RBCC Red Blood Cell Collection

CD36 (GP3B, GP4) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Platelet glycoprotein 4 (Fatty acid translocase; FAT; Glycoprotein IIIb; GPIIIB; Leukocyte differentiation antigen CD36; PAS IV; PAS-4; Platelet collagen receptor; Platelet glycoprotein IV; GPIV; Thrombospondin receptor; CD36)

UniProt P16671
ID CD36_HUMAN Reviewed; 472 AA.
AC P16671; Q13966; Q16093; Q8TCV7; Q9BPZ8; Q9BQC2; Q9BZM8; Q9BZN3;
read moreAC Q9BZN4; Q9BZN5;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 155.
DE RecName: Full=Platelet glycoprotein 4;
DE AltName: Full=Fatty acid translocase;
DE Short=FAT;
DE AltName: Full=Glycoprotein IIIb;
DE Short=GPIIIB;
DE AltName: Full=Leukocyte differentiation antigen CD36;
DE AltName: Full=PAS IV;
DE AltName: Full=PAS-4;
DE AltName: Full=Platelet collagen receptor;
DE AltName: Full=Platelet glycoprotein IV;
DE Short=GPIV;
DE AltName: Full=Thrombospondin receptor;
DE AltName: CD_antigen=CD36;
GN Name=CD36; Synonyms=GP3B, GP4;
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].
RC TISSUE=Placenta;
RX PubMed=2473841; DOI=10.1016/0092-8674(89)90406-6;
RA Oquendo P., Hundt E., Lawler J., Seed B.;
RT "CD36 directly mediates cytoadherence of Plasmodium falciparum
RT parasitized erythrocytes.";
RL Cell 58:95-101(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Sugimoto Y., Tsuruo T.;
RL Submitted (AUG-1992) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7693552; DOI=10.1016/0378-1119(93)90639-K;
RA Taylor K.T., Tang Y., Sobieski D.A., Lipsky R.H.;
RT "Characterization of two alternatively spliced 5'-untranslated exons
RT of the human CD36 gene in different cell types.";
RL Gene 133:205-212(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Platelet;
RX PubMed=7505064;
RA Wyler B., Daviet L., Bortkiewicz H., Bordet J.C., McGregor J.L.;
RT "Cloning of the cDNA encoding human platelet CD36: comparison to PCR
RT amplified fragments of monocyte, endothelial and HEL cells.";
RL Thromb. Haemost. 70:500-505(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7518447;
RA Armesilla A.L., Vega M.A.;
RT "Structural organization of the gene for human CD36 glycoprotein.";
RL J. Biol. Chem. 269:18985-18991(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JAN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
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 [8]
RP PROTEIN SEQUENCE OF 2-37, AND GLYCOSYLATION.
RC TISSUE=Platelet;
RX PubMed=2468669;
RA Tandon N.N., Lipsky R.H., Burgess W.H., Jamieson G.A.;
RT "Isolation and characterization of platelet glycoprotein IV (CD36).";
RL J. Biol. Chem. 264:7570-7575(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 41-203; 274-375 AND 419-472, AND
RP VARIANTS LYS-123; ALA-174; ASN-232 INS AND THR-271.
RX PubMed=11668637; DOI=10.1002/humu.1215;
RA Gelhaus A., Scheding A., Browne E., Burchard G.D., Horstmann R.D.;
RT "Variability of the CD36 gene in West Africa.";
RL Hum. Mutat. 18:444-450(2001).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 144-203.
RX PubMed=7503937; DOI=10.1006/geno.1993.1401;
RA Fernandez-Ruiz E., Armesilla A.L., Sanchez-Madrid F., Vega M.A.;
RT "Gene encoding the collagen type I and thrombospondin receptor CD36 is
RT located on chromosome 7q11.2.";
RL Genomics 17:759-761(1993).
RN [11]
RP PROTEIN SEQUENCE OF 261-273 AND 369-385.
RC TISSUE=Adipocyte;
RX PubMed=15242332; DOI=10.1042/BJ20040647;
RA Aboulaich N., Vainonen J.P., Stralfors P., Vener A.V.;
RT "Vectorial proteomics reveal targeting, phosphorylation and specific
RT fragmentation of polymerase I and transcript release factor (PTRF) at
RT the surface of caveolae in human adipocytes.";
RL Biochem. J. 383:237-248(2004).
RN [12]
RP INTERACTION WITH THBS1 AND THBS2.
RX PubMed=1371676; DOI=10.1016/0006-291X(92)91860-S;
RA Asch A.S., Silbiger S., Heimer E., Nachman R.L.;
RT "Thrombospondin sequence motif (CSVTCG) is responsible for CD36
RT binding.";
RL Biochem. Biophys. Res. Commun. 182:1208-1217(1992).
RN [13]
RP PALMITOYLATION AT CYS-3; CYS-7; CYS-464 AND CYS-466.
RX PubMed=8798390; DOI=10.1074/jbc.271.37.22315;
RA Tao N., Wagner S.J., Lublin D.M.;
RT "CD36 is palmitoylated on both N- and C-terminal cytoplasmic tails.";
RL J. Biol. Chem. 271:22315-22320(1996).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-417, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.M500324-MCP200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-321, AND MASS
RP SPECTROMETRY.
RC TISSUE=Milk;
RX PubMed=18780401; DOI=10.1002/pmic.200701057;
RA Picariello G., Ferranti P., Mamone G., Roepstorff P., Addeo F.;
RT "Identification of N-linked glycoproteins in human milk by hydrophilic
RT interaction liquid chromatography and mass spectrometry.";
RL Proteomics 8:3833-3847(2008).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-205 AND ASN-417, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [17]
RP VARIANT PG4D SER-90.
RX PubMed=7533783; DOI=10.1172/JCI117749;
RA Kashiwagi H., Tomiyama Y., Honda S., Kosugi S., Shiraga M., Nagao N.,
RA Sekiguchi S., Kanayama Y., Kurata Y., Matsuzawa Y.;
RT "Molecular basis of CD36 deficiency. Evidence that a 478C-->T
RT substitution (proline90-->serine) in CD36 cDNA accounts for CD36
RT deficiency.";
RL J. Clin. Invest. 95:1040-1046(1995).
RN [18]
RP VARIANT PHE-154.
RX PubMed=10391209; DOI=10.1038/10290;
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RT "Characterization of single-nucleotide polymorphisms in coding regions
RT of human genes.";
RL Nat. Genet. 22:231-238(1999).
RN [19]
RP ERRATUM.
RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N.,
RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L.,
RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q.,
RA Lander E.S.;
RL Nat. Genet. 23:373-373(1999).
RN [20]
RP ROLE IN MALARIA INFECTION.
RX PubMed=10890433; DOI=10.1038/35016636;
RA Aitman T.J., Cooper L.D., Norsworthy P.J., Wahid F.N., Gray J.K.,
RA Curtis B.R., McKeigue P.M., Kwiatkowski D., Greenwood B.M., Snow R.W.,
RA Hill A.V., Scott J.;
RT "Malaria susceptibility and CD36 mutation.";
RL Nature 405:1015-1016(2000).
RN [21]
RP VARIANTS PG4D SER-90; LEU-254 AND LEU-413.
RX PubMed=11950861; DOI=10.1136/jmg.39.4.286;
RA Hanawa H., Watanabe K., Nakamura T., Ogawa Y., Toba K., Fuse I.,
RA Kodama M., Kato K., Fuse K., Aizawa Y.;
RT "Identification of cryptic splice site, exon skipping, and novel point
RT mutations in type I CD36 deficiency.";
RL J. Med. Genet. 39:286-291(2002).
RN [22]
RP VARIANT LEU-127, AND ROLE IN MALARIA INFECTION.
RX PubMed=12506336; DOI=10.1086/346091;
RA Omi K., Ohashi J., Patarapotikul J., Hananantachai H., Naka I.,
RA Looareesuwan S., Tokunaga K.;
RT "CD36 polymorphism is associated with protection from cerebral
RT malaria.";
RL Am. J. Hum. Genet. 72:364-374(2003).
RN [23]
RP INVOLVEMENT IN CHDS7.
RX PubMed=15282206; DOI=10.1093/hmg/ddh233;
RA Ma X., Bacci S., Mlynarski W., Gottardo L., Soccio T., Menzaghi C.,
RA Iori E., Lager R.A., Shroff A.R., Gervino E.V., Nesto R.W.,
RA Johnstone M.T., Abumrad N.A., Avogaro A., Trischitta V., Doria A.;
RT "A common haplotype at the CD36 locus is associated with high free
RT fatty acid levels and increased cardiovascular risk in Caucasians.";
RL Hum. Mol. Genet. 13:2197-2205(2004).
RN [24]
RP ERRATUM.
RA Ma X., Bacci S., Mlynarski W., Gottardo L., Soccio T., Menzaghi C.,
RA Iori E., Lager R.A., Shroff A.R., Gervino E.V., Nesto R.W.,
RA Johnstone M.T., Abumrad N.A., Avogaro A., Trischitta V., Doria A.;
RL Hum. Mol. Genet. 14:3973-3973(2005).
CC -!- FUNCTION: Seems to have numerous potential physiological
CC functions. Binds to collagen, thrombospondin, anionic
CC phospholipids and oxidized LDL. May function as a cell adhesion
CC molecule. Directly mediates cytoadherence of Plasmodium falciparum
CC parasitized erythrocytes. Binds long chain fatty acids and may
CC function in the transport and/or as a regulator of fatty acid
CC transport. Receptor for thombospondins, THBS1 AND THBS2, mediating
CC their antiangiogenic effects.
CC -!- SUBUNIT: Interacts with THBS1 and THBS2; the interactions mediate
CC the THBS antiangiogenic activity.
CC -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein.
CC -!- PTM: N-glycosylated and O-glycosylated with a ratio of 2:1.
CC -!- POLYMORPHISM: Genetic variations in CD36 are involved in
CC susceptibility to malaria and influence the severity and outcome
CC of malaria infection [MIM:611162].
CC -!- DISEASE: Platelet glycoprotein IV deficiency (PG4D) [MIM:608404]:
CC A disorder characterized by macrothrombocytopenia without notable
CC hemostatic problems and bleeding tendency. Platelet glycoprotein
CC IV deficiency can be divided into 2 subgroups. The type I
CC phenotype is characterized by platelets and monocytes/macrophages
CC exhibiting complete CD36 deficiency. The type II phenotype lacks
CC the surface expression of CD36 in platelets, but expression in
CC monocytes/macrophages is near normal. Note=The disease is caused
CC by mutations affecting the gene represented in this entry.
CC -!- DISEASE: Coronary heart disease 7 (CHDS7) [MIM:610938]: A
CC multifactorial disease characterized by an imbalance between
CC myocardial functional requirements and the capacity of the
CC coronary vessels to supply sufficient blood flow. Decreased
CC capacity of the coronary vessels is often associated with
CC thickening and loss of elasticity of the coronary arteries.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the CD36 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAM14636.2; Type=Frameshift; Positions=53;
CC -!- WEB RESOURCE: Name=Wikipedia; Note=CD36 entry;
CC URL="http://en.wikipedia.org/wiki/CD36";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CD36";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/cd36/";
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DR EMBL; M24795; AAA35534.1; -; mRNA.
DR EMBL; M98398; AAA58412.1; -; mRNA.
DR EMBL; M98399; AAA58413.1; -; mRNA.
DR EMBL; L06850; AAA16068.1; -; mRNA.
DR EMBL; S67532; AAD13993.1; -; mRNA.
DR EMBL; Z32770; CAA83662.1; -; Genomic_DNA.
DR EMBL; Z32754; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32755; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32756; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32757; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32758; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32759; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32760; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32761; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32762; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32763; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; Z32764; CAA83662.1; JOINED; Genomic_DNA.
DR EMBL; AY095373; AAM14636.2; ALT_FRAME; Genomic_DNA.
DR EMBL; BC008406; AAH08406.1; -; mRNA.
DR EMBL; AF300626; AAG60625.1; -; Genomic_DNA.
DR EMBL; AF300627; AAG60626.1; -; Genomic_DNA.
DR EMBL; AF300628; AAG60627.1; -; Genomic_DNA.
DR EMBL; AF300633; AAG60632.1; -; Genomic_DNA.
DR EMBL; AF300634; AAG60633.1; -; Genomic_DNA.
DR EMBL; AF300635; AAG60634.1; -; Genomic_DNA.
DR EMBL; AF300639; AAG60638.1; -; Genomic_DNA.
DR EMBL; AF300640; AAG60639.1; -; Genomic_DNA.
DR EMBL; S67044; AAB28992.1; -; mRNA.
DR EMBL; Z22924; CAA80504.1; -; Genomic_DNA.
DR PIR; A54870; A54870.
DR RefSeq; NP_000063.2; NM_000072.3.
DR RefSeq; NP_001001547.1; NM_001001547.2.
DR RefSeq; NP_001001548.1; NM_001001548.2.
DR RefSeq; NP_001120915.1; NM_001127443.1.
DR RefSeq; NP_001120916.1; NM_001127444.1.
DR RefSeq; XP_005250770.1; XM_005250713.1.
DR RefSeq; XP_005250771.1; XM_005250714.1.
DR RefSeq; XP_005250772.1; XM_005250715.1.
DR RefSeq; XP_005250773.1; XM_005250716.1.
DR UniGene; Hs.120949; -.
DR ProteinModelPortal; P16671; -.
DR IntAct; P16671; 7.
DR ChEMBL; CHEMBL1744526; -.
DR TCDB; 9.B.39.1.4; the long chain fatty acid translocase (lcfat) family.
DR PhosphoSite; P16671; -.
DR DMDM; 115982; -.
DR PaxDb; P16671; -.
DR PRIDE; P16671; -.
DR DNASU; 948; -.
DR Ensembl; ENST00000309881; ENSP00000308165; ENSG00000135218.
DR Ensembl; ENST00000394788; ENSP00000378268; ENSG00000135218.
DR Ensembl; ENST00000432207; ENSP00000411411; ENSG00000135218.
DR Ensembl; ENST00000435819; ENSP00000399421; ENSG00000135218.
DR Ensembl; ENST00000447544; ENSP00000415743; ENSG00000135218.
DR GeneID; 948; -.
DR KEGG; hsa:948; -.
DR UCSC; uc003uhc.3; human.
DR CTD; 948; -.
DR GeneCards; GC07P080069; -.
DR HGNC; HGNC:1663; CD36.
DR HPA; CAB025866; -.
DR HPA; HPA002018; -.
DR MIM; 173510; gene.
DR MIM; 248310; phenotype.
DR MIM; 608404; phenotype.
DR MIM; 610938; phenotype.
DR MIM; 611162; phenotype.
DR neXtProt; NX_P16671; -.
DR PharmGKB; PA26212; -.
DR eggNOG; NOG257244; -.
DR HOVERGEN; HBG002754; -.
DR InParanoid; P16671; -.
DR KO; K06259; -.
DR OMA; KRNYIVP; -.
DR OrthoDB; EOG79SDWX; -.
DR PhylomeDB; P16671; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_160300; Binding and Uptake of Ligands by Scavenger Receptors.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR GeneWiki; CD36; -.
DR GenomeRNAi; 948; -.
DR NextBio; 3938; -.
DR PRO; PR:P16671; -.
DR ArrayExpress; P16671; -.
DR Bgee; P16671; -.
DR Genevestigator; P16671; -.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:BHF-UCL.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0045335; C:phagocytic vesicle; TAS:Reactome.
DR GO; GO:0031092; C:platelet alpha granule membrane; TAS:Reactome.
DR GO; GO:0008035; F:high-density lipoprotein particle binding; IEA:Ensembl.
DR GO; GO:0008289; F:lipid binding; IDA:BHF-UCL.
DR GO; GO:0070892; F:lipoteichoic acid receptor activity; IEA:Ensembl.
DR GO; GO:0030169; F:low-density lipoprotein particle binding; IDA:BHF-UCL.
DR GO; GO:0005041; F:low-density lipoprotein receptor activity; IMP:BHF-UCL.
DR GO; GO:0070053; F:thrombospondin receptor activity; ISS:BHF-UCL.
DR GO; GO:0050431; F:transforming growth factor beta binding; ISS:BHF-UCL.
DR GO; GO:0002479; P:antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent; TAS:Reactome.
DR GO; GO:0043277; P:apoptotic cell clearance; IEA:Ensembl.
DR GO; GO:0007155; P:cell adhesion; TAS:ProtInc.
DR GO; GO:0007166; P:cell surface receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0044255; P:cellular lipid metabolic process; TAS:Reactome.
DR GO; GO:0071221; P:cellular response to bacterial lipopeptide; IEA:Ensembl.
DR GO; GO:0071447; P:cellular response to hydroperoxide; IEA:Ensembl.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
DR GO; GO:0019934; P:cGMP-mediated signaling; IDA:BHF-UCL.
DR GO; GO:0030301; P:cholesterol transport; ISS:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0019915; P:lipid storage; IMP:BHF-UCL.
DR GO; GO:0042953; P:lipoprotein transport; IMP:BHF-UCL.
DR GO; GO:0044539; P:long-chain fatty acid import; IDA:UniProtKB.
DR GO; GO:0034383; P:low-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0055096; P:low-density lipoprotein particle mediated signaling; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0044130; P:negative regulation of growth of symbiont in host; IEA:Ensembl.
DR GO; GO:0042992; P:negative regulation of transcription factor import into nucleus; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IDA:BHF-UCL.
DR GO; GO:0006910; P:phagocytosis, recognition; IEA:Ensembl.
DR GO; GO:0015911; P:plasma membrane long-chain fatty acid transport; IDA:BHF-UCL.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0030194; P:positive regulation of blood coagulation; IEA:Ensembl.
DR GO; GO:2000334; P:positive regulation of blood microparticle formation; IEA:Ensembl.
DR GO; GO:0001954; P:positive regulation of cell-matrix adhesion; IDA:BHF-UCL.
DR GO; GO:0010886; P:positive regulation of cholesterol storage; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEA:Ensembl.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
DR GO; GO:0010744; P:positive regulation of macrophage derived foam cell differentiation; IMP:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IEA:Ensembl.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IEA:Ensembl.
DR GO; GO:0060100; P:positive regulation of phagocytosis, engulfment; IEA:Ensembl.
DR GO; GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:2000121; P:regulation of removal of superoxide radicals; IEA:Ensembl.
DR GO; GO:0035634; P:response to stilbenoid; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR InterPro; IPR002159; CD36.
DR InterPro; IPR005428; CD36_antigen.
DR PANTHER; PTHR11923; PTHR11923; 1.
DR Pfam; PF01130; CD36; 1.
DR PRINTS; PR01610; CD36ANTIGEN.
DR PRINTS; PR01609; CD36FAMILY.
PE 1: Evidence at protein level;
KW Cell adhesion; Complete proteome; Direct protein sequencing;
KW Disease mutation; Disulfide bond; Glycoprotein; Lipoprotein; Membrane;
KW Palmitate; Polymorphism; Receptor; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 472 Platelet glycoprotein 4.
FT /FTId=PRO_0000144151.
FT TOPO_DOM 2 7 Cytoplasmic (Potential).
FT TRANSMEM 8 29 Helical; (Potential).
FT TOPO_DOM 30 439 Extracellular (Potential).
FT TRANSMEM 440 461 Helical; (Potential).
FT TOPO_DOM 462 472 Cytoplasmic (Potential).
FT REGION 93 120 Required for interaction with
FT thrombospondins, THBS1 and THBS2.
FT LIPID 3 3 S-palmitoyl cysteine.
FT LIPID 7 7 S-palmitoyl cysteine.
FT LIPID 464 464 S-palmitoyl cysteine.
FT LIPID 466 466 S-palmitoyl cysteine.
FT CARBOHYD 79 79 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 102 102 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 134 134 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 163 163 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 205 205 N-linked (GlcNAc...).
FT CARBOHYD 220 220 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 235 235 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 247 247 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 321 321 N-linked (GlcNAc...).
FT CARBOHYD 417 417 N-linked (GlcNAc...).
FT DISULFID 243 311 By similarity.
FT DISULFID 272 333 By similarity.
FT DISULFID 313 322 By similarity.
FT VARIANT 90 90 P -> S (in PG4D; type I; degradation in
FT the cytoplasm due to defects in
FT maturation; dbSNP:rs3765187).
FT /FTId=VAR_017913.
FT VARIANT 123 123 E -> K (in individuals from a malaria
FT endemic area in West Africa;
FT dbSNP:rs183461468).
FT /FTId=VAR_017914.
FT VARIANT 127 127 S -> L (in dbSNP:rs201765331).
FT /FTId=VAR_019049.
FT VARIANT 154 154 V -> F (in dbSNP:rs5957).
FT /FTId=VAR_013918.
FT VARIANT 174 174 T -> A (in individuals from a malaria
FT endemic area in West Africa).
FT /FTId=VAR_017915.
FT VARIANT 232 232 G -> GN (in individuals from a malaria
FT endemic area in West Africa).
FT /FTId=VAR_017916.
FT VARIANT 254 254 F -> L (in PG4D; type I;
FT dbSNP:rs142186404).
FT /FTId=VAR_017917.
FT VARIANT 271 271 I -> T (in individuals from a malaria
FT endemic area in West Africa).
FT /FTId=VAR_017918.
FT VARIANT 413 413 I -> L (in PG4D; type I).
FT /FTId=VAR_017919.
FT CONFLICT 44 44 L -> R (in Ref. 4; AAD13993).
FT CONFLICT 238 238 Y -> D (in Ref. 4; AAD13993).
FT CONFLICT 374 374 E -> Q (in Ref. 3; AAA16068 and 11; AA
FT sequence).
SQ SEQUENCE 472 AA; 53053 MW; 543E748259A094FA CRC64;
MGCDRNCGLI AGAVIGAVLA VFGGILMPVG DLLIQKTIKK QVVLEEGTIA FKNWVKTGTE
VYRQFWIFDV QNPQEVMMNS SNIQVKQRGP YTYRVRFLAK ENVTQDAEDN TVSFLQPNGA
IFEPSLSVGT EADNFTVLNL AVAAASHIYQ NQFVQMILNS LINKSKSSMF QVRTLRELLW
GYRDPFLSLV PYPVTTTVGL FYPYNNTADG VYKVFNGKDN ISKVAIIDTY KGKRNLSYWE
SHCDMINGTD AASFPPFVEK SQVLQFFSSD ICRSIYAVFE SDVNLKGIPV YRFVLPSKAF
ASPVENPDNY CFCTEKIISK NCTSYGVLDI SKCKEGRPVY ISLPHFLYAS PDVSEPIDGL
NPNEEEHRTY LDIEPITGFT LQFAKRLQVN LLVKPSEKIQ VLKNLKRNYI VPILWLNETG
TIGDEKANMF RSQVTGKINL LGLIEMILLS VGVVMFVAFM ISYCACRSKT IK
//

MIM 173510
*RECORD*
*FIELD* NO
173510
*FIELD* TI
*173510 CD36 ANTIGEN; CD36
;;LEUKOCYTE DIFFERENTIATION ANTIGEN CD36;;
PLATELET GLYCOPROTEIN IV; GP4;;
read moreGLYCOPROTEIN IIIb; GP3B;;
GP IIIb;;
THROMBOSPONDIN RECEPTOR;;
COLLAGEN RECEPTOR, PLATELET;;
FATTY ACID TRANSLOCASE; FAT
*FIELD* TX

DESCRIPTION

Platelet glycoprotein IV, alternatively known as GP IIIb, is
immunologically related to the leukocyte differentiation antigen CD36.
It is the fourth major glycoprotein of the platelet surface and serves
as a receptor for thrombospondin (188060) in platelets and various cell
lines. Since thrombospondins are widely distributed proteins involved in
a variety of adhesive processes, GP IV may have important functions as a
cell adhesion molecule. Other platelet glycoproteins include GP Ib
(606672), the platelet receptor for thrombin (176930) and von Willebrand
factor (231200), and the complex of GP IIb (607759) and GP IIIa
(173470), the platelet-binding site for fibrinogen and fibronectin
(134820) (see review by Greenwalt et al., 1992).

CLONING

Tandon et al. (1989) isolated and characterized the platelet GP IV
protein. Oquendo et al. (1989) reported sequencing of the CD36 cDNA
which encodes a deduced 472-amino acid protein.

GENE STRUCTURE

Armesilla and Vega (1994) demonstrated that the CD36 gene contains 15
exons and spans more than 32 kb.

MAPPING

Fernandez-Ruiz et al. (1993) mapped the human CD36 gene to chromosome
7q11.2 by fluorescence in situ hybridization.

GENE FUNCTION

Tandon et al. (1989) demonstrated that GP IV is the primary receptor for
adhesion of platelets to collagen. (See 120340 for another type of
receptor involved in cell adhesion to collagen.)

Oquendo et al. (1989) found that expression of a CD36 cDNA clone in COS
cells supported cytoadherence of erythrocytes parasitized by Plasmodium
falciparum. Van Schravendijk et al. (1992) showed that normal human
erythrocytes express CD36; thus, this adhesion molecule may have a
biologic role in normal individuals as well as in the pathology of
falciparum malaria (see 611162).

Tomiyama et al. (1990) demonstrated that the platelet-specific
alloantigen Nak(a) is carried on GP IV, and noted that antibodies
against GP IV may play an important role in refractoriness to platelet
transfusions. Savill et al. (1992) found that CD36, using thrombospondin
as a molecular bridge with ITGAV (193210), mediates macrophage
scavenging of senescent polymorphonuclear cells undergoing apoptosis.

Endemann et al. (1993) demonstrated that CD36 is a physiologic receptor
for oxidized low density lipoprotein (LDL). Transfection of a CD36 clone
into human kidney cells resulted in specific and high affinity binding
of oxidized LDL, followed by its internalization and degradation. Nozaki
et al. (1995) found that macrophages derived from patients with CD36
deficiency (608404) showed a 40% decrease in binding and uptake of
oxidized LDL.

Griffin et al. (2001) reported a glucose-mediated increase in CD36 mRNA
translation efficiency that resulted in increased expression of CD36,
and proposed that a link between diabetes and atherosclerosis may be
indicated by the findings. Expression of CD36 was increased in
endarterectomy lesions from patients with a history of hyperglycemia.
Macrophages that were differentiated from human peripheral blood
monocytes in the presence of high glucose concentrations showed
increased expression of cell surface CD36 secondary to an increase in
translational efficiency of CD36 mRNA. They obtained similar data from
primary cells isolated from human vascular lesions. They concluded that
increased translation of macrophage CD36 transcripts under high glucose
conditions provides a mechanism for accelerated atherosclerosis in
diabetics.

Hoebe et al. (2005) showed in mice that an N-ethyl-N-nitrosourea-induced
nonsense mutation in Cd36 (173510) causes a recessive immunodeficiency
phenotype (oblivious) in which macrophages are insensitive to the
R-enantiomer of MALP2 (a diacylated bacterial lipopeptide) and to
lipoteichoic acid (LTA). Both MALP2 and LTA are Tlr 2/6-dependent
microbial stimuli. Homozygous mice are hypersusceptible to
Staphylococcus aureus infection. Cd36(oblivious) macrophages readily
detect S-MALP2, synthetic acylated lipopeptides, and zymosan, revealing
that some, but not all, TLR2 ligands are dependent on CD36. The results
showed that CD36 is a selective and nonredundant sensor of microbial
diacylglycerides that signal through the TLR2/6 heterodimer.

Using a genomewide RNA interference screen in Drosophila macrophage-like
cells using Mycobacterium fortuitum, Philips et al. (2005) identified
factors required for general phagocytosis, as well as those needed
specifically for mycobacterial infection. One specific factor, Peste
(Pes), is a CD36 family member required for uptake of mycobacteria, but
not E. coli or S. aureus. Moreover, mammalian class B scavenger
receptors (SRs) conferred uptake of bacteria into nonphagocytic cells,
with SR-B1 (601040) and SR-BII (602257) uniquely mediating uptake of M.
fortuitum, which suggests a conserved role for class B SRs in pattern
recognition and innate immunity.

Using multiple mouse in vivo thrombosis models, Podrez et al. (2007)
demonstrated that genetic deletion of Cd36 protects mice from
hyperlipidemia-associated enhanced platelet reactivity and the
accompanying prothrombotic phenotype. Structurally defined oxidized
choline glycerophospholipids that serve as high-affinity ligands for
CD36 were at markedly increased levels in the plasma of hyperlipidemic
mice and in the plasma of humans with low HDL levels, were able to bind
platelets via CD36 and, at pathophysiologic levels, promoted platelet
activation via CD36. Thus, Podrez et al. (2007) concluded that
interactions of platelet CD36 with specific endogenous oxidized lipids
play a crucial role in the well-known clinical associations between
dyslipidemia, oxidant stress, and a prothrombotic phenotype.

Means et al. (2009) showed that the scavenger receptors Scarf1 (607873)
and Cd36 mediated mouse defense against 2 fungal pathogens, Cryptococcus
neoformans and Candida albicans, by enabling production of antimicrobial
peptides. Studies in C. elegans indicated that the homologous proteins
protected nematodes. Macrophage binding and cytokine production required
Cd36, but not Tlr2 (603028), and binding was dependent on recognition of
pathogen beta-glucans. Mice lacking Cd36, but expressing other
beta-glucan receptors (e.g., CLEC7A; 606264), had a higher fungal burden
and greater mortality after intravenous infection with C. neoformans
compared with wildtype mice. Means et al. (2009) concluded that SCARF1
and CD36 are beta-glucan-binding receptors and are involved in an
evolutionarily conserved pathway for the innate sensing of fungal
pathogens.

BIOCHEMICAL FEATURES

- Crystal Structure

Neculai et al. (2013) determined the crystal structure of LIMP2 (602257)
and inferred, by homology modeling, the structure of SRBI (601040) and
CD36. LIMP2 shows a helical bundle where beta-glucocerebrosidase (GBA;
606463) binds, and where ligands are most likely to bind to SRBI and
CD36. Remarkably, the crystal structure also shows the existence of a
large cavity that traverses the entire length of the molecule.
Mutagenesis of SRBI indicates that the cavity serves as a tunnel through
which cholesterol(esters) are delivered from the bound lipoprotein to
the outer leaflet of the plasma membrane. Neculai et al. (2013) provided
evidence supporting a model whereby lipidic constituents of the ligands
attached to the receptor surface are handed off to the membrane through
the tunnel, accounting for the selective lipid transfer characteristic
of SRBI and CD36.

MOLECULAR GENETICS

In platelets from 4 of 5 Japanese patients with type II platelet
glycoprotein IV deficiency (608404), Kashiwagi et al. (1993) identified
a mutation in the CD36 gene (P90S; 173510.0001). In 2 patients with type
II CD36 deficiency, Kashiwagi et al. (1995) identified the P90S mutation
in both platelets and monocytes. Among 28 Japanese patients with type I
CD36 deficiency, Kashiwagi et al. (2001) found that the P90S mutation
had a greater than 50% frequency. None of the 4 subjects who possessed
isoantibodies against CD36 had the P90S mutation, suggesting that this
mutation prevents the production of isoantibodies against CD36.

In patients with CD36 deficiency, Hanawa et al. (2002) identified
several splice site mutations in the CD36 gene (see, e.g., 173510.0005).

CD36 is a major receptor for Plasmodium falciparum-infected
erythrocytes. Aitman et al. (2000) identified 2 mutations in the CD36
gene (173510.0002-173510.0003) that were associated with increased
susceptibility to severe cerebral 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. Results of this study suggested that LD mapping has
potential for detecting a disease-associated variant on the basis of
haplotype blocks.

One of the genetic mechanisms that has been found to be at the basis of
the characteristic phenotype of Prader-Willi syndrome (PWS; 176270) is
uniparental maternal disomy upd(15)mat, which results in the absence of
expression of imprinted genes in 15q11-q13, normally expressed from the
paternal allele only. A distinguishing characteristic of this syndrome
is the apparently insatiable hunger that develops as early as 2 years of
age and results in life-threatening obesity if access to food is not
controlled. In order to identify candidate downstream gene pathways
affected in PWS, Horsthemke et al. (2003) performed a genomewide
expression study using fibroblast cell lines derived from a PWS patient
with somatic mosaicism for upd(15)mat. As expected, the mRNA levels of
the paternally expressed SNRPN (182279) and NECDIN (602117) were
strongly reduced in the upd(15)mat cells. Among the genes not mapped to
15q11-q13, CD36 showed the highest change (a greater than 9-fold
reduction with 1 probe set and a greater than 4-fold reduction with a
second probe set).

Webb et al. (2006) undertook a study to confirm the reduced CD36
expression levels in PWS found by Horsthemke et al. (2003) by
investigating blood cells from a large cohort of people with PWS, either
with the common 15q11-q13 deletion or with upd(15)mat. They also
investigated whether any possible change in CD36 expression levels might
be associated with a common characteristic of people with PWS, such as
obesity. This was undertaken by correlation analysis within the PWS
group and by including control groups of people without PWS whose body
mass indices (BMI) ranged from lean to obese. They found that CD36
expression in the non-PWS population was inversely correlated with body
mass index but that this correlation did not hold in PWS. CD36, which
maps to 7q11.2, was the first gene outside the 15q11-q13 region whose
level of expression appeared to be reduced in people with PWS. Low CD36
expression levels in PWS pointed to an abnormal control of lipid and
glucose homeostasis which may explain the insatiable hunger in these
patients.

Love-Gregory et al. (2008) evaluated 36 tag SNPs across CD36 in 2,020
African American individuals from the HyperGEN study and identified 5
SNPs that were associated with increased odds for metabolic syndrome
(see 605552) (p = 0.0027 to 0.03; odds ratio, 1.3 to 1.4). In contrast,
the coding SNP dbSNP rs3211938 (173510.0002) was associated with
protection against the metabolic syndrome, as well as increased HDL
cholesterol and decreased triglycerides. Fifteen additional SNPs were
associated with HDLC (p = 0.0028 to 0.044). Love-Gregory et al. (2008)
concluded that CD36 variants may impact metabolic syndrome-related
pathophysiology and HDL metabolism.

ANIMAL MODEL

The human insulin-resistance syndromes--type II diabetes, obesity,
combined hyperlipidemia, and essential hypertension--are complex
disorders. Determining the genetic basis of such disorders is difficult;
see Reaven (1988), Groop et al. (1989), Reaven et al. (1996), and Aitman
et al. (1997). The spontaneously hypertensive rat (SHR) is insulin
resistant and a model of these human syndromes. Quantitative trait loci
(QTLs) for SHR defects in glucose and fatty acid metabolism,
hypertriglyceridemia, and hypertension map to a single locus on rat
chromosome 4. Aitman et al. (1999) combined use of cDNA microarrays,
congenic mapping, and radiation hybrid mapping to identify a defective
SHR gene, Cd36 (also known as Fat, as it encodes fatty acid
translocase), at the peak of linkage to these QTLs. They found that SHR
Cd36 cDNA contains multiple sequence variants, caused by unequal genomic
recombination of a duplicated ancestral gene. The encoded protein
product was undetectable in SHR adipocyte plasma membrane. Transgenic
mice overexpressing Cd36 had reduced blood lipids. Aitman et al. (1999)
concluded that Cd36 deficiency underlies insulin resistance, defective
fatty acid metabolism, and hypertriglyceridemia in SHR, and may be
important in the pathogenesis of human insulin-resistance syndromes.

Pravenec et al. (1999) developed a congenic rat strain in which the
segment of chromosome 4 with the deletion of Cd36 in the SHR was
replaced by a corresponding segment from the normotensive BN rat. This
replacement induced significant reduction of systolic blood pressure and
ameliorated fructose-induced glucose intolerance, hyperinsulinemia, and
hypertriglyceridemia.

Results that appeared to support an etiologic role of Cd36 in the
spontaneously hypertensive rat had been reported. However, Gotoda et al.
(1999) showed that the Cd36 mutation is absent in the original SHR
strains, maintained since their development in Japan, and questioned the
etiologic relevance of the Cd36 mutation to insulin resistance in SHR.
They emphasized the genetic and phenotypic heterogeneity of SHR that
must be considered when investigating this important animal model.

Pravenec et al. (2001) showed that transgenic expression of Cd36 in the
SHR ameliorates insulin resistance and lowers serum fatty acids. The
results provided direct evidence that Cd36 deficiency can promote
defective insulin action and disordered fatty-acid metabolism in
spontaneous hypertension.

Coburn et al. (2000) found that Cd36-null mice had reduced uptake of 2
iodinated fatty acid analogs in heart, skeletal muscle, and adipose
tissue compared with wildtype mice. Reduced uptake was associated with
decreased incorporation of palmitate into triglycerides and a higher
accumulation of palmitate in diglycerides, which could not be explained
by changes in the specific activities of long-chain acyl-CoA synthetase
(see 604443) and diacylglycerol acyltransferase (DGAT; 604900). These
activities were similar in wildtype and Cd36-null mice. Coburn et al.
(2000) concluded that CD36 facilitates a large fraction of fatty acid
uptake by heart, skeletal muscle, and adipose tissues. Importantly, CD36
deficiency, rather than some other defect, explains the defective
myocardial fatty acid uptake observed in humans.

In Cd36-null mice given a fat bolus by gavage or fed a high-fat diet,
Drover et al. (2005) observed accumulation of neutral lipid in the
proximal intestine, indicating abnormal lipid processing. Using a lymph
fistula model to measure lipid output directly, they obtained evidence
of defective lipoprotein secretion, which suggested an impaired ability
of Cd36-null enterocytes to synthesize triacylglycerols efficiently from
dietary fatty acids in the endoplasmic reticulum. There was also slow
clearance of intestine-derived lipoproteins despite normal lipoprotein
lipase (238600) activity. Drover et al. (2005) concluded that CD36 is
important for both secretion and clearance of intestinal lipoproteins.

Laugerette et al. (2005) observed that CD36 deficiency fully abolished
the preference for long-chain fatty acid-enriched solutions and solid
diet seen in wildtype mice. Furthermore, in rats and wildtype mice with
an esophageal ligation, deposition of unsaturated long-chain fatty acids
onto the tongue led to a rapid and sustained rise in flux and protein
content of pancreatobiliary secretions. Laugerette et al. (2005)
concluded that CD36 is involved in oral long-chain fatty acid detection
and suggested that an alteration in lingual fat perception may be linked
to feeding dysregulation.

Franke-Fayard et al. (2005) reported the use of real-time in vivo
imaging of sequestration of luciferase-expressing rodent malaria
parasites (P. berghei). The studies showed that, in addition to lung,
adipose tissue contributes significantly to sequestration, that Cd36 is
the major receptor for P. berghei, even though orthologs of the surface
variant PfEMP1 in the human P. falciparum malaria parasite are absent in
the rodent parasite, and that cerebral malaria still develops in Cd36
-/- mice in the absence of sequestration. Franke-Fayard et al. (2005)
concluded that sequestration is dissociated from cerebral
malaria-associated pathology, that there are alternative parasite
ligands for CD36, and that real-time in vivo imaging of parasitic
processes is useful in delineating the molecular basis of pathology.

To identify renally expressed genes that influence risk for
hypertension, Pravenec et al. (2008) integrated quantitative trait locus
analysis of the kidney with genomewide correlation analysis of renal
expression profiles and blood pressure in recombinant inbred strains
derived from the SHR rat. This strategy, together with renal
transplantation studies in SHR progenitor, transgenic, and congenic
strains, identified deficient renal expression of Cd36, encoding fatty
acid translocase, as a genetically determined risk factor for
spontaneous hypertension.

*FIELD* AV
.0001
PLATELET GLYCOPROTEIN IV DEFICIENCY
CD36, PRO90SER

In platelets from 4 of 5 Japanese patients with type II platelet
glycoprotein IV deficiency (608404), Kashiwagi et al. (1993)
demonstrated a 478C-T transition in the CD36 gene, resulting in a
pro90-to-ser (P90S) substitution.

In platelets and monocytes from a patient with type I platelet
glycoprotein IV deficiency, Kashiwagi et al. (1995) identified the P90S
mutation. Expression assay using the C478 or T478 form of CD36 cDNA in
transfected cells revealed that there was an 81-kD precursor form of
CD36, and that the maturation of the 81-kD precursor form to the 88-kD
mature form of CD36 was markedly impaired by the substitution. The
mutated precursor form of CD36 was subsequently degraded in the
cytoplasm. These results indicated that the C-T substitution at
nucleotide 478 of the cDNA (which corresponds to nucleotide 12293 in
exon 4 of the genomic sequence) directly leads to CD36 deficiency via
defects in posttranslational modification, and that this substitution is
the major defect underlying CD36 deficiency. Thus, type I individuals
are presumably homozygous for P90S, whereas type II individuals are
heterozygous.

Yanai et al. (2000) found that the CD36 478T allele had a frequency of
3.5% among Japanese control chromosomes.

In 6 patients with type I CD36 deficiency, Hanawa et al. (2002)
identified homozygosity for the P90S mutation. Three additional type I
patients were compound heterozygotes for the P90S mutation and another
CD36 mutation. Clinical features of these patients included ischemic
heart disease, hypertension, and congestive heart failure.

.0002
PLATELET GLYCOPROTEIN IV DEFICIENCY
MALARIA, CEREBRAL, SUSCEPTIBILITY TO, INCLUDED
CD36, T1264G

In 5 African American patients with CD36 deficiency (608404), Aitman et
al. (2000) identified a common 1264T-G transversion in the CD36 gene,
predicted to result in a premature termination codon in exon 10. This
allele accounted for 80% of mutant alleles detected and was present in
9.9% of control U.K. Afro Caribbeans. Among a large population of over
500 individuals with malaria from Gambia and Kenya, the authors found
that the 1264T-G allele was overrepresented in patients with severe
cerebral malaria (611162).

Love-Gregory et al. (2008) demonstrated absence of CD36 expression on
monocytes and platelets from a subject homozygous for the G allele of
dbSNP rs3211938. In an analysis of 2,020 African American individuals,
dbSNP rs3211938 was associated with protection from metabolic syndrome
(p = 0.0012; odds ratio, 0.61), increased high-density lipoprotein (HDL)
cholesterol (p = 0.00018), and decreased triglycerides (p = 0.0059).

.0003
PLATELET GLYCOPROTEIN IV DEFICIENCY
MALARIA, CEREBRAL, SUSCEPTIBILITY TO, INCLUDED
CD36, G1439C, 1-BP DEL, 1444A

Aitman et al. (2000) identified a compound mutation in exon 12 of the
CD36 gene: a 1439G-C transversion, resulting in an ala-to-pro
substitution, and a frameshift deletion at nucleotide 1444. This
mutation was found in the carrier state in 3.7% of control Gambians and
0.3% of healthy U.K. Afro Caribbeans. This allele was overrepresented in
patients with severe cerebral malaria (611162).

.0004
PLATELET GLYCOPROTEIN IV DEFICIENCY
MALARIA, CEREBRAL, RESISTANCE TO, INCLUDED
CD36, IVS3 (TG)12

Omi et al. (2003) found that a (TG)12 repeat in intron 3 of the CD36
gene was strongly associated with reduction in the risk of cerebral
malaria (611162) in Thailand. They showed that this variant is involved
in the nonproduction of the variant CD36 transcript that lacks exons 4
and 5. Exon 5 of the CD36 gene is known to encode the ligand-binding
domain of P. falciparum-infected erythrocytes.

.0005
PLATELET GLYCOPROTEIN IV DEFICIENCY
CD36, 1-BP INS, 1159A

In a patient with type I CD36 deficiency (608404), Hanawa et al. (2002)
identified homozygosity for a 1-bp insertion, 1159A, in the CD36 gene.
Two of her affected children were compound heterozygous for the 1159A
insertion and P90S (173510.0001). The authors suggested that this was a
splice site mutation, as the patients showed shortened RT-PCR products.
Additional studies found no reduction in levels of CD36 mRNA in patients
with the 1159A insertion compared to controls. Hanawa et al. (2002)
noted that Kashiwagi et al. (1996) had reported that the 1159A insertion
led to a marked reduction in the level of CD36 mRNA.

.0006
PLATELET GLYCOPROTEIN IV DEFICIENCY
CD36, PHE253LEU

In a patient with CD36 type I deficiency (608404), Hanawa et al. (2002)
identified a homozygous phe253-to-leu (F253L) change in the CD36 gene.
RT-PCR showed a cryptic splice site of exon 4 and skipping of exon 9.

.0007
PLATELET GLYCOPROTEIN IV DEFICIENCY
CD36, ILE413LEU

In a patient with type I CD36 deficiency (608404), Hanawa et al. (2002)
identified compound heterozygosity for an ile413-to-leu (I413L) change
and the P90S mutation (173510.0001). RT-PCR showed skipping of exon 13.

.0008
CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 7
CD36, HAPLOTYPE, AAGIC

In a population of nondiabetic individuals of Caucasian ancestry, Ma et
al. (2004) found that a common haplotype at the CD36 locus, AAGIC, was
associated with increased fasting levels of free fatty acids and
triglycerides. The haplotype represents the risk alleles of 5
polymorphisms, -33137A-G, -31118A-G (dbSNP rs1761667), 25444G-A,
27645del/ins, and 30294C-G (dbSNP rs1049673). The same haplotype was
associated with increased risk of coronary artery disease (CHD7; 610938)
in 197 type 2 diabetic individuals from the United States. A similar
tendency was observed in a group of 321 type 2 diabetic individuals from
Italy, resulting in an overall relative risk of 1.6 (1.1-2.3, p = 0.015)
in the 2 populations considered together. (In the original publication
by Ma et al. (2004), 2 of the alleles were incorrectly reported (-31118
as G-A and 30294 as C-G); thus, the risk allele was incorrectly reported
as AGGIG.)

*FIELD* SA
Ikeda et al. (1989)
*FIELD* RF
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Gray, J. K.; Curtis, B. R.; McKeigue, P. M.; Kwiatkowski, D.; Greenwood,
B. M.; Snow, R. W.; Hill, A. V.; Scott, J.: Malaria susceptibility
and CD36 mutation. Nature 405: 1015-1016, 2000.

2. Aitman, T. J.; Glazier, A. M.; Wallace, C. A.; Cooper, L. D.; Norsworthy,
P. J.; Wahid, F. N.; Al-Majali, K. M.; Trembling, P. M.; Mann, C.
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V.; Pravenec, M.; Ibrahimi, A.; Abumrad, N. A.; Stanton, L. W.; Scott,
J.: Identification of Cd36 (Fat) as an insulin-resistance gene causing
defective fatty acid and glucose metabolism in hypertensive rats. Nature
Genet. 21: 76-83, 1999.

3. Aitman, T. J.; Godsland, I. F.; Farren, B.; Crook, D.; Wong, H.
J.; Scott, J.: Defects of insulin action on fatty acid and carbohydrate
metabolism in familial combined hyperlipidemia. Arterioscler. Thromb.
Vasc. Biol. 17: 748-754, 1997.

4. Armesilla, A. L.; Vega, M. A.: Structural organization of the
gene for human CD36 glycoprotein. J. Biol. Chem. 269: 18985-18991,
1994.

5. Coburn, C. T.; Knapp, F. F., Jr.; Febbraio, M.; Beets, A. L.; Silverstein,
R. L.; Abumrad, N. A.: Defective uptake and utilization of long chain
fatty acids in muscle and adipose tissues of CD36 knockout mice. J.
Biol. Chem. 275: 32523-32529, 2000.

6. Drover, V. A.; Ajmal, M.; Nassir, F.; Davidson, N. O.; Nauli, A.
M.; Sahoo, D.; Tso, P.; Abumrad, N. A.: CD36 deficiency impairs intestinal
lipid secretion and clearance of chylomicrons from the blood. J.
Clin. Invest. 115: 1290-1297, 2005.

7. Endemann, G.; Stanton, L. W.; Madden, K. S.; Bryant, C. M.; White,
R. T.; Protter, A. A.: CD36 is a receptor for oxidized low density
lipoprotein. J. Biol. Chem. 268: 11811-11816, 1993.

8. Fernandez-Ruiz, E.; Armesilla, A. L.; Sanchez-Madrid, F.; Vega,
M. A.: Gene encoding the collagen type I and thrombospondin receptor
CD36 is located on chromosome 7q11.2. Genomics 17: 759-761, 1993.

9. Franke-Fayard, B.; Janse, C. J.; Cunha-Rodrigues, M.; Ramesar,
J.; Buscher, P.; Que, I.; Lowik, C.; Voshol, P. J.; den Boer, M. A.
M.; van Duinen, S. G.; Febbraio, M.; Mota, M. M.; Waters, A. P.:
Murine malaria parasite sequestration: CD36 is the major receptor,
but cerebral pathology is unlinked to sequestration. Proc. Nat. Acad.
Sci. 102: 11468-11473, 2005.

10. Gotoda, T.; Iizuka, Y.; Kato, N.; Osuga, J.; Bihoreau, M.-T.;
Murakami, T.; Yamori, Y.; Shimano, H.; Ishibashi, S.; Yamada, N.:
Absence of Cd36 mutation in the original spontaneously hypertensive
rats with insulin resistance. (Letter) Nature Genet. 22: 226-228,
1999.

11. Greenwalt, D. E.; Lipsky, R. H.; Ockenhouse, C. F.; Ikeda, H.;
Tandon, N. N.; Jamieson, G. A.: Membrane glycoprotein CD36: a review
of its roles in adherence, signal transduction, and transfusion medicine. Blood 80:
1105-1115, 1992.

12. Griffin, E.; Re, A.; Hamel, N.; Fu, C.; Bush, H.; McCaffrey, T.;
Asch, A. S.: A link between diabetes and atherosclerosis: glucose
regulates expression of CD36 at the level of translation. Nature
Med. 7: 840-846, 2001.

13. Groop, L. C.; Bonadonna, R. C.; DelPrato, S.; Ratheiser, K.; Zyck,
K.; Ferrannini, E.; DeFronzo, R. A.: Glucose and free fatty acid
metabolism in non-insulin-dependent diabetes mellitus: evidence for
multiple sites of insulin resistance. J. Clin. Invest. 84: 205-213,
1989.

14. Hanawa, H.; Watanabe, K.; Nakamura, T.; Ogawa, Y.; Toba, K.; Fuse,
I.; Kodama, M.; Kato, K.; Fuse, K.; Aizawa, Y.: Identification of
cryptic splice site, exon skipping, and novel point mutations in type
I CD36 deficiency. (Letter) J. Med. Genet. 39: 286-291, 2002.

15. Hoebe, K.; Georgel, P.; Rutschmann, S.; Du, X.; Mudd, S.; Crozat,
K.; Sovath, S.; Shamel, L.; Hartung, T.; Zahringer, U.; Beutler, B.
: CD36 is a sensor of diacylglycerides. Nature 433: 523-527, 2005.

16. Horsthemke, B.; Nazlican, H.; Husing, J.; Klein-Hitpass, L.; Claussen,
U.; Michel, S.; Lich, C.; Gillessen-Kaesbach, G.; Buiting, K.: Somatic
mosaicism for maternal uniparental disomy 15 in a girl with Prader-Willi
syndrome: confirmation by cell cloning and identification of candidate
downstream genes. Hum. Molec. Genet. 12: 2723-2732, 2003.

17. Ikeda, H.; Mitani, T.; Ohnuma, M.; Haga, H.; Ohtzuka, S.; Kato,
T.; Nakase, T.; Sekiguchi, S.: A new platelet-specific antigen, Nak(a),
involved in the refractoriness of HLA-matched platelet transfusion. Vox
Sang. 57: 213-217, 1989.

18. Kashiwagi, H.; Honda, S.; Tomiyama, Y.; Mizutani, H.; Take, H.;
Honda, Y.; Kosugi, S.; Kanayama, Y.; Kurata, Y.; Matsuzawa, Y.: A
novel polymorphism in glycoprotein IV (replacement of proline-90 by
serine) predominates in subjects with platelet GPIV deficiency. Thromb.
Haemost. 69: 481-484, 1993.

19. Kashiwagi, H.; Tomiyama, Y.; Honda, S.; Kosugi, S.; Shiraga, M.;
Nagao, N.; Sekiguchi, S.; Kanayama, Y.; Kurata, Y.; Matsuzawa, Y.
: Molecular basis of CD36 deficiency: evidence that a 478-C-to-T substitution
(proline90-to-serine) in CD36 cDNA accounts for CD36 deficiency. J.
Clin. Invest. 95: 1040-1046, 1995.

20. Kashiwagi, H.; Tomiyama, Y.; Nozaki, S.; Honda, S.; Kosugi, S.;
Shiraga, M.; Nakagawa, T.; Nagao, N.; Kanakura, Y.; Kurata, Y.; Matsuzawa,
Y.: A single nucleotide insertion in codon 317 of the CD36 gene leads
to CD36 deficiency. Arterioscler. Thromb. Vasc. Biol. 16: 1026-1032,
1996.

21. Kashiwagi, H.; Tomiyama, Y.; Nozaki, S.; Kiyoi, T.; Tadokoro,
S.; Matsumoto, K.; Honda, S.; Kosugi, S.; Kurata, Y.; Matsuzawa, Y.
: Analyses of genetic abnormalities in type I CD36 deficiency in Japan:
identification and cell biological characterization of two novel mutations
that cause CD36 deficiency in man. Hum. Genet. 108: 459-466, 2001.

22. Laugerette, F.; Passilly-Degrace, P.; Patris, B.; Niot, I.; Febbraio,
M.; Montmayeur, J.-P.; Besnard, P.: CD36 involvement in orosensory
detection of dietary lipids, spontaneous fat preference, and digestive
secretions. J. Clin. Invest. 115: 3177-3184, 2005.

23. Love-Gregory, L.; Sherva, R.; Sun, L.; Wasson, J.; Schappe, T.;
Doria, A.; Rao, D. C.; Hunt, S. C.; Klein, S.; Neuman, R. J.; Permutt,
M. A.; Abumrad, N. A.: Variants in the CD36 gene associate with the
metabolic syndrome and high-density lipoprotein cholesterol. Hum.
Molec. Genet. 17: 1695-1704, 2008.

24. Ma, X.; Bacci, S.; Mlynarski, W.; Gottardo, L.; Soccio, T.; Menzaghi,
C.; Iori, E.; Lager, R. A.; Shroff, A. R.; Gervino, E. V.; Nesto,
R. W.; Johnstone, M. T.; Abumrad, N. A.; Avogaro, A.; Trischitta,
V.; Doria, A.: A common haplotype at the CD36 locus is associated
with high free fatty acid levels and increased cardiovascular risk
in Caucasians. Hum. Molec. Genet. 13: 2197-2205, 2004. Note: Erratum:
Hum. Molec. Genet. 14: 3973 only, 2005.

25. Means, T. K.; Mylonakis, E.; Tampakakis, E.; Colvin, R. A.; Seung,
E.; Puckett, L.; Tai, M. F.; Stewart, C. R.; Pukkila-Worley, R.; Hickman,
S. E.; Moore, K. J.; Calderwood, S. B.; Hacohen, N.; Luster, A. D.;
El Khoury, J.: Evolutionarily conserved recognition and innate immunity
to fungal pathogens by the scavenger receptors SCARF1 and CD36. J.
Exp. Med. 206: 637-653, 2009.

26. Neculai, D.; Schwake, M.; Ravichandran, M.; Zunke, F.; Collins,
R. F.; Peters, J.; Neculai, M.; Plumb, J.; Loppnau, P.; Pizarro, J.
C.; Seitova, A.; Trimble, W. S.; Saftig, P.; Grinstein, S.; Dhe-Paganon,
S. Structure of LIMP-2 provides functional insights with implications
for SR-BI and CD36. Nature 504: 172-176, 2013.

27. Nozaki, S.; Kashiwagi, H.; Yamashita, S.; Nakagawa, T.; Kostner,
B.; Tomiyama, Y.; Nakata, A.; Ishigami, M.; Miyagawa, J.; Kameda-Takemura,
K.; Kurata, Y.; Matsuzawa, Y.: Reduced uptake of oxidized low density
lipoproteins in monocyte-derived macrophages from CD36-deficient subjects. J.
Clin. Invest. 96: 1859-1865, 1995.

28. Omi, K.; Ohashi, J.; Patarapotikul, J.; Hananantachai, H.; Naka,
I.; Looareesuwan, S.; Tokunaga, K.: CD36 polymorphism is associated
with protection from cerebral malaria. Am. J. Hum. Genet. 72: 364-374,
2003.

29. Oquendo, P.; Hundt, E.; Lawler, J.; Seed, B.: CD36 directly mediates
cytoadherence of Plasmodium falciparum parasitized erythrocytes. Cell 58:
95-101, 1989.

30. Philips, J. A.; Rubin, E. J.; Perrimon, N.: Drosophila RNAi screen
reveals CD36 family member required for mycobacterial infection. Science 309:
1251-1253, 2005.

31. Podrez, E. A.; Byzova, T. V.; Febbraio, M.; Salomon, R. G.; Ma,
Y.; Valiyaveettil, M.; Poliakov, E.; Sun, M.; Finton, P. J.; Curtis,
B. R.; Chen, J.; Zhang, R.; Silverstein, R. L.; Hazen, S. L.: Platelet
CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nature
Med. 13: 1086-1095, 2007.

32. Pravenec, M.; Churchill, P. C.; Churchill, M. C.; Viklicky, O.;
Kazdova, L.; Aitman, T. J.; Petretto, E.; Hubner, N.; Wallace, C.
A.; Zimdahl, H.; Zidek, V.; Landa, V.; and 9 others: Identification
of renal Cd36 as a determinant of blood pressure and risk for hypertension. Nature
Genet. 40: 952-954, 2008.

33. Pravenec, M.; Landa, V.; Zidek, V.; Musilova, A.; Kren, V.; Kazdova,
L.; Aitman, T. J.; Glazier, A. M.; Ibrahimi, A.; Abumrad, N. A.; Qi,
N.; Wang, J.-M.; St. Lezin, E. M.; Kurtz, T. W.: Transgenic rescue
of defective Cd36 ameliorates insulin resistance in spontaneously
hypertensive rats. Nature Genet. 27: 156-158, 2001.

34. Pravenec, M.; Zidek, V.; Simakova, M.; Kren, V.; Krenova, D.;
Horky, K.; Jachymova, M.; Mikova, B.; Kazdova, L.; Aitman, T. J.;
Churchill, P. C.; Webb, R. C.; Hingarh, N. H.; Yang, Y.; Wang, J.-M.;
St. Lezin, E. M.; Kurtz, T. W.: Genetics of Cd36 and the clustering
of multiple cardiovascular risk factors in spontaneous hypertension. J.
Clin. Invest. 103: 1651-1657, 1999.

35. Reaven, G. M.: Role of insulin resistance in human disease. Diabetes 37:
1595-1607, 1988.

36. Reaven, G. M.; Lithell, H.; Landsberg, L.: Hypertension and associated
metabolic abnormalities: the role of insulin resistance and the sympathoadrenal
system. New Eng. J. Med. 334: 374-381, 1996.

37. Savill, J.; Hogg, N.; Ren, Y.; Haslett, C.: Thrombospondin cooperates
with CD36 and the vitronectin receptor in macrophage recognition of
neutrophils undergoing apoptosis. J. Clin. Invest. 90: 1513-1522,
1992.

38. Tandon, N. N.; Kralisz, U.; Jamieson, G. A.: Identification of
glycoprotein IV (CD36) as a primary receptor for platelet-collagen
adhesion. J. Biol. Chem. 264: 7576-7583, 1989.

39. Tandon, N. N.; Lipsky, R. H.; Burgess, W. H.; Jamieson, G. A.
: Isolation and characterization of platelet glycoprotein IV (CD36). J.
Biol. Chem. 264: 7570-7575, 1989.

40. Tomiyama, Y.; Take, H.; Ikeda, H.; Mitani, T.; Furubayashi, T.;
Mizutani, H.; Yamamoto, N.; Tandon, N. N.; Sekiguchi, S.; Jamieson,
G. A.; Kurata, Y.; Yonezawa, T.; Tarui, S.: Identification of the
platelet-specific alloantigen, Nak(a), on platelet membrane glycoprotein
IV. Blood 75: 684-687, 1990.

41. van Schravendijk, M. R.; Handunnetti, S. M.; Barnwell, J. W.;
Howard, R. J.: Normal human erythrocytes express CD36, an adhesion
molecule of monocytes, platelets, and endothelial cells. Blood 80:
2105-2114, 1992.

42. Webb, T.; Whittington, J.; Holland, A. J.; Soni, S.; Boer, H.;
Clarke, D.; Horsthemke, B.: CD36 expression and its relationship
with obesity in blood cells from people with and without Prader-Willi
syndrome. Clin. Genet. 69: 26-32, 2006.

43. Yanai, H.; Chiba, H.; Morimoto, M.; Abe, K.; Fujiwara, H.; Fuda,
H.; Hui, S.-P.; Takahashi, Y.; Akita, H.; Jamieson, G. A.; Kobayashi,
K.; Matsuno, K.: Human CD36 deficiency is associated with elevation
in low-density lipoprotein-cholesterol. Am. J. Med. Genet. 93: 299-304,
2000.

*FIELD* CN
Ada Hamosh - updated: 02/05/2014
Paul J. Converse - updated: 11/30/2010
Marla J. F. O'Neill - updated: 8/25/2010
Ada Hamosh - updated: 10/24/2008
Ada Hamosh - updated: 3/26/2008
George E. Tiller - updated: 4/5/2007
Paul J. Converse - updated: 4/20/2006
Victor A. McKusick - updated: 3/7/2006
Marla J. F. O'Neill - updated: 12/16/2005
Cassandra L. Kniffin - updated: 10/10/2005
Ada Hamosh - updated: 9/15/2005
Marla J. F. O'Neill - updated: 5/20/2005
Ada Hamosh - updated: 3/1/2005
Cassandra L. Kniffin - reorganized: 1/22/2004
Cassandra L. Kniffin - updated: 1/22/2004
Victor A. McKusick - updated: 2/27/2003
Victor A. McKusick - updated: 10/9/2001
Victor A. McKusick - updated: 8/20/2001
Victor A. McKusick - updated: 1/26/2001
Paul J. Converse - updated: 1/16/2001
Paul J. Converse - updated: 9/15/2000
Ada Hamosh - updated: 6/29/2000
Victor A. McKusick - updated: 11/18/1999
Wilson H. Y. Lo - updated: 9/1/1999
Victor A. McKusick - updated: 6/23/1999
Victor A. McKusick - updated: 12/22/1998

*FIELD* CD
Victor A. McKusick: 6/6/1989

*FIELD* ED
alopez: 02/05/2014
carol: 4/4/2013
mgross: 12/2/2010
terry: 11/30/2010
wwang: 8/30/2010
terry: 8/25/2010
alopez: 11/6/2008
terry: 10/24/2008
terry: 3/26/2008
mgross: 7/5/2007
carol: 5/14/2007
alopez: 4/18/2007
terry: 4/5/2007
terry: 11/15/2006
mgross: 4/21/2006
terry: 4/20/2006
alopez: 3/13/2006
terry: 3/7/2006
wwang: 12/16/2005
ckniffin: 10/14/2005
carol: 10/12/2005
ckniffin: 10/10/2005
alopez: 9/16/2005
terry: 9/15/2005
wwang: 5/26/2005
wwang: 5/24/2005
terry: 5/20/2005
terry: 3/16/2005
wwang: 3/7/2005
wwang: 3/3/2005
terry: 3/1/2005
wwang: 2/16/2005
terry: 2/10/2005
carol: 1/22/2004
ckniffin: 1/20/2004
ckniffin: 5/15/2003
tkritzer: 2/28/2003
terry: 2/27/2003
carol: 11/13/2001
mcapotos: 10/24/2001
terry: 10/9/2001
carol: 8/24/2001
mcapotos: 8/20/2001
alopez: 1/29/2001
terry: 1/26/2001
mgross: 1/22/2001
terry: 1/16/2001
carol: 1/12/2001
mgross: 9/15/2000
alopez: 6/29/2000
mgross: 12/7/1999
terry: 11/18/1999
carol: 9/1/1999
alopez: 6/29/1999
terry: 6/23/1999
mgross: 3/17/1999
alopez: 1/6/1999
alopez: 12/23/1998
terry: 12/22/1998
alopez: 10/27/1997
terry: 3/19/1997
mark: 4/4/1995
carol: 10/14/1994
carol: 9/22/1993
carol: 9/21/1993
carol: 7/22/1993
carol: 7/6/1993

MIM 248310
*RECORD*
*FIELD* NO
248310
*FIELD* TI
%248310 PLASMODIUM FALCIPARUM BLOOD INFECTION LEVEL
;;PFBI;;
PLASMODIUM FALCIPARUM PARASITEMIA
read more*FIELD* TX
For general information on malaria and the influence of genetic factors
on malaria susceptibility, progression, severity, and resistance, see
611162.

POPULATION GENETICS

Abel et al. (1992), using methods similar to those they used for
studying the genetic basis of resistance to leprosy (246300) and
schistosomiasis (181460), applied complex segregation analysis to
falciparum malaria. The phenotype studied was parasite density (PD),
which was based on the parasite/leukocyte ratio by counting 500
leukocytes on a Giemsa-stained thick smear. A logarithmic
transformation, based on log(PD + 1), was applied to PD values to allow
for zero counts. In studies of 42 Cameroonian families, Abel et al.
(1992) concluded that there is a recessive major gene controlling the
degree of infection in malaria. They estimated that the deleterious
allele has a frequency of 0.44-0.48, indicating that about 21% of the
population is predisposed to high levels of infection.

MAPPING

Rihet et al. (1998) provided evidence for linkage of the level of blood
infection with Plasmodium falciparum and the chromosome region 5q31-q33,
which contains numerous candidate genes encoding immunologic molecules.
They performed a sib-pair linkage analysis on 153 sibs from 34 families.
The results, obtained by means of a 2-point Haseman-Elston method and a
nonparametric approach, showed linkage of parasitemia to D5S393 (P =
0.002) and D5S658 (P = 0.0004). Multipoint analyses confirmed linkage,
with a peak close to D5S658. The heritability of the locus was 0.48,
according to the 2-point results, and 0.43, according to the multipoint
results; this indicated that its variation accounted for approximately
45% of the variance of blood infection levels and that the locus plays a
central role in the control of parasitemia. Garcia et al. (1998) and
Flori et al. (2003) also found association between P. falciparum blood
infection levels and 5q31-q33.

Hernandez-Valladares et al. (2004) used an F(11) advance intercross line
in a population of mice infected with Plasmodium chabaudi to identify
mouse quantitative trait loci (QTLs) for control of parasitemia on mouse
chromosomes 11 and 18, which carry regions homologous to human 5q31-q33.
They identified a novel QTL for parasitemia control on mouse chromosome
11, linked to marker D11Mit242, and involved in the clearance stages of
the parasites from the bloodstream.

*FIELD* RF
1. Abel, L.; Cot, M.; Mulder, L.; Carnevale, P.; Feingold, J.: Segregation
analysis detects a major gene controlling blood infection levels in
human malaria. Am. J. Hum. Genet. 50: 1308-1317, 1992.

2. Flori, L.; Kumulungui, B.; Aucan, C.; Esnault, C.; Traore, A. S.;
Fumoux, F.; Rihet, P.: Linkage and association between Plasmodium
falciparum blood infection levels and chromosome 5q31-q33. Genes
Immun. 4: 265-268, 2003.

3. Garcia, A.; Marquet, S.; Bucheton, B.; Hillaire, D.; Cot, M.; Fievet,
N.; Dessein, A. J.; Abel, L.: Linkage analysis of blood Plasmodium
falciparum levels: interest of the 5q31-q33 chromosome region. Am.
J. Trop. Med. Hyg. 58: 705-709, 1998.

4. Hernandez-Valladares, M.; Rihet, P.; ole-MoiYoi, O. K.; Iraqi,
F. A.: Mapping of a new quantitative trait locus for resistance to
malaria in mice by a comparative mapping approach with human chromosome
5q31-q33. Immunogenetics 56: 115-117, 2004.

5. Rihet, P.; Traore, Y.; Abel, L.; Aucan, C.; Traore-Leroux, T.;
Fumoux, F.: Malaria in humans: Plasmodium falciparum blood infection
levels are linked to chromosome 5q31-q33. Am. J. Hum. Genet. 63:
498-505, 1998.

*FIELD* CS

Misc:
Malarial infection intensity

Inheritance:
Autosomal recessive

*FIELD* CN
Matthew B. Gross - updated: 07/05/2007
Ada Hamosh - updated: 7/27/2005
Victor A. McKusick - updated: 8/24/2004
George E. Tiller - updated: 12/10/2003
Victor A. McKusick - updated: 11/30/2000
Ada Hamosh - updated: 6/29/2000
Victor A. McKusick - updated: 7/17/1998

*FIELD* CD
Victor A. McKusick: 7/16/1992

*FIELD* ED
mgross: 07/05/2007
alopez: 7/28/2005
terry: 7/27/2005
alopez: 1/7/2005
alopez: 1/6/2005
tkritzer: 9/7/2004
terry: 8/24/2004
carol: 3/17/2004
carol: 1/22/2004
mgross: 12/10/2003
carol: 1/3/2002
mcapotos: 12/12/2000
mcapotos: 12/6/2000
terry: 11/30/2000
alopez: 6/29/2000
terry: 8/5/1998
alopez: 7/17/1998
terry: 7/17/1998
alopez: 7/10/1997
mark: 10/9/1996
mimadm: 3/11/1994
carol: 7/20/1992
carol: 7/16/1992

MIM 608404
*RECORD*
*FIELD* NO
608404
*FIELD* TI
#608404 PLATELET GLYCOPROTEIN IV DEFICIENCY
;;BLEEDING DISORDER, PLATELET-TYPE, 10; BDPLT10;;
read moreCD36 DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because platelet glycoprotein
IV (CD36) deficiency is caused by homozygous or compound heterozygous
mutation in the CD36 antigen gene (173510) on chromosome 7q11.2.

CLINICAL FEATURES

CD36 deficiency can be divided into 2 subgroups (Yamamoto et al., 1994).
The type I phenotype is characterized by platelets and
monocytes/macrophages exhibiting CD36 deficiency; indeed, probably no
cells express CD36. The type II phenotype lacks the surface expression
of CD36 in platelets, but expression in monocytes/macrophages is near
normal.

Yufu et al. (1990) found decreased glycosylation of platelet membrane
glycoprotein IV in a 45-year-old male who had been found to have
macrothrombocytopenia on routine blood examination. He had no history of
hemorrhagic diathesis. Four members of his family, including a son, also
had macrothrombocytopenia without notable bleeding tendency. The
Bernard-Soulier syndrome (231200) is another form of familial
macrothrombocytopenia, which is caused by a defect in platelet
glycoprotein Ib (138720).

In a thrombocytopenic patient with refractoriness to HLA-matched
platelet transfusion, Ikeda et al. (1989) demonstrated a new
platelet-specific antigen, Nak(a); Tomiyama et al. (1990) demonstrated
that the corresponding antibody reacts with GP IV. Yamamoto et al.
(1990) demonstrated that Nak(a)-negative platelets lacked detectable GP
IV. The authors observed that these individuals with deficiency of
platelet GP IV are apparently healthy and suffer no obvious hemostatic
problems, but they are at risk for developing isoantibodies after
infusion of Nak(a)-positive platelets.

Tanaka et al. (1997) stated that up to 40% of Japanese patients with
hereditary hypertrophic cardiomyopathy (192600) have CD36 deficiency.
They also noted that others have reported an increased frequency of CD36
deficiency in Japanese patients with coronary heart disease, as well as
the occurrence of type II diabetes with either insulin resistance or
hypertriglyceridemia, hypertension, and coronary heart disease in
patients with CD36 deficiency.

Yanai et al. (2000) found that 44 Japanese individuals with type II CD36
deficiency had significantly increased serum LDL cholesterol compared to
731 controls. Similar findings were observed for 4 individuals with type
I CD36 deficiency, but the differences were not statistically
significant because of small sample size.

Miyaoka et al. (2001) examined 26 Japanese patients with CD36 deficiency
and found increased levels of plasma triglycerides, fasting plasma
glucose, and high blood pressure. Five patients who underwent glucose
clamp studies were all found to have systemic insulin resistance.
Miyaoka et al. (2001) concluded that CD36 deficiency might be a cause of
human insulin resistance syndrome in the Japanese population.

Yanai et al. (2007) evaluated the aerobic exercise capacity of 12 women
with CD36 deficiency, including 2 with type I and 10 with type II.
Whereas normal controls showed a decrease in serum fatty acid levels
during exercise, fatty acid levels in patients with CD36 deficiency did
not change, indicating decreased fatty acid uptake and utilization.
Patients also showed significantly lower ventilatory threshold compared
to controls. The findings indicated that CD36-mediated fatty acid
oxidation is an important determinant for aerobic exercise capacity in
humans.

POPULATION GENETICS

CD36 deficiency is present in 2 to 3% of Japanese, Thais, and Africans,
but in less than 0.3% of Americans of European descent (Ikeda et al.,
1989; Yamamoto et al., 1990; Kashiwagi et al., 1995; Urwijitaroon et
al., 1995; Curtis and Aster, 1996).

Lee et al. (1999) found that CD36 deficiency is frequent in sub-Saharan
Africans, as it is in Asians, and that development of anti-CD36 can lead
to serious complications in multiply transfused patients, such as those
with sickle cell disease.

Aitman et al. (2000) found that African populations contain an
exceptionally high frequency of mutations in the CD36 gene.
Unexpectedly, these mutations that cause CD36 deficiency
(173510.0002-173510.0003) are associated with susceptibility to severe
cerebral malaria (61162), suggesting that the presence of distinct CD36
mutations in Africans and Asians is due to some selection pressure other
than malaria.

In a study of 790 Japanese individuals, Yanai et al. (2000) determined
that the frequency of type I and type II CD36 deficiency in Japanese was
0.5 and 5.7%, respectively.

Kashiwagi et al. (2001) stated that the incidence of type I and type II
CD36-deficient subjects in Japanese is 0.3% and 4.0%, respectively. Type
I subjects may produce isoantibodies against CD36 during pregnancy or
transfusion, leading to neonatal immune thrombocytopenia, refractoriness
to HLA-matched platelet transfusion, or posttransfusion purpura.

MOLECULAR GENETICS

In platelets from 4 of 5 Japanese patients with type II platelet
glycoprotein IV deficiency, Kashiwagi et al. (1993) identified a
mutation in the CD36 gene (P90S; 173510.0001). In 2 patients with type I
CD36 deficiency, Kashiwagi et al. (1995) identified the P90S mutation in
both platelets and monocytes. Among 28 Japanese patients with type I
CD36 deficiency, Kashiwagi et al. (2001) found that the P90S mutation
had a greater than 50% frequency. None of the 4 subjects who possessed
isoantibodies against CD36 had the P90S mutation, suggesting that this
mutation prevents the production of isoantibodies against CD36.

*FIELD* RF
1. Aitman, T. J.; Cooper, L. D.; Norsworthy, P. J.; Wahid, F. N.;
Gray, J. K.; Curtis, B. R.; McKeigue, P. M.; Kwiatkowski, D.; Greenwood,
B. M.; Snow, R. W.; Hill, A. V.; Scott, J.: Malaria susceptibility
and CD36 mutation. Nature 405: 1015-1016, 2000.

2. Curtis, B. R.; Aster, R. H.: Incidence of the Nak(a)-negative
platelet phenotype in African Americans is similar to that of Asians. Transfusion 36:
331-334, 1996.

3. Ikeda, H.; Mitani, T.; Ohnuma, M.; Haga, H.; Ohtzuka, S.; Kato,
T.; Nakase, T.; Sekiguchi, S.: A new platelet-specific antigen, Nak(a),
involved in the refractoriness of HLA-matched platelet transfusion. Vox
Sang. 57: 213-217, 1989.

4. Kashiwagi, H.; Honda, S.; Tomiyama, Y.; Mizutani, H.; Take, H.;
Honda, Y.; Kosugi, S.; Kanayama, Y.; Kurata, Y.; Matsuzawa, Y.: A
novel polymorphism in glycoprotein IV (replacement of proline-90 by
serine) predominates in subjects with platelet GPIV deficiency. Thromb.
Haemost. 69: 481-484, 1993.

5. Kashiwagi, H.; Tomiyama, Y.; Honda, S.; Kosugi, S.; Shiraga, M.;
Nagao, N.; Sekiguchi, S.; Kanayama, Y.; Kurata, Y.; Matsuzawa, Y.
: Molecular basis of CD36 deficiency: evidence that a 478-C-to-T substitution
(proline90-to-serine) in CD36 cDNA accounts for CD36 deficiency. J.
Clin. Invest. 95: 1040-1046, 1995.

6. Kashiwagi, H.; Tomiyama, Y.; Nozaki, S.; Kiyoi, T.; Tadokoro, S.;
Matsumoto, K.; Honda, S.; Kosugi, S.; Kurata, Y.; Matsuzawa, Y.:
Analyses of genetic abnormalities in type I CD36 deficiency in Japan:
identification and cell biological characterization of two novel mutations
that cause CD36 deficiency in man. Hum. Genet. 108: 459-466, 2001.

7. Lee, K.; Godeau, B.; Fromont, P.; Plonquet, A.; Debili, N.; Bachir,
D.; Reviron, D.; Gourin, J.; Fernandez, E.; Galacteros, F.; Bierling,
P.: CD36 deficiency is frequent and can cause platelet immunization
in Africans. Transfusion 39: 873-879, 1999.

8. Miyaoka, K.; Kuwasako, T.; Hirano, K.; Nozaki, S.; Yamashita, S.;
Matsuzawa, Y.: CD36 deficiency associated with insulin resistance.
(Letter) Lancet 357: 686-687, 2001.

9. Tanaka, T.; Sohmiya, K.; Kawamura, K.: Is CD36 deficiency an etiology
of hereditary hypertrophic cardiomyopathy? J. Molec. Cell. Cardiol. 29:
121-127, 1997.

10. Tomiyama, Y.; Take, H.; Ikeda, H.; Mitani, T.; Furubayashi, T.;
Mizutani, H.; Yamamoto, N.; Tandon, N. N.; Sekiguchi, S.; Jamieson,
G. A.; Kurata, Y.; Yonezawa, T.; Tarui, S.: Identification of the
platelet-specific alloantigen, Nak(a), on platelet membrane glycoprotein
IV. Blood 75: 684-687, 1990.

11. Urwijitaroon, Y.; Barusrux, S.; Romphruk, A.; Puapairoj, C.:
Frequency of human platelet antigens among blood donors in northeastern
Thailand. Transfusion 35: 868-870, 1995.

12. Yamamoto, N.; Akamatsu, N.; Sakuraba, H.; Yamazaki, H.; Tanoue,
K.: Platelet glycoprotein IV (CD36) deficiency is associated with
the absence (type I) or the presence (type II) of glycoprotein IV
on monocytes. Blood 83: 392-397, 1994.

13. Yamamoto, N.; Ikeda, H.; Tandon, N. N.; Herman, J.; Tomiyama,
Y.; Mitani, T.; Sekiguchi, S.; Lipsky, R.; Kralisz, U.; Jamieson,
G. A.: A platelet membrane glycoprotein (GP) deficiency in healthy
blood donors: Nak(a-) platelets lack detectable GPIV (CD36). Blood 76:
1698-1703, 1990.

14. Yanai, H.; Chiba, H.; Morimoto, M.; Abe, K.; Fujiwara, H.; Fuda,
H.; Hui, S.-P.; Takahashi, Y.; Akita, H.; Jamieson, G. A.; Kobayashi,
K.; Matsuno, K.: Human CD36 deficiency is associated with elevation
in low-density lipoprotein-cholesterol. Am. J. Med. Genet. 93: 299-304,
2000.

15. Yanai, H.; Watanabe, I.; Ishii, K.; Morimoto, M.; Fujiwara, H.;
Yoshida, S.; Hui, S.-P.; Matsuno, K.; Chiba, H.: Attenuated aerobic
exercise capacity in CD36 deficiency. J. Med. Genet. 44: 445-447,
2007.

16. Yufu, Y.; Ideguchi, H.; Narishige, T.; Suematsu, E.; Toyoda, K.;
Nishimura, J.; Nawata, H.; Oda, S.: Familial macrothrombocytopenia
associated with decreased glycosylation of platelet membrane glycoprotein
IV. Am. J. Hemat. 33: 271-273, 1990.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEMATOLOGY:
Variable bleeding tendencies;
Thrombocytopenia;
Giant platelets;
No neutrophil inclusions;
Low-to-normal platelet count (45 x 10(9)/l);
Median platelet volume 15.5fl;
Prolonged bleeding time 15-to->30 minutes

MISCELLANEOUS:
Two types of platelet GPIV deficiency - type I, absence GPIV on monocytes
(173510.0005) and type II, presence GPIV on monocytes (173510.0001)

MOLECULAR BASIS:
Caused by mutation in the CD36 antigen gene (CD36, 173510.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 9/8/2011

*FIELD* CD
Kelly A. Przylepa: 3/1/2007

*FIELD* ED
joanna: 12/29/2011
joanna: 12/28/2011
ckniffin: 9/8/2011
joanna: 3/1/2007

*FIELD* CN
Cassandra L. Kniffin - updated: 8/28/2007
Cassandra L. Kniffin - updated: 10/10/2005
Marla J. F. O'Neill - updated: 2/16/2005

*FIELD* CD
Cassandra L. Kniffin: 1/16/2004

*FIELD* ED
carol: 09/13/2011
ckniffin: 9/8/2011
carol: 9/6/2007
ckniffin: 8/28/2007
mgross: 7/5/2007
carol: 10/12/2005
ckniffin: 10/10/2005
wwang: 2/16/2005
carol: 1/22/2004
ckniffin: 1/20/2004

MIM 610938
*RECORD*
*FIELD* NO
610938
*FIELD* TI
#610938 CORONARY HEART DISEASE, SUSCEPTIBILITY TO, 7; CHDS7
*FIELD* TX
A number sign (#) is used with this entry because a common haplotype in
read morethe CD36 gene (173510) is associated with high free fatty acid levels
and increased cardiovascular risk in Caucasians.

For a discussion of genetic heterogeneity of coronary heart disease
(CHD), see 607339.

MOLECULAR GENETICS

Ma et al. (2004) investigated whether genetic variability at CD36 could
be a determinant of free fatty acid plasma levels and risk of coronary
artery disease in Caucasians. Two linkage disequilibrium blocks were
identified that could be tagged by 5 polymorphisms (-33137A-G,
-31118A-G, 25444G-A, 27645del/ins, and 30294C-G; see AAGIC,
173510.0008). Among 585 nondiabetic individuals of Caucasian origin, the
men carrying the AAGIC haplotype (representing the risk alleles of all 5
polymorphisms) had 31% higher free fatty acid (p = 0.0002) and 20%
higher triglycerides (p = 0.025) than noncarriers. The same haplotype
was associated with increased risk of coronary artery disease in 197
type 2 diabetic (125853) individuals from the United States (odds ratio
= 2.3, 95% CI 1.2-4.2). A similar tendency was observed in a group of
321 type 2 diabetic individuals from Italy (odds ratio = 1.4, 0.9-2.3),
resulting in an overall relative risk of 1.6 (1.1-2.3, p = 0.015) in the
2 populations considered together. By targeted resequencing, a common
variant in the CD36 promoter (-22674T-C) was identified that was in
strong linkage disequilibrium with the AAGIC haplotype and could be
partly responsible for these findings. Ma et al. (2004) concluded that
common polymorphisms at CD36 may modulate lipid metabolism and
cardiovascular risk in Caucasians. (In the original publication of Ma et
al. (2004), 2 of the alleles were incorrectly reported (-31118 as G-A
and 30294 as C-G); thus, the risk allele was incorrectly reported as
AGGIG.)

*FIELD* RF
1. Ma, X.; Bacci, S.; Mlynarski, W.; Gottardo, L.; Soccio, T.; Menzaghi,
C.; Iori, E.; Lager, R. A.; Shroff, A. R.; Gervino, E. V.; Nesto,
R. W.; Johnstone, M. T.; Abumrad, N. A.; Avogaro, A.; Trischitta,
V.; Doria, A.: A common haplotype at the CD36 locus is associated
with high free fatty acid levels and increased cardiovascular risk
in Caucasians. Hum. Molec. Genet. 13: 2197-2205, 2004. Note: Erratum:
Hum. Molec. Genet. 13: 3973 only, 2005.

*FIELD* CN
Marla J. F. O'Neill - updated: 10/16/2008

*FIELD* CD
George E. Tiller: 4/18/2007

*FIELD* ED
carol: 03/21/2013
wwang: 10/16/2008
alopez: 6/26/2007
alopez: 4/18/2007

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