLUDED;;
MALARIA, CEREBRAL, SUSCEPTIBILITY TO, INCLUDED;;
MALARIA, CEREBRAL, RESISTANCE TO, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because variation in several
different genes influences susceptibility and resistance to malaria, as
well as disease progression and severity. These genes include HBB
(141900), ICAM1 (147840), CD36 (173510), CR1 (120620), GYPA (111300),
GYPB (111740), GYPC (110750), TNF (191160), NOS2A (163730), TIRAP
(606252), FCGR2B (604590), and CISH (602441). In addition, a locus
associated with Plasmodium falciparum blood infection level has been
mapped to chromosome 5q31-q33 (PFBI; 248310), a locus for susceptibility
to mild malaria has been mapped to chromosome 6p21.3 (MALS; 609148), a
locus associated with malaria fever episodes has been mapped to
chromosome 10p15 (PFFE1; 611384), and a locus for susceptibility to
placental malarial infection has been mapped to chromosome 6 (FUT9;
606865). Complete protection from Plasmodium vivax infection is
associated with the Duffy blood group-negative phenotype (see 110700).
Alpha(+)-thalassemia (141800), the X-linked disorder G6PD deficiency
(300908), and Southeast Asian ovalocytosis (109270) are associated with
resistance to malaria.

DESCRIPTION

Malaria, a major cause of child mortality worldwide, is caused by
mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the
4 species that infect humans, P. falciparum causes the most severe forms
of malaria and is the major cause of death and disease. Although less
fatal, P. malariae, P. ovale, and, in particular, P. vivax infections
are major causes of morbidity. The parasite cycle involves a first stage
in liver cells and a subsequent stage at erythrocytes, when malaria
symptoms occur. A wide spectrum of phenotypes are observed, from
asymptomatic infection to mild disease, including fever and mild anemia,
to severe disease, including cerebral malaria, profound anemia, and
respiratory distress. Genetic factors influence the response to
infection, as well as disease progression and severity. Malaria is the
strongest known selective pressure in the recent history of the human
genome, and it is the evolutionary driving force behind sickle-cell
disease (603903), thalassemia (see 141800), glucose-6-phosphatase
deficiency (300908), and other erythrocyte defects that together
constitute the most common mendelian diseases of humans (Kwiatkowski,
2005; Campino et al., 2006).

PATHOGENESIS

Compared with other microorganisms, P. falciparum malaria parasites
reach very high densities in blood. P. falciparum-infected erythrocytes
(PfIRBCs) induce ICAM1 (147840) expression on human brain microvascular
endothelial cells (HBMECs), but not on human umbilical vein endothelial
cells. PfIRBCs compromise the electrical function of brain endothelium
independently of PfIRBC binding phenotype, suggesting a role for soluble
parasite factors. By performing genomewide transcriptional profiling of
HBMECs after exposure to isogenic PfIRBCs, followed by ELISA for protein
identification, Tripathi et al. (2009) identified upregulated molecules
involved in immune response, apoptosis and antiapoptosis, inflammatory
response, cell-cell signaling, and signal transduction and activation of
the NF-kappa-B (see 164011) cascade. Proinflammatory molecules,
including CCL20 (601960), CXCL1 (155730), CXCL2 (139110), IL6 (147620),
and IL8 (146930), were upregulated more than 100-fold. Tripathi et al.
(2009) concluded that PfIRBC exposure to HBMECs results in a
predominantly proinflammatory response mediated by NF-kappa-B
activation.

By incubating erythrocytes with increasing amounts of anti-CR1
antibodies or soluble CR1 (120620), followed by immunoprecipitation
analysis, Tham et al. (2010) showed that the P. falciparum merozoite
ligand PfRh4 bound to CR1. Levels of PfRh4 binding correlated with CR1
expression on the erythrocyte surface, which is controlled by the CR1
exon 22 SNP (120620.0001). Binding was reduced in individuals homozygous
for low CR1 expression. Parasite invasion of neuraminidase-treated
erythrocytes was also reduced. Tham et al. (2010) concluded that CR1 is
an erythrocyte receptor used by P. falciparum PfRh4 for sialic
acid-independent invasion.

By systematic screening of a library of erythrocyte proteins, Crosnier
et al. (2011) identified basigin (BSG; 109480) as a receptor for PfRh5,
a P. falciparum ligand essential for blood stage growth of the parasite.
Soluble basigin or basigin knockdown inhibited erythrocyte invasion by
all P. falciparum strains, and complete blocking was achieved by
anti-basigin antibodies. OK(a-) red blood cells, which express the
glu92-to-lys (E92K; 109480.0001) variant of basigin, had reduced binding
to PfRh5 due to slower association and faster dissociation rates.
Another basigin variant, leu90 to pro (L90P), did not interact with
PfRh5 at all. Crosnier et al. (2011) concluded that the dependence on a
single receptor-ligand pair across many P. falciparum strains may
provide novel possibilities for therapeutic intervention.

By screening an array of full-length plasma membrane proteins expressed
on human embryonic kidney cells, Turner et al. (2013) identified the
endothelial protein C receptor (EPCR; 600646) as a binding partner of
domain cassette-8 of the Plasmodium falciparum erythrocyte membrane
protein-1 (DC8-PfEMP1). They mapped the PfEMP1 EPCR-binding domain by
ELISA with DC8-PfEMP1C8 variants. Further analysis confirmed that PfEmp1
proteins have diverged into CD36 (173510)- and EPCR-binding subtypes.
DC8-PfEMP1-expressing and parasitized erythrocytes bound to brain
endothelial cells and were inhibited by recombinant EPCR or anti-EPCR
antibodies. Turner et al. (2013) proposed that PfEMP1-EPCR-mediated
cytoadhesion is the major virulence phenotype for severe malaria.

Cserti-Gazdewich et al. (2012) conducted a prospective analysis of ABO
blood groups (see 110300) and cytoadhesion receptors CD36 and ICAM1 in
approximately 2,000 Ugandan children with either uncomplicated or severe
malaria, including cerebral malaria (CM), severe anemia (SA), and lactic
acidosis (LA). Survival was enhanced in individuals with blood group O
and increased monocyte expression of CD36 and ICAM1. Blood group O was
nearly 50% in 180,000 adult blood donors and in children with
uncomplicated malaria, whereas it was approximately 40% in children with
severe malaria. High case fatality rates in cerebral malaria and lactic
acidosis were associated with high platelet CD36 expression and
thrombocytopenia, whereas severe anemia was characterized by low ICAM1
expression. Logistic regression analysis showed that the odds ratios for
the mitigating effects of blood group O, CD36, and ICAM1 phenotypes were
greater than that of sickle cell hemoglobin. Cserti-Gazdewich et al.
(2012) concluded that selection pressure by P. falciparum continues to
shape the human genome.

MAPPING

Rihet et al. (1998) provided evidence for linkage of the level of blood
infection with Plasmodium falciparum and chromosome region 5q31-q33 (see
248310).

Flori et al. (2003) demonstrated linkage of mild malaria to the MHC
region in an urban population living in an endemic area in Burkina Faso
(see 609148).

Timmann et al. (2007) reported significant association between malaria
fever episodes and a locus on chromosome 10p15 (PFFE1; 611384) in a
rural Ghanaian population.

Fortin et al. (2002) reviewed the mapping of gene effects in malaria,
both in humans and in mice, using population studies and experimental
models of malaria susceptibility.

- Associations Pending Confirmation

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) identified novel
resistance loci for severe malaria within the ATP2B4 gene (108732) on
chromosome 1q32.1 and near the MARVELD3 gene (614094) on chromosome
16q22.2. Several SNPs within the ATP2B4 gene showed significant
association, with dbSNP rs10900585 within intron 2 showing strongest
association (odds ratio = 0.65; P = 6.1 x 10(-9)). ATP2B4 encodes the
major Ca(2+) pump in erythrocytes, the host cells of the pathogenic
stage of malaria, and Timmann et al. (2012) hypothesized that variants
in ATP2B4 may disturb homeostasis of intraerythrocytic Ca(2+)
concentrations and impact parasite reproduction and maturation. The
associated SNP on chromosome 16q22.2, dbSNP 2334880 (odds ratio = 1.24;
P = 3.9 x 10(-8)), is located 6.4 kb upstream of the MARVELD3 gene. The
MARVELD3 product is part of tight junction structures of epithelial and
vascular endothelial cells, and Timmann et al. (2012) noted that
endothelial adherence is important in the pathology of severe malaria.

MOLECULAR GENETICS

- Variation in HBB and Resistance to Malaria

In a review, Kwiatkowski (2005) noted that 3 coding SNPs in the HBB gene
confer resistance to malaria and have risen to high frequency in
different populations: HbS (141900.0243), HbC (141900.0038), and HbE
(141900.0071). The HbS allele is maintained at a frequency of 10% in
malaria-endemic regions, including sub-Saharan Africa and parts of the
Middle East. HbS homozygotes have sickle-cell disease (603903), a
debilitating and often fatal disorder. The heterozygous state, denoted
HbAS, is not associated with any clinical abnormality and confers a
10-fold increase in protection from life-threatening malaria and lesser
protection against mild malaria. The HbC allele is found in several
parts of West Africa, but is less common than HbS. Homozygotes have
relatively mild hemolytic anemia, and both homozygotes and heterozygotes
are protected against severe malaria, though homozygotes show
substantially greater protection. HbE is common in Southeast Asia.
Homozygotes generally have symptomless anemia, and erythrocytes from HbE
heterozygotes are resistant to invasion by P. falciparum.

Rihet et al. (2004) surveyed 256 individuals (71 parents and 185 sibs)
from 53 families in Burkina Faso over 2 years and found that hemoglobin
C carriers were found to have less frequent malaria attacks than AA
individuals within the same age group (P = 0.01). Analysis of individual
hemoglobin alleles yielded a negative association between Hb C and
malaria attack (P = 0.00013). Analyses that took into account
confounding factors confirmed the negative association of Hb C with
malaria attack (P = 0.0074) and evidenced a negative correlation between
Hb C and parasitemia (P = 0.0009).

Fairhurst et al. (2005) reported a marked effect of hemoglobin C on the
cell-surface properties of P. falciparum-infected erythrocytes involved
in pathogenesis. Relative to parasite-infected normal erythrocytes (Hb
AA), parasitized AC and CC erythrocytes showed reduced adhesion to
endothelial monolayers expressing CD36 (173510) and intercellular
adhesion molecule-1 (ICAM1; 147840). They also showed impaired rosetting
interactions with nonparasitized erythrocytes, and reduced agglutination
in the presence of pooled sera from malaria-immune adults. Abnormal
cell-surface display of the main variable cytoadherence ligand, PfEMP-1
(P. falciparum erythrocyte membrane protein-1), correlated with these
findings. The abnormalities in PfEMP-1 display were associated with
markers of erythrocyte senescence, and were greater in CC than in AC
erythrocytes. Fairhurst et al. (2005) suggested that hemoglobin C might
protect against malaria by reducing PfEMP1-mediated adherence of
parasitized erythrocytes, thereby mitigating the effects of their
sequestration in the microvasculature.

Ayodo et al. (2007) performed an association study combined with
evidence of natural selection. The association study tested 10 putative
resistance variants in 471 severe malaria cases (mean age 2.6 years) and
474 controls (mean age 16.9 years) from the Luo tribe, who live in a
malaria-endemic region of Kenya. The authors replicated associations
with HBB and CD36. In the selection study, Ayodo et al. (2007) assembled
population control samples from the Masai, Kikuyu, and Yoruba ethnic
groups. They found that the same variants are unusually differentiated
between the Luo and Yoruba (also historically exposed to malaria in
Nigeria) and the Masai and Kikuyu tribes (both living in nonendemic
regions of Kenya). Although evidence of association for HBB and CD36 was
only moderate by the association analysis alone, formal combination of
evidence of association with evidence from the selection test yielded
greatly increased significance, up to P = 0.000018 for HBB and P =
0.00043 for CD36. Ayodo et al. (2007) concluded that they empirically
demonstrated the theoretical concept of increasing statistical power by
orders of magnitude to detect disease variants by combining association
analysis with evidence of natural selection.

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) confirmed the
protective effect of sickle cell trait.

- Thalassemia and Resistance to Malaria

The suggestion that alpha(+)-thalassemia (141800) has achieved a high
frequency in some populations as a result of selection by malaria is
based on a number of epidemiologic studies. In the southwest Pacific
region, there is a striking geographic correlation between the frequency
of alpha(+)-thalassemia and the endemicity of Plasmodium falciparum.
Allen et al. (1997) undertook a prospective case-control study of
children with severe malaria on the north coast of Papua New Guinea,
where malaria transmission is intense and alpha(+)-thalassemia affects
more than 90% of the population (homozygotes comprise approximately 55%
and heterozygotes 37% of the population). Compared with normal children,
the risk of having severe malaria was 0.40 in alpha(+)-thalassemia
homozygotes and 0.66 in heterozygotes. Unexpectedly, the risk of
hospital admission with infections other than malaria also was reduced
to a similar degree in homozygotes (0.36) and heterozygotes (0.63). This
clinical study demonstrated that a malaria resistance gene protects
against disease caused by infections other than malaria. A reduction in
mortality greater than that attributable directly to malaria had been
observed after the prevention of malaria by insecticides,
chemoprophylaxis, and insecticide-impregnated bed nets. Previous
observations that direct malaria mortality cannot account for observed
hemoglobin S gene frequencies suggest that the findings of this study
may apply equally to other malaria resistance genes.

In a study of the epidemiology of childhood malaria on the southwestern
Pacific island of Espiritu Santo in Vanuatu, Williams et al. (1996)
found that, paradoxically, both the incidence of uncomplicated malaria
and the prevalence of splenomegaly, an index of malarial infection, were
significantly higher in young children with alpha(+)-thalassemia than in
normal children. Furthermore, this effect was most marked in the
youngest children and for the nonlethal parasite Plasmodium vivax. The
authors speculated that the alpha(+)-thalassemias may have been selected
for the ability to increase susceptibility to P. vivax, which, by acting
as a natural vaccine in this community, induced limited cross-species
protection against subsequent severe P. falciparum malaria.

- Variation in FY and Resistance to P. Vivax Infection

The Duffy-null phenotype (see 110700), which results from a promoter SNP
in the DARC gene (613665.0002), provides complete protection against P.
vivax infection (Kwiatkowski, 2005).

- G6PD Deficiency and Resistance to Malaria

Among Nigerian children with convulsions and heavy parasitemia from
falciparum malaria, Martin et al. (1979) noted a reduced frequency of
G6PD deficiency (305900), an X-linked disorder. They pointed out that
the only support for a role of malaria in selecting for deficiency genes
had been geographic association. The mechanism of protection of
G6PD-deficient cells against falciparum malaria was worked out by
Friedman and Trager (1981). G6PD is critical to the regeneration of
NADPH, a coenzyme that is essential for protection against and repair of
oxidative damage. Red cells deficient in G6PD are more sensitive to
hydrogen peroxide generated by the malaria parasite. The loss of
potassium from the cell and from the parasite is largely responsible for
the death of the parasite. The fava bean contains a variety of
substances that increase the red cells' sensitivity to oxidants. Eating
fava beans and perhaps other foods as yet not identified would be
expected to increase the level of protection against malaria in people
who are heterozygous for G6PD deficiency and for thalassemia. Fetal red
cells likewise have an increased sensitivity to oxidants and a resulting
resistance to malaria. This is true of adult cells that have unusually
high concentration of fetal hemoglobin. Roth et al. (1983) found that
G6PD-deficient red cells of Sardinian hemizygotes and heterozygotes
supported growth of the Plasmodium falciparum parasite in vitro only
about one-third as well as normal red cells. No abnormality of growth
could be demonstrated in red cells from Sardinians with the
beta-zero-thalassemia trait. The authors suggested that the data support
a selective advantage of G6PD deficiency in malarious areas; the
advantage of the female heterozygote may be particularly strong if
resistance to malaria equals that in the hemizygous male, without the
risk of fatal hemolysis.

That resistance to severe malaria is the basis of the high frequency of
G6PD deficiency and that both hemizygotes and heterozygotes enjoy an
advantage was established by Ruwando et al. (1995) in 2 large
case-control studies of more than 2,000 African children. They found
that the common African form of G6PD deficiency (G6PD A-; 305900.0002)
was associated with a 46 to 58% reduction in risk of severe malaria for
both female heterozygotes and male hemizygotes. A mathematical model
incorporating the measured selective advantage against malaria suggested
that a counterbalancing selective disadvantage, associated with this
enzyme deficiency, has retarded its rise in frequency in malaria-endemic
regions.

Cappadoro et al. (1998) found that with 5 different strains of
Plasmodium falciparum, there was no significant difference in either
invasion or maturation when the parasites were grown in either normal or
G6PD-deficient (Mediterranean variant; 305900.0006) erythrocytes. With
all of these strains and at different maturation stages, they were
unable to detect any difference in the amount of P. falciparum-specific
G6PD mRNA in normal versus deficient parasitized erythrocytes. By
contrast, in studies of phagocytosis of parasitized erythrocytes by
human adherent monocytes, they found that when the parasites were at the
ring stage, deficient ring-stage parasitized erythrocytes (RPE) were
phagocytized 2.3 times more intensely than normal RPEs, whereas there
was no difference when the parasites were at the more mature trophozoite
stage, i.e., trophozoite-stage parasitized erythrocytes (TPEs). The
level of reduced glutathione was remarkably lower in deficient RPEs
compared with normal RPEs. Cappadoro et al. (1998) concluded that
impaired antioxidant defense in deficient RPEs may be responsible for
membrane damage followed by phagocytosis. Because RPEs, unlike TPEs, are
nontoxic to phagocytes, the increased removal by phagocytosis of RPEs
would reduce maturation to TPEs and to schizonts and may be a highly
efficient mechanism of malaria resistance in deficient subjects.

Louicharoen et al. (2009) investigated the effect of the G6PD-Mahidol
487A variant (305900.0005) on human survival related to P. vivax and P.
falciparum malaria in Southeast Asia. They showed that strong and recent
positive selection has targeted the Mahidol variant over the past 1,500
years. The authors found that the G6PD-Mahidol variant reduces vivax,
but not falciparum, parasite density in humans, which indicates that P.
vivax has been a driving force behind the strong selective advantage
conferred by this mutation.

- Variation in GYPA and Resistance to Malaria

Red cells with the rare En(a-) variant of GYPA (111300) are resistant to
falciparum malaria (Pasvol et al., 1982).

- Variation in GYPB and Resistance to Malaria

Red cells with the rare U(-) variant of GYPB (111740) are relatively
resistant to invasion by P. falciparum (Pasvol and Wilson, 1982).

- Variation in GYPC and Resistance to Malaria

Deletion of exon 3 in the GYPC gene (110750.0002) has been found in
Melanesians; this alteration changes the serologic phenotype of the
Gerbich (Ge) blood group system (110750), resulting in Ge negativity
(Booth and McLoughlin, 1972; Serjeantson et al., 1994). The GYPC exon 3
deletion allele reaches a high frequency (46.5%) in coastal areas of
Papua New Guinea where malaria is hyperendemic (Patel et al., 2001).
Plasmodium falciparum erythrocyte-binding antigen-140 (EBA140, also
known as BAEBL) binds with high affinity to the surface of human
erythrocytes. Maier et al. (2003) showed that the receptor for EBA140 is
glycophorin C and that this interaction mediates a principal P.
falciparum invasion pathway into human erythrocytes. EBA140 does not
bind to GYPC in Ge-negative erythrocytes, nor can P. falciparum invade
such cells using this invasion pathway. This provides compelling
evidence that Ge negativity has arisen in Melanesian populations through
natural selection by severe malaria.

- Southeast Asian Ovalocytosis and Resistance to Cerebral
Malaria

Kidson et al. (1981) found that ovalocytic erythrocytes from Melanesians
were resistant to invasion by malaria parasites. Baer (1988) suggested
that Malaysian elliptocytosis (109270) may be a balanced polymorphism,
i.e., that individuals homozygous for the elliptocytosis allele may be
differentially susceptible to mortality, whereas the heterozygote is at
an advantage. Hadley et al. (1983) showed that Melanesian elliptocytes
were highly resistant to invasion by Plasmodium knowlesi and P.
falciparum in vitro.

The band 3 variant in southeast Asian ovalocytosis (109270.0002) may
prevent cerebral malaria, but it exacerbates malarial anemia and may
also increase acidosis, a major determinant of mortality in malaria.
Allen et al. (1999) undertook a case-control study of children admitted
to hospital in a malarious area of Papua New Guinea. The 24-bp deletion,
detected by PCR, was present in 0 of 68 children with cerebral malaria,
compared with 6 (8.8%) of 68 matched community controls. Median
hemoglobin levels were 1.2 g/dl lower in malaria cases with southeast
Asian ovalocytosis than in controls (P = 0.035), but acidosis was not
affected. The band 3 protein mediates the cytoadherence of parasitized
erythrocytes in vitro. The remarkable protection that the variant
affords against cerebral malaria may offer a valuable approach to a
better understanding of the mechanisms of adherence of parasitized
erythrocytes to vascular endothelium and the pathogenesis of cerebral
malaria.

- Variation in CD36 and Susceptibility or Resistance to Cerebral
Malaria

CD36 is a major receptor for Plasmodium falciparum-infected
erythrocytes. Aitman et al. (2000) found that African populations
contain an exceptionally high frequency of mutations in CD36 (173510).
Unexpectedly, these mutations (173510.0002 and 173510.0003) that cause
CD36 deficiency (608404) were associated with susceptibility to severe
cerebral malaria, suggesting that the presence of distinct CD36
mutations in Africans and Asians is due to some selection pressure other
than malaria.

In 475 adult Thai patients with P. falciparum malaria, Omi et al. (2003)
screened for variation in the CD36 gene and examined possible
association between CD36 polymorphisms and the severity of malaria. They
identified 9 CD36 polymorphisms with a frequency of more than 15% for
the minor allele. Of these, the -14T-C allele in the upstream promoter
region and the -53G-T allele in the downstream promoter region were
significantly decreased in patients with cerebral malaria compared with
those with mild malaria. Linkage disequilibrium (LD) analysis between
the 9 common polymorphisms revealed 2 blocks with strong LD in the CD36
gene; the -14T-C and -53G-T polymorphisms were within the upstream block
of 35 kb from the upstream promoter to exon 8. Another polymorphism,
consisting of 12 TG repeats in intron 3 (173510.0004), was strongly
associated with reduction in the risk of cerebral malaria. Omi et al.
(2003) demonstrated by RT-PCR amplification that this IVS3(TG)12
polymorphism is involved in the nonproduction of the variant CD36
transcript that lacks exons 4 and 5. Because exon 5 of the gene is known
to encode the ligand-binding domain for P. falciparum-infected
erythrocytes, IVS3(TG)12 itself or a primary variant on the haplotype
with IVS3(TG)12 may be responsible for protection from cerebral malaria
in Thailand.

Ayodo et al. (2007) sought to demonstrate that statistical power to
detect disease variants can be increased by weighting candidates by
their evidence of natural selection. Although evidence of association
for HBB and CD36 was only moderate by an association analysis alone,
formal combination of evidence of association with evidence from a
selection test yielded greatly increased significance, up to P =
0.000018 for HBB and P = 0.00043 for CD36.

- Variation in CR1 and Resistance to Malaria

The Knops blood group system (607486) is a system of antigens located on
CR1. Rowe et al. (1997) demonstrated that CR1 is involved in malarial
rosetting, a process associated with cerebral malaria, which is the
major cause of mortality in Plasmodium falciparum malaria. They showed
that rosette formation was considerably reduced with Sl(a-) Knops
phenotype RBCs, indicating that this antigen on CR1 is involved in
rosetting. Because Sl(a-) is more common in persons of African ancestry,
a protective role was suggested (Moulds and Moulds, 2000).

CR1-deficient RBCs show greatly reduced rosetting, leading Cockburn et
al. (2004) to hypothesize that if rosetting is a direct cause of malaria
pathology, CR1-deficient individuals should be protected against severe
disease. They showed that RBC CR1 deficiency occurs in up to 80% of
healthy individuals from the malaria-endemic regions of Papua New
Guinea. This RBC CR1 deficiency is associated with polymorphisms in the
CR1 gene (e.g., 120620.0001) and, unexpectedly, with alpha-thalassemia,
a common genetic disorder in Melanesian populations. Analysis of a
case-control study demonstrated that the CR1 polymorphisms and
alpha-thalassemia independently confer protection against severe
malaria. Thus, Cockburn et al. (2004) identified CR1 as a new malaria
resistance gene and provided compelling evidence that rosetting is an
important parasite virulence phenotype that should be a target for drug
and vaccine development.

- Variation in ICAM1 and Susceptibility to Cerebral Malaria

The malarial parasite Plasmodium falciparum has acted as a potent
selective force on the human genome. The particular virulence of this
organism was thought to be due to the adherence of parasitized red blood
cells to small vessel endothelium through several receptors, including
CD36, thrombospondin (THBS1; 188060), and ICAM1, and parasite isolates
differ in their ability to bind to each. Immunohistochemical studies
implicated ICAM1 as having potential importance in the pathogenesis of
cerebral malaria, leading Fernandez-Reyes et al. (1997) to reason that
if any single receptor were involved in the development of cerebral
malaria, then in view of the high mortality of that complication,
natural selection should have produced variants with reduced binding
capacity. Fernandez-Reyes et al. (1997) amplified and sequenced the
N-terminal immunoglobulin-like domain of the ICAM1 gene from the genomic
DNA of 24 asymptomatic children in Kilifi, Kenya. The only mutation
found was an A-to-T transversion at nucleotide 179, causing a
lys29-to-met substitution (K29M; 147840.0001), which the authors called
'ICAM1 Kilifi.' In studies of the association of the K29M polymorphism
with cerebral malaria, they found, to their surprise, that the
homozygous ICAM1 Kilifi genotype was associated with susceptibility to
cerebral malaria with a relative risk of 2.23, and heterozygotes with a
relative risk of 1.39. The frequency of the K29 allele was 0.668 and the
frequency of the M29 Kilifi allele was 0.332. Fernandez-Reyes et al.
(1997) noted that, while this association strengthened the link between
ICAM1 and cerebral malaria, a mutation that confers susceptibility is
unlikely to have arisen at such high frequency in the absence of some
counteractive selective advantage. These counterintuitive results had
implications for the mechanism of malaria pathogenesis, resistance to
other infectious agents, and transplant immunology. The Kilifi allele
was not identified in 99 unrelated Caucasians or in 40 multigeneration
families from the CEPH collection. Screening of 20 Gambian samples
produced a similar frequency of the Kilifi allele to that seen in Kenya.

Bellamy et al. (1998) found no association between the ICAM1 Kilifi
variant and cerebral malaria in a case-control study of West Africans.

- Variation in Major Histocompatibility Complex Genes and
Resistance to Severe Malaria

By means of a large case-controlled study of malaria in West African
children, Hill et al. (1991) showed that HLA-Bw53 (see HLA-B; 142830)
and the HLA class II haplotype, DRB1*1302/DQB1*0501 (see HLA-DRB1;
142857), were independently associated with protection from severe
malaria. The antigens listed are common in West Africans but rare in
other racial groups. In this population, they account for as great a
reduction in disease incidence as the sickle-cell hemoglobin variant.
Although the relative strength of the protection is less than that of
the sickle-cell variant, the greater frequency of the DQB1 (see
HLA-DQB1; 604305) polymorphism makes the net effect on resistance to
malaria comparable. The findings support the hypothesis that the
extraordinary polymorphism of major histocompatibility complex genes has
evolved primarily through natural selection by infectious pathogens.

Hill et al. (1992) further investigated the protective association
between HLA-B53 and severe malaria by sequencing peptides eluted from
this molecule followed by screening of candidate epitopes from
pre-erythrocytic-stage antigens of Plasmodium falciparum in biochemical
and cellular assays. Among malaria-immune Africans, they found that
HLA-B53-restricted cytotoxic T lymphocytes recognized a conserved
nonamer peptide from liver-stage-specific antigen-1 (LSA-1), but no
HLA-B53-restricted epitopes were identified in other malaria antigens.
The findings of this 'reverse immunogenetic' approach indicated a
possible molecular basis for this HLA-disease association and supported
the candidacy of LSA-1 as a component for a malaria vaccine.

Sjoberg et al. (1992) found that levels of antibody to a major malarial
antigen developing in individuals living in northern Liberia, where
malaria is holoendemic and perennial, were more concordant within
monozygotic twin pairs than in dizygotic pairs or in age- and
sex-matched sibs living under similar environmental conditions. The
results supported the conclusion that the antibody responses were
genetically regulated. No association was found with different HLA class
II alleles and haplotypes, suggesting that the variation in the antibody
response found in this study reflected the impact of factors encoded by
genes outside the HLA class II region.

- Variation in TNF and Susceptibility to Cerebral Malaria

Because fatal cerebral malaria is associated with high circulating
levels of TNFA (TNF; 191160), McGuire et al. (1994) undertook a large
case-control study in Gambian children. The study showed that
homozygotes for the TNF2 allele (-308G-A; 191160.0004), a variant of the
TNFA gene promoter region, had a relative risk of 7 for death or severe
neurologic sequelae due to cerebral malaria. Although the TNF2 allele is
in linkage disequilibrium with several neighboring HLA alleles, McGuire
et al. (1994) showed that this disease association was independent of
HLA class I and class II variation. The data suggested that regulatory
polymorphisms of cytokine genes can affect the outcome of severe
infection. The maintenance of the TNF2 allele at a gene frequency of
0.16 in The Gambia implies that the increased risk of cerebral malaria
in homozygotes is counterbalanced by some biologic advantage.

Through systematic DNA fingerprinting of the TNF promoter region, Knight
et al. (1999) identified a SNP (-376G-A; 191160.0003) that caused the
helix-turn-helix transcription factor OCT1 (POU2F1; 164175) to bind to a
novel region of complex protein-DNA interactions and alter gene
expression in human monocytes. The OCT1-binding genotype, found in
approximately 5% of Africans, was associated with 4-fold increased
susceptibility to cerebral malaria in large studies comparing cases and
controls in West African and East African populations, after correction
for other known TNF polymorphisms and linked HLA alleles.

- Variation in NOS2A and Resistance to Malaria

Kun et al. (1998) examined whether high plasma concentrations of nitric
oxide found in severe malaria were due to variation in the promoter
region of NOS2 (163730). Heterozygosity for a -969G-C SNP (163730.0002)
was present in 30 of 100 Gambian children with mild malaria, but in only
17 of 100 Gambian children with severe malaria. The SNP was not found in
any of 100 Germans. Heterozygous individuals were also at a
significantly lower risk of reinfection.

From studies in Tanzania and Kenya, Hobbs et al. (2002) identified a
novel SNP, -1173C-T (163730.0001), in the NOS2A promoter that was
significantly associated with protection from symptomatic malaria and
severe malarial anemia.

- Variation in TIRAP and Resistance to Malaria

Khor et al. (2007) reported a case-control study of 6,106 individuals
from the U.K., Vietnam, and several African countries with invasive
pneumococcal disease (see 610799), bacteremia, malaria, and tuberculosis
(607948). Genotyping 33 SNPs, they found that heterozygous carriage of a
leucine substitution of ser180 (606252.0001) in TIRAP (606252) was
associated independently with all 4 infectious diseases in the different
study populations. Combining the study groups, they found substantial
support for protective effect of S180L heterozygosity against these
infectious diseases.

- Variation in FCGR2B and Resistance to Malaria

Clatworthy et al. (2007) found an increased frequency of the I232T
polymorphism (604590.0001) of the FCGR2B gene (604590) in Asian and
African populations, broadly corresponding to regions where malaria is
endemic. The systemic lupus erythematosus (SLE; 152700)-associated I232T
polymorphism was associated with enhanced phagocytosis of Plasmodium
falciparum-infected human erythrocytes. Clatworthy et al. (2007)
concluded that FCGR2B is important in controlling the immune response to
malaria parasites and suggested that polymorphisms predisposing to SLE
in Asians and Africans may be maintained because the variants reduce
susceptibility to malaria.

By comparing genotypes of patients with SLE from Hong Kong and the UK
with those of ethnically matched controls, followed by metaanalysis
using with other studies on southeast Asian and Caucasian SLE patients,
Willcocks et al. (2010) found that homozygosity for T232 of the I232T
polymorphism was strongly associated with SLE in both ethnic groups.
When studies in Caucasians and southeast Asians were combined, T232
homozygosity was associated with SLE with an odds ratio of 1.73 (P = 8.0
x 10(-6)). Willcocks et al. (2010) noted that the T232 allele of the SNP
is more common in southeast Asians and Africans, populations where
malaria is endemic, than in Caucasians. Homozygosity for T232 was
significantly associated with protection from severe malaria in Kenyan
children (odds ratio = 0.56; P = 7.1 x 10(-5)), but no association was
found with susceptibility to bacterial infection. Willcocks et al.
(2010) proposed that malaria may have driven retention of a polymorphism
predisposing to a polygenic autoimmune disease and thus may begin to
explain the ethnic differences seen in the frequency of SLE.

- Blood Group O and Resistance to Severe Malaria

Rowe et al. (2007) noted that Plasmodium falciparum-induced rosetting
(i.e., the spontaneous binding of infected erythrocytes to uninfected
erythrocytes) is thought to contribute to the pathogenesis of severe
malaria by obstructing microvascular blood flow. Rosetting is reduced in
blood group O (see 110300) erythrocytes compared with non-O blood
groups, presumably due to group O individuals having disaccharide H
antigens resulting from a lack of the terminal glycosyltransferases
necessary to produce the trisaccharides found with A and B antigens.
Rosettes that do form in group O red cells are smaller and more easily
disrupted than those in group A, B, or AB red cells. Rowe et al. (2007)
confirmed that rosetting was reduced in individuals with blood group O,
intermediate in blood groups A and B, and highest in group AB. A matched
case control study of 567 Malian children found that group O was present
in only 21% of severe malaria cases compared with approximately 44% of
uncomplicated malaria control cases and healthy controls. Rowe et al.
(2007) concluded that group O is associated with a 66% reduction in the
odds of developing severe malaria compared with non-O blood groups, and
they reported preliminary evidence that similar protection is found in
Kenyan children. The authors also proposed that group O does not occur
at higher frequency in some malaria endemic regions due to increased
susceptibility to cholera and other diarrheal diseases, resulting in
balanced polymorphism.

In a genomewide association study of patients with severe malaria and
unaffected controls from Ghana, Timmann et al. (2012) confirmed the
protective effect of blood group O.

- Variation in GNAS and Susceptibility to Severe Malaria

Using metaanalysis combining data from case control and family studies
in Gambia, Kenya, and Malawi and a case control study from Ghana, Auburn
et al. (2008) detected associations between intronic or conservative
SNPs of GNAS (139320) and severe malaria. SNPs with significant
associations clustered in the 5-prime end of GNAS. Auburn et al. (2008)
proposed that the impact of GNAS on malaria parasite invasion efficacy
may alter susceptibility to disease.

- Variation in TIM1 and Resistance to Cerebral Malaria

By screening for polymorphisms of TIM1 (HAVCR1; 606518), TIM3 (HAVCR2;
606652), and TIM4 (TIM4D; 610096) in 478 Thai patients infected with
Plasmodium falciparum, Nuchnoi et al. (2008) identified a statistically
significant association between protection against cerebral malaria and
a TIM1 promoter haplotype consisting of 3 derived alleles, -1637G-A
(dbSNP rs7702919), -1549G-C (dbSNP rs41297577), and -1454G-A (dbSNP
rs41297579). Allele-specific transcription quantification analysis
revealed that TIM1 mRNA levels were higher for the protective promoter
haplotype than for the other promoter haplotype. Nuchnoi et al. (2008)
proposed that engagement of TIM1 and T-cell receptor stimulation may
induce antiinflammatory Th2 cytokine production and protect from
development of cerebral malaria by downregulating inflammatory cytokines
such as TNF (191160) and IFNG (147570).

- Variation in IL12B and Susceptibility to Cerebral Malaria

Using a family-based association study with 240 Malian families, Marquet
et al. (2008) investigated 21 markers in IL12-related genes for
involvement in susceptibility to cerebral malaria (CM). They found that
the IL12B (161561) promoter polymorphism dbSNP rs17860508, in which GC
is replaced with CTCTAA, was associated with susceptibility to CM. The
CTCTAA allele and the GC/CTCTAA heterozygous genotype were associated
with increased risk of CM (P of 0.0002 and 0.00002, respectively).
Children with the GC/CTCTAA genotype had a higher risk of CM than
children homozygous for either allele (odds ratio of 2.11; P less than
0.0001). Among 134 CM children with a heterozygous parent, a significant
number received the CTCTAA allele. Marquet et al. (2008) noted that
heterozygosity for dbSNP rs17860508 is associated with reduced IL12B
expression and reduced IL12 secretion, and that low IL12 and IFNG
(147570) levels are associated with CM. They proposed that Th1 responses
may reduce the parasite load and severe malaria risk.

- Variation in FUT9 and Susceptibility to Placental Malaria
Infection

Sikora et al. (2009) carried out a nested case-control study on 180
Mozambican pregnant women with placental malaria infection and 180
controls within an intervention trial of malaria prevention. Subjects
were genotyped at 880 SNPs in a set of 64 functionally related genes
involved in glycosylation and innate immunity. A T-C SNP (dbSNP
rs3811070) located in the 5-prime untranslated region (UTR) of the FUT9
gene (606865) on chromosome 6q16 was significantly associated with
placental malaria infection (odds ratio, 2.31; corrected p = 0.038).
Haplotype analysis revealed a similarly strong association for a common
4-SNP TTCA haplotype including dbSNP rs3811070. The TTCA haplotype spans
40 kb in the 5-prime UTR and contains the second exon of FUT9. The FUT9
gene encodes a fucosyltransferase that catalyzes the last step in the
biosynthesis of the Lewis-x antigen, which forms part of the Lewis blood
group-related antigens. Sikora et al. (2009) suggested an involvement of
this antigen in the pathogenesis of placental malaria infection.

- Variation in FCGR2A and Susceptibility to Severe Malaria

The his131-to-arg (H131R; 146790.0001) polymorphism in the extracellular
domain of FCGR2A reduces the receptor's affinity for IgG2 and IgG3
isotypes (see 147100) but increases its binding of C-reactive protein
(CRP; 123260). By studying 2,504 Ghanaian children with severe malaria
and 2,027 healthy matched controls, Schuldt et al. (2010) found that
homozygosity for 131R was positively associated with severe malaria
(odds ratio = 1.20; p = 0.007; p corrected for multiple testing =
0.021), and, after stratification for phenotypes, with severe anemia
(odds ratio = 1.33; p = 0.001; p corrected = 0.009), but not with
cerebral malaria or other malaria complications or with parasitemia
levels. Schuldt et al. (2010) concluded that the CRP-binding variant of
FCGR2A is associated with malarial anemia, suggesting a role for CRP
defense mechanisms in pathogenesis of this condition.

- Resistance Versus Tolerance

Hosts can in principle employ 2 different strategies to defend
themselves against parasites: resistance and tolerance. Animals
typically exhibit considerable genetic variation for resistance. Using
rodent malaria in laboratory mice as a model system and the statistical
framework developed by plant pathogen biologists, Raberg et al. (2007)
demonstrated genetic variation for tolerance, as measured by the extent
to which anemia and weight loss increased with increasing parasite
burden. Moreover, resistance and tolerance were negatively genetically
correlated. Raberg et al. (2007) concluded that their results mean that
animals, like plants, can evolve 2 conceptually different types of
defense, a finding that has important implications for the understanding
of the epidemiology and evolution of infectious diseases.

- Reviews

Nagel and Roth (1989) reviewed genetic disorders of the red cell,
including abnormal hemoglobins, G6PD deficiency, and absence of Duffy
blood group antigen, that influence resistance against malaria infection
in humans.

Kwiatkowski (2005) provided an overview of genetic resistance to
malaria.

Campino et al. (2006) reviewed mendelian and complex genetics of
susceptibility and resistance to parasitic infections, including
malaria.

ANIMAL MODEL

Ferreira et al. (2011) demonstrated that wildtype mice or mice
expressing normal human Hb, but not mice expressing sickle human Hb
(Hbs; 141900.0243), developed experimental cerebral malaria (ECM) 6 to
12 days after infection with the murine malaria parasite, Plasmodium
berghei. The Hbs mice eventually succumbed to the unrelated condition of
hyperparasitemia-induced anemia. Tolerance to Plasmodium infection was
associated with high levels of Hmox1 (141250) expression in
hematopoietic cells, and mice expressing Hbs became susceptible to ECM
when Hmox1 expression was inhibited. Hbs induced expression of Hmox1 in
an Nrf2 (NFE2L2; 600492)-dependent manner, which inhibited the
production of chemokines and Cd8-positive T cells associated with ECM
pathogenesis. Ferreira et al. (2011) concluded that sickle hemoglobin
suppresses the onset of ECM via induction of HMOX1 and the production of
carbon monoxide, which inhibits the accumulation of free heme, affording
tolerance to Plasmodium infection.

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*FIELD* CN
Paul J. Converse - updated: 12/9/2013
Paul J. Converse - updated: 8/22/2013
Paul J. Converse - updated: 7/29/2013
Paul J. Converse - updated: 9/26/2012
Paul J. Converse - updated: 6/19/2012
Paul J. Converse - updated: 1/18/2012
Paul J. Converse - updated: 11/11/2011
Paul J. Converse - updated: 5/5/2011
Paul J. Converse - updated: 4/29/2011
George E. Tiller - updated: 6/28/2010
Ada Hamosh - updated: 1/6/2010
Paul J. Converse - updated: 11/24/2009
Paul J. Converse - updated: 11/2/2009
Paul J. Converse - updated: 1/26/2009
Paul J. Converse - updated: 1/8/2009
Paul J. Converse - updated: 8/21/2008
Ada Hamosh - updated: 11/21/2007
Paul J. Converse - updated: 7/17/2007
George E. Tiller - updated: 7/6/2007
Paul J. Converse - updated: 7/5/2007

*FIELD* CD
Matthew B. Gross: 7/2/2007

*FIELD* ED
mgross: 01/06/2014
mcolton: 12/9/2013
mgross: 10/25/2013
carol: 10/24/2013
mgross: 8/22/2013
alopez: 8/7/2013
alopez: 7/29/2013
mgross: 9/27/2012
terry: 9/26/2012
terry: 7/3/2012
mgross: 6/19/2012
mgross: 1/18/2012
mgross: 11/17/2011
terry: 11/11/2011
terry: 5/20/2011
mgross: 5/11/2011
terry: 5/5/2011
mgross: 5/3/2011
terry: 4/29/2011
mgross: 12/21/2010
wwang: 7/21/2010
terry: 6/28/2010
alopez: 6/10/2010
alopez: 1/19/2010
terry: 1/6/2010
alopez: 11/24/2009
mgross: 11/2/2009
wwang: 8/24/2009
terry: 4/8/2009
carol: 3/31/2009
mgross: 1/26/2009
mgross: 1/8/2009
mgross: 8/21/2008
terry: 8/21/2008
mgross: 4/1/2008
alopez: 11/28/2007
terry: 11/21/2007
mgross: 8/27/2007
terry: 7/17/2007
mgross: 7/9/2007
wwang: 7/6/2007
mgross: 7/5/2007