RBCC Red Blood Cell Collection

CR1 (C3BR) [Confidence: high (a blood group or CD marker)]
Complement receptor type 1 (C3b/C4b receptor; CD35; Flags: Precursor)

hRBCD IPI00018287
IPI00018287 Complement receptor type 1 precursor Complement receptor type 1 precursor membrane n/a n/a 4 2 4 n/a 2 n/a n/a n/a n/a 2 3 n/a n/a 1 1 n/a n/a n/a Type I membrane protein n/a found at its expected molecular weight found at molecular weight

BGMUT knops
452 knops CR1 CR 1 4014C 4014A>C none exon 22 11313284 Moulds et al. 2006-04-17 20:06:46.773 NA

UniProt P17927
ID CR1_HUMAN Reviewed; 2039 AA.
AC P17927; Q16744; Q16745; Q5SR43; Q5SR45; Q9UQV2;
DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 02-MAR-2010, sequence version 3.
DT 22-JAN-2014, entry version 149.
DE RecName: Full=Complement receptor type 1;
DE AltName: Full=C3b/C4b receptor;
DE AltName: CD_antigen=CD35;
DE Flags: Precursor;
GN Name=CR1; Synonyms=C3BR;
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] (ALLELE S AND ALLELE F).
RX PubMed=2972794; DOI=10.1084/jem.168.5.1699;
RA Klickstein L.B., Bartow T.J., Miletic V., Rabson L.D., Smith J.A.,
RA Fearon D.T.;
RT "Identification of distinct C3b and C4b recognition sites in the human
RT C3b/C4b receptor (CR1, CD35) by deletion mutagenesis.";
RL J. Exp. Med. 168:1699-1717(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ALLELE S AND ALLELE F), AND
RP VARIANTS VAL-1615; ARG-1827; ASP-1850 AND ALA-1969.
RX PubMed=8245463;
RA Vik D.P., Wong W.W.;
RT "Structure of the gene for the F allele of complement receptor type 1
RT and sequence of the coding region unique to the S allele.";
RL J. Immunol. 151:6214-6224(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT THR-1610.
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE OF 1-41.
RX PubMed=2564414; DOI=10.1084/jem.169.3.847;
RA Wong W.W., Cahill J.M., Rosen M.D., Kennedy C.A., Bonaccio E.T.,
RA Morris M.J., Wilson J.G., Klickstein L.B., Fearon D.T.;
RT "Structure of the human CR1 gene. Molecular basis of the structural
RT and quantitative polymorphisms and identification of a new CR1-like
RT allele.";
RL J. Exp. Med. 169:847-863(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 26-584.
RX PubMed=2971757; DOI=10.1084/jem.168.4.1255;
RA Hourcade D., Miesner D.R., Atkinson J.P., Holers V.M.;
RT "Identification of an alternative polyadenylation site in the human
RT C3b/C4b receptor (complement receptor type 1) transcriptional unit and
RT prediction of a secreted form of complement receptor type 1.";
RL J. Exp. Med. 168:1255-1270(1988).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 503-2039, AND VARIANT ALA-1969.
RX PubMed=2951479; DOI=10.1084/jem.165.4.1095;
RA Klickstein L.B., Wong W.W., Smith J.A., Weis J.H., Wilson J.G.,
RA Fearon D.T.;
RT "Human C3b/C4b receptor (CR1). Demonstration of long homologous
RT repeating domains that are composed of the short consensus repeats
RT characteristics of C3/C4 binding proteins.";
RL J. Exp. Med. 165:1095-1112(1987).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 761-783; 831-845 AND 1179-1195.
RX PubMed=2933745; DOI=10.1073/pnas.82.22.7711;
RA Wong W.W., Klickstein L.B., Smith J.A., Weis J.H., Fearon D.T.;
RT "Identification of a partial cDNA clone for the human receptor for
RT complement fragments C3b/C4b.";
RL Proc. Natl. Acad. Sci. U.S.A. 82:7711-7715(1985).
RN [8]
RP POLYMORPHISM.
RX PubMed=8706338; DOI=10.1046/j.1365-2249.1996.d01-748.x;
RA Moulds J.M., Reveille J.D., Arnett F.C.;
RT "Structural polymorphisms of complement receptor 1 (CR1) in systemic
RT lupus erythematosus (SLE) patients and normal controls of three ethnic
RT groups.";
RL Clin. Exp. Immunol. 105:302-305(1996).
RN [9]
RP POLYMORPHISM, AND INVOLVEMENT IN PROTECTION AGAINST MALARIA.
RX PubMed=14694201; DOI=10.1073/pnas.0305306101;
RA Cockburn I.A., Mackinnon M.J., O'Donnell A., Allen S.J., Moulds J.M.,
RA Baisor M., Bockarie M., Reeder J.C., Rowe J.A.;
RT "A human complement receptor 1 polymorphism that reduces Plasmodium
RT falciparum rosetting confers protection against severe malaria.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:272-277(2004).
RN [10]
RP VARIANTS ARG-1208; GLU-1590; GLY-1601; THR-1610; VAL-1615; ARG-1827
RP AND ASP-1850.
RX PubMed=11313284; DOI=10.1182/blood.V97.9.2879;
RA Moulds J.M., Zimmerman P.A., Doumbo O.K., Kassambara L., Sagara I.,
RA Diallo D.A., Atkinson J.P., Krych-Goldberg M., Hauhart R.E.,
RA Hourcade D.E., McNamara D.T., Birmingham D.J., Rowe J.A., Moulds J.J.,
RA Miller L.H.;
RT "Molecular identification of Knops blood group polymorphisms found in
RT long homologous region D of complement receptor 1.";
RL Blood 97:2879-2885(2001).
RN [11]
RP VARIANTS SL(2)/VIL GLY-1601 AND SL(3) THR-1610.
RX PubMed=11896343; DOI=10.1046/j.1537-2995.2002.00002.x;
RA Moulds J.M., Zimmerman P.A., Doumbo O.K., Diallo D.A., Atkinson J.P.,
RA Krych-Goldberg M., Hourcade D.E., Moulds J.J.;
RT "Expansion of the Knops blood group system and subdivision of Sl(a).";
RL Transfusion 42:251-256(2002).
RN [12]
RP STRUCTURE BY NMR OF 942-1133.
RX PubMed=11955431; DOI=10.1016/S0092-8674(02)00672-4;
RA Smith B.O., Mallin R.L., Krych-Goldberg M., Wang X., Hauhart R.E.,
RA Bromek K., Uhrin D., Atkinson J.P., Barlow P.N.;
RT "Structure of the C3b binding site of CR1 (CD35), the immune adherence
RT receptor.";
RL Cell 108:769-780(2002).
CC -!- FUNCTION: Mediates cellular binding of particles and immune
CC complexes that have activated complement.
CC -!- SUBUNIT: Monomer.
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- TISSUE SPECIFICITY: Present on erythrocytes, leukocytes,
CC glomerular podocytes, and splenic follicular dendritic cells.
CC -!- POLYMORPHISM: CR1 contains a system of antigens called the Knops
CC blood group system. Polymorphisms within this system are involved
CC in malarial rosetting, a process associated with cerebral malaria,
CC the major cause of mortality in Plasmodium falciparum malaria.
CC Common Knops system antigens include McCoy (McC) and Sl(a)/Vil
CC (Kn4, or Swain-Langley; Vil or Villien). Sl(a-) phenotype is more
CC common in persons of African descent and may protect against fatal
CC malaria.
CC -!- POLYMORPHISM: Other polymorphic forms of CR1 contain 23, 37 or 44
CC Sushi (CCP/SCR) domains instead of the 30 Sushi (CCP/SCR) domains.
CC The most frequent alleles are the F allotype (shown here) and the
CC S allotype (37 repeat Sushi domains). The gene frequencies of the
CC F allotype and S allotype are 0.87 and 0.11 in Caucasians, 0.82
CC and 0.11 in African Americans, 0.89 and 0.11 in Mexicans.
CC -!- POLYMORPHISM: Genetic variations in CR1 resulting in CR1
CC deficiency are involved in protection against severe malaria
CC [MIM:611162]. Parasitized red blood cells (RBCs) from children
CC suffering from severe malaria often adhere to complement receptor
CC 1 (CR1) on uninfected RBCs to form clumps of cells known as
CC rosettes. CR1-deficient red blood cells show greatly reduced
CC rosetting and CR1 deficiency occurs in healthy individuals from
CC malaria-endemic regions.
CC -!- SIMILARITY: Belongs to the receptors of complement activation
CC (RCA) family.
CC -!- SIMILARITY: Contains 30 Sushi (CCP/SCR) domains.
CC -!- WEB RESOURCE: Name=dbRBC/BGMUT; Note=Blood group antigen gene
CC mutation database;
CC URL="http://www.ncbi.nlm.nih.gov/gv/mhc/xslcgi.cgi?cmd=bgmut/systems_info&system;=knops";
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DR EMBL; Y00816; CAA68755.1; -; mRNA.
DR EMBL; L17418; AAB60694.1; -; Genomic_DNA.
DR EMBL; L17390; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17399; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17409; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17419; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17420; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17421; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17422; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17423; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17391; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17392; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17393; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17394; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17395; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17396; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17397; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17398; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17400; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17401; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17402; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17403; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17404; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17405; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17406; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17407; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17408; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17410; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17411; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17412; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17413; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17414; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17415; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17416; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17417; AAB60694.1; JOINED; Genomic_DNA.
DR EMBL; L17418; AAB60695.1; -; Genomic_DNA.
DR EMBL; L17390; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17391; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17392; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17393; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17394; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17395; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17396; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17397; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17398; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17399; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17400; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17401; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17402; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17403; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17404; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17405; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17406; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17407; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17408; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17409; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17410; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17411; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17412; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17413; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17414; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17415; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17416; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17417; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17419; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17420; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17421; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17422; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17423; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17424; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17425; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17426; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17427; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17428; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17429; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; L17430; AAB60695.1; JOINED; Genomic_DNA.
DR EMBL; AL137789; CAI16042.1; -; Genomic_DNA.
DR EMBL; AL691452; CAI16042.1; JOINED; Genomic_DNA.
DR EMBL; AL137789; CAI16043.1; -; Genomic_DNA.
DR EMBL; AL691452; CAI16043.1; JOINED; Genomic_DNA.
DR EMBL; AL691452; CAI16723.1; -; Genomic_DNA.
DR EMBL; AL137789; CAI16723.1; JOINED; Genomic_DNA.
DR EMBL; AL691452; CAI16725.1; -; Genomic_DNA.
DR EMBL; AL137789; CAI16725.1; JOINED; Genomic_DNA.
DR EMBL; X14362; CAA32541.1; -; mRNA.
DR EMBL; X05309; CAA28933.1; -; mRNA.
DR EMBL; M11569; AAA52297.1; -; mRNA.
DR EMBL; M11617; AAA52298.1; -; mRNA.
DR EMBL; M11618; AAA52299.1; -; mRNA.
DR PIR; I73012; I73012.
DR RefSeq; NP_000564.2; NM_000573.3.
DR RefSeq; NP_000642.3; NM_000651.4.
DR UniGene; Hs.334019; -.
DR PDB; 1GKG; NMR; -; A=1002-1133.
DR PDB; 1GKN; NMR; -; A=942-1065.
DR PDB; 1GOP; Model; -; A=942-1133.
DR PDB; 1PPQ; NMR; -; A=1002-1065.
DR PDB; 2MCY; NMR; -; A=102-233.
DR PDB; 2MCZ; NMR; -; A=41-163.
DR PDB; 2Q7Z; X-ray; -; A=42-1972.
DR PDBsum; 1GKG; -.
DR PDBsum; 1GKN; -.
DR PDBsum; 1GOP; -.
DR PDBsum; 1PPQ; -.
DR PDBsum; 2MCY; -.
DR PDBsum; 2MCZ; -.
DR PDBsum; 2Q7Z; -.
DR ProteinModelPortal; P17927; -.
DR SMR; P17927; 42-1961.
DR IntAct; P17927; 7.
DR MINT; MINT-1508305; -.
DR STRING; 9606.ENSP00000356016; -.
DR PhosphoSite; P17927; -.
DR DMDM; 290457678; -.
DR PaxDb; P17927; -.
DR PRIDE; P17927; -.
DR Ensembl; ENST00000367051; ENSP00000356018; ENSG00000203710.
DR Ensembl; ENST00000367053; ENSP00000356020; ENSG00000203710.
DR Ensembl; ENST00000400960; ENSP00000383744; ENSG00000203710.
DR GeneID; 1378; -.
DR KEGG; hsa:1378; -.
DR UCSC; uc001hfy.3; human.
DR CTD; 1378; -.
DR GeneCards; GC01P207669; -.
DR HGNC; HGNC:2334; CR1.
DR HPA; CAB002491; -.
DR HPA; CAB016271; -.
DR HPA; HPA042455; -.
DR HPA; HPA043579; -.
DR HPA; HPA049348; -.
DR MIM; 120620; gene.
DR MIM; 607486; phenotype.
DR MIM; 611162; phenotype.
DR neXtProt; NX_P17927; -.
DR Orphanet; 536; Systemic lupus erythematosus.
DR PharmGKB; PA26855; -.
DR eggNOG; NOG12793; -.
DR HOGENOM; HOG000139590; -.
DR HOVERGEN; HBG005397; -.
DR KO; K04011; -.
DR Reactome; REACT_6900; Immune System.
DR EvolutionaryTrace; P17927; -.
DR GeneWiki; Complement_receptor_1; -.
DR GenomeRNAi; 1378; -.
DR NextBio; 5589; -.
DR PRO; PR:P17927; -.
DR ArrayExpress; P17927; -.
DR Bgee; P17927; -.
DR CleanEx; HS_CR1; -.
DR Genevestigator; P17927; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:UniProtKB.
DR GO; GO:0001851; F:complement component C3b binding; IDA:UniProtKB.
DR GO; GO:0004877; F:complement component C3b receptor activity; IDA:UniProtKB.
DR GO; GO:0001855; F:complement component C4b binding; IDA:UniProtKB.
DR GO; GO:0001861; F:complement component C4b receptor activity; IDA:UniProtKB.
DR GO; GO:0006958; P:complement activation, classical pathway; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0045957; P:negative regulation of complement activation, alternative pathway; IDA:UniProtKB.
DR GO; GO:0045959; P:negative regulation of complement activation, classical pathway; IDA:UniProtKB.
DR GO; GO:1900004; P:negative regulation of serine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:1900005; P:positive regulation of serine-type endopeptidase activity; IDA:UniProtKB.
DR InterPro; IPR000436; Sushi_SCR_CCP.
DR Pfam; PF00084; Sushi; 30.
DR SMART; SM00032; CCP; 30.
DR SUPFAM; SSF57535; SSF57535; 30.
DR PROSITE; PS50923; SUSHI; 30.
PE 1: Evidence at protein level;
KW 3D-structure; Blood group antigen; Complement pathway;
KW Complete proteome; Disulfide bond; Glycoprotein; Immunity;
KW Innate immunity; Membrane; Polymorphism; Pyrrolidone carboxylic acid;
KW Receptor; Reference proteome; Repeat; Signal; Sushi; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 41
FT CHAIN 42 2039 Complement receptor type 1.
FT /FTId=PRO_0000006009.
FT TOPO_DOM 42 1971 Extracellular (Potential).
FT TRANSMEM 1972 1996 Helical; (Potential).
FT TOPO_DOM 1997 2039 Cytoplasmic (Potential).
FT DOMAIN 42 101 Sushi 1.
FT DOMAIN 102 163 Sushi 2.
FT DOMAIN 164 234 Sushi 3.
FT DOMAIN 236 295 Sushi 4.
FT DOMAIN 295 355 Sushi 5.
FT DOMAIN 356 418 Sushi 6.
FT DOMAIN 419 489 Sushi 7.
FT DOMAIN 491 551 Sushi 8.
FT DOMAIN 552 613 Sushi 9.
FT DOMAIN 614 684 Sushi 10.
FT DOMAIN 686 745 Sushi 11.
FT DOMAIN 745 805 Sushi 12.
FT DOMAIN 806 868 Sushi 13.
FT DOMAIN 869 939 Sushi 14.
FT DOMAIN 941 1001 Sushi 15.
FT DOMAIN 1002 1063 Sushi 16.
FT DOMAIN 1064 1134 Sushi 17.
FT DOMAIN 1136 1195 Sushi 18.
FT DOMAIN 1195 1255 Sushi 19.
FT DOMAIN 1256 1318 Sushi 20.
FT DOMAIN 1319 1389 Sushi 21.
FT DOMAIN 1394 1454 Sushi 22.
FT DOMAIN 1455 1516 Sushi 23.
FT DOMAIN 1517 1587 Sushi 24.
FT DOMAIN 1589 1648 Sushi 25.
FT DOMAIN 1648 1708 Sushi 26.
FT DOMAIN 1709 1771 Sushi 27.
FT DOMAIN 1772 1842 Sushi 28.
FT DOMAIN 1846 1906 Sushi 29.
FT DOMAIN 1907 1967 Sushi 30.
FT MOD_RES 42 42 Pyrrolidone carboxylic acid (Potential).
FT CARBOHYD 56 56 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 252 252 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 410 410 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 447 447 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 509 509 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 578 578 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 702 702 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 860 860 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 897 897 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 959 959 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1028 1028 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1152 1152 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1310 1310 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1481 1481 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1504 1504 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1534 1534 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1540 1540 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1605 1605 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1763 1763 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 1908 1908 N-linked (GlcNAc...) (Potential).
FT DISULFID 43 86 By similarity.
FT DISULFID 73 99 By similarity.
FT DISULFID 104 145 By similarity.
FT DISULFID 131 161 By similarity.
FT DISULFID 166 215 By similarity.
FT DISULFID 195 232 By similarity.
FT DISULFID 238 280 By similarity.
FT DISULFID 266 293 By similarity.
FT DISULFID 297 340 By similarity.
FT DISULFID 326 353 By similarity.
FT DISULFID 358 400 By similarity.
FT DISULFID 386 416 By similarity.
FT DISULFID 421 470 By similarity.
FT DISULFID 450 487 By similarity.
FT DISULFID 493 536 By similarity.
FT DISULFID 523 549 By similarity.
FT DISULFID 554 595 By similarity.
FT DISULFID 581 611 By similarity.
FT DISULFID 616 665 By similarity.
FT DISULFID 645 682 By similarity.
FT DISULFID 688 730 By similarity.
FT DISULFID 716 743 By similarity.
FT DISULFID 747 790 By similarity.
FT DISULFID 776 803 By similarity.
FT DISULFID 808 850 By similarity.
FT DISULFID 836 866 By similarity.
FT DISULFID 871 920 By similarity.
FT DISULFID 900 937 By similarity.
FT DISULFID 943 986 By similarity.
FT DISULFID 973 999 By similarity.
FT DISULFID 1004 1045
FT DISULFID 1031 1061
FT DISULFID 1066 1115
FT DISULFID 1095 1132
FT DISULFID 1138 1180 By similarity.
FT DISULFID 1166 1193 By similarity.
FT DISULFID 1197 1240 By similarity.
FT DISULFID 1226 1253 By similarity.
FT DISULFID 1258 1300 By similarity.
FT DISULFID 1286 1316 By similarity.
FT DISULFID 1321 1370 By similarity.
FT DISULFID 1350 1387 By similarity.
FT DISULFID 1396 1439 By similarity.
FT DISULFID 1426 1452 By similarity.
FT DISULFID 1457 1498 By similarity.
FT DISULFID 1484 1514 By similarity.
FT DISULFID 1519 1568 By similarity.
FT DISULFID 1548 1585 By similarity.
FT DISULFID 1591 1633 By similarity.
FT DISULFID 1619 1646 By similarity.
FT DISULFID 1650 1693 By similarity.
FT DISULFID 1679 1706 By similarity.
FT DISULFID 1711 1753 By similarity.
FT DISULFID 1739 1769 By similarity.
FT DISULFID 1774 1823 By similarity.
FT DISULFID 1803 1840 By similarity.
FT DISULFID 1848 1891 By similarity.
FT DISULFID 1877 1904 By similarity.
FT DISULFID 1909 1952 By similarity.
FT DISULFID 1938 1965 By similarity.
FT VARIANT 1208 1208 H -> R (in dbSNP:rs2274567).
FT /FTId=VAR_013819.
FT VARIANT 1408 1408 T -> I.
FT /FTId=VAR_013820.
FT VARIANT 1408 1408 T -> M (in dbSNP:rs3737002).
FT /FTId=VAR_020263.
FT VARIANT 1540 1540 N -> S (in dbSNP:rs17259045).
FT /FTId=VAR_055685.
FT VARIANT 1590 1590 K -> E (in MCC(b) antigen;
FT dbSNP:rs17047660).
FT /FTId=VAR_013821.
FT VARIANT 1601 1601 R -> G (in Sl(2)/Vil antigen and Sl(3)
FT antigen; dbSNP:rs17047661).
FT /FTId=VAR_013822.
FT VARIANT 1610 1610 S -> T (in Sl(3) antigen;
FT dbSNP:rs4844609).
FT /FTId=VAR_013823.
FT VARIANT 1615 1615 I -> V (in dbSNP:rs6691117).
FT /FTId=VAR_013824.
FT VARIANT 1827 1827 P -> R (in dbSNP:rs3811381).
FT /FTId=VAR_013825.
FT VARIANT 1850 1850 H -> D.
FT /FTId=VAR_013826.
FT VARIANT 1969 1969 T -> A (in dbSNP:rs2296160).
FT /FTId=VAR_055686.
FT CONFLICT 173 173 T -> A (in Ref. 3; CAI16042/CAI16723).
FT CONFLICT 445 445 T -> A (in Ref. 1; CAA68755, 2; AAB60694
FT and 5; CAA32541).
FT CONFLICT 1876 1876 I -> T (in Ref. 1; CAA68755 and 6;
FT CAA28933).
FT STRAND 950 954
FT STRAND 961 966
FT STRAND 968 973
FT STRAND 977 979
FT STRAND 982 986
FT STRAND 988 990
FT STRAND 1014 1016
FT STRAND 1026 1030
FT STRAND 1033 1037
FT STRAND 1041 1047
FT STRAND 1049 1056
FT STRAND 1061 1063
FT STRAND 1090 1093
FT STRAND 1107 1109
FT STRAND 1112 1114
FT STRAND 1118 1122
SQ SEQUENCE 2039 AA; 223663 MW; FB01870F19D5E6DD CRC64;
MGASSPRSPE PVGPPAPGLP FCCGGSLLAV VVLLALPVAW GQCNAPEWLP FARPTNLTDE
FEFPIGTYLN YECRPGYSGR PFSIICLKNS VWTGAKDRCR RKSCRNPPDP VNGMVHVIKG
IQFGSQIKYS CTKGYRLIGS SSATCIISGD TVIWDNETPI CDRIPCGLPP TITNGDFIST
NRENFHYGSV VTYRCNPGSG GRKVFELVGE PSIYCTSNDD QVGIWSGPAP QCIIPNKCTP
PNVENGILVS DNRSLFSLNE VVEFRCQPGF VMKGPRRVKC QALNKWEPEL PSCSRVCQPP
PDVLHAERTQ RDKDNFSPGQ EVFYSCEPGY DLRGAASMRC TPQGDWSPAA PTCEVKSCDD
FMGQLLNGRV LFPVNLQLGA KVDFVCDEGF QLKGSSASYC VLAGMESLWN SSVPVCEQIF
CPSPPVIPNG RHTGKPLEVF PFGKTVNYTC DPHPDRGTSF DLIGESTIRC TSDPQGNGVW
SSPAPRCGIL GHCQAPDHFL FAKLKTQTNA SDFPIGTSLK YECRPEYYGR PFSITCLDNL
VWSSPKDVCK RKSCKTPPDP VNGMVHVITD IQVGSRINYS CTTGHRLIGH SSAECILSGN
AAHWSTKPPI CQRIPCGLPP TIANGDFIST NRENFHYGSV VTYRCNPGSG GRKVFELVGE
PSIYCTSNDD QVGIWSGPAP QCIIPNKCTP PNVENGILVS DNRSLFSLNE VVEFRCQPGF
VMKGPRRVKC QALNKWEPEL PSCSRVCQPP PDVLHAERTQ RDKDNFSPGQ EVFYSCEPGY
DLRGAASMRC TPQGDWSPAA PTCEVKSCDD FMGQLLNGRV LFPVNLQLGA KVDFVCDEGF
QLKGSSASYC VLAGMESLWN SSVPVCEQIF CPSPPVIPNG RHTGKPLEVF PFGKAVNYTC
DPHPDRGTSF DLIGESTIRC TSDPQGNGVW SSPAPRCGIL GHCQAPDHFL FAKLKTQTNA
SDFPIGTSLK YECRPEYYGR PFSITCLDNL VWSSPKDVCK RKSCKTPPDP VNGMVHVITD
IQVGSRINYS CTTGHRLIGH SSAECILSGN TAHWSTKPPI CQRIPCGLPP TIANGDFIST
NRENFHYGSV VTYRCNLGSR GRKVFELVGE PSIYCTSNDD QVGIWSGPAP QCIIPNKCTP
PNVENGILVS DNRSLFSLNE VVEFRCQPGF VMKGPRRVKC QALNKWEPEL PSCSRVCQPP
PEILHGEHTP SHQDNFSPGQ EVFYSCEPGY DLRGAASLHC TPQGDWSPEA PRCAVKSCDD
FLGQLPHGRV LFPLNLQLGA KVSFVCDEGF RLKGSSVSHC VLVGMRSLWN NSVPVCEHIF
CPNPPAILNG RHTGTPSGDI PYGKEISYTC DPHPDRGMTF NLIGESTIRC TSDPHGNGVW
SSPAPRCELS VRAGHCKTPE QFPFASPTIP INDFEFPVGT SLNYECRPGY FGKMFSISCL
ENLVWSSVED NCRRKSCGPP PEPFNGMVHI NTDTQFGSTV NYSCNEGFRL IGSPSTTCLV
SGNNVTWDKK APICEIISCE PPPTISNGDF YSNNRTSFHN GTVVTYQCHT GPDGEQLFEL
VGERSIYCTS KDDQVGVWSS PPPRCISTNK CTAPEVENAI RVPGNRSFFS LTEIIRFRCQ
PGFVMVGSHT VQCQTNGRWG PKLPHCSRVC QPPPEILHGE HTLSHQDNFS PGQEVFYSCE
PSYDLRGAAS LHCTPQGDWS PEAPRCTVKS CDDFLGQLPH GRVLLPLNLQ LGAKVSFVCD
EGFRLKGRSA SHCVLAGMKA LWNSSVPVCE QIFCPNPPAI LNGRHTGTPF GDIPYGKEIS
YACDTHPDRG MTFNLIGESS IRCTSDPQGN GVWSSPAPRC ELSVPAACPH PPKIQNGHYI
GGHVSLYLPG MTISYICDPG YLLVGKGFIF CTDQGIWSQL DHYCKEVNCS FPLFMNGISK
ELEMKKVYHY GDYVTLKCED GYTLEGSPWS QCQADDRWDP PLAKCTSRTH DALIVGTLSG
TIFFILLIIF LSWIILKHRK GNNAHENPKE VAIHLHSQGG SSVHPRTLQT NEENSRVLP
//

MIM 120620
*RECORD*
*FIELD* NO
120620
*FIELD* TI
*120620 COMPLEMENT COMPONENT RECEPTOR 1; CR1
;;COMPLEMENT COMPONENT 3b/4b RECEPTOR;;
read moreC3-BINDING PROTEIN;;
C3BR;;
C4BR;;
CD35
*FIELD* TX

DESCRIPTION

CR1 is a multiple modular protein that binds C3b (120700)/C4b
(120820)-opsonized foreign antigens. By doing so, CR1 mediates the
immune adherence phenomenon, a fundamental event for destroying microbes
and initiating an immunologic response (Smith et al., 2002).

MAPPING

Although C3BR was assigned to chromosome 6 by somatic cell hybrid
studies (Curry et al., 1976), the immunoelectrophoretic polymorphism
does not show linkage to HLA. Atkinson (1983) counseled caution in
interpretation of the studies of Curry et al. (1976) because the ligands
used were no longer considered acceptable reagents for identifying the
receptors, the C3bi receptor (unknown in 1976) may account for all or
part of the rosette data, and the Raji cell does not have the CR1
C3b/C4b receptor.

Rodriguez de Cordoba et al. (1985) concluded that factor H (HF; 134370),
C4BP (120830), C3BR, and C3DR (CR2; 120650) represent a linked cluster
of genes for proteins regulating the activation of C3. They called the
cluster RCA for regulators of complement activation. They showed,
furthermore, that RCA segregates independently of HLA, the C2, C4, Bf
cluster (on 6p), and C3 (on 19p).

Weis et al. (1987) mapped both CR1 and CR2 to chromosome 1q32 by use of
partial cDNA clones in in situ hybridization and in Southern analysis of
DNA from somatic cell hybrids. Using cDNA probes, Hing et al. (1988)
assigned the genes for HF and C3-binding protein to chromosome 1q. Weis
et al. (1987) indicated that C3b receptor is the same as C4b receptor
(see 120830); it may be, however, that the 2 are closely related
proteins determined by closely linked genes on chromosome 1.

BIOCHEMICAL FEATURES

Smith et al. (2002) reported the structure of the principal
C3b/C4b-binding site (residues 901 to 1,095) of CR1, which revealed 3
complement control protein modules (modules 15 to 17) in an extended
head-to-tail arrangement, with flexibility at the 16-17 junction.
Structure-guided mutagenesis identified a positively charged surface
region on module 15 that is critical for C4b binding.

GENE FUNCTION

In studying Treponema pallidum, Nelson (1953) observed a phenomenon he
called immune adherence. Immune adherence is the specific attachment of
primate red cells to antigen-antibody complexes in the presence of
complement and involves the binding of complement-fixing immune
complexes to the immune-adherence receptor, CR1, normally present on
human red cells.

CR2 is part of an activating signal complex with CD19 (107265) and CD81
(186845) that transduces a positive signal upon coligation with surface
IgM on B cells. Jozsi et al. (2002) showed that aggregated C3, mimicking
multimeric C3b, strongly binds to CR1 and inhibits, in a dose-dependent
manner, the anti-IgM-induced tyrosine phosphorylation of cytoplasmic
proteins, intracellular calcium increase, and proliferation of B
lymphocytes. This inhibitory activity occurred even in the presence of
IL2 (147680) and IL15 (600554). Jozsi et al. (2002) concluded that CR1
plays a role opposite that of CR2 in the regulation of B-cell
activation.

Plasmodium falciparum is responsible for the most severe form of malaria
(see 611162) in humans. By incubating erythrocytes with increasing
amounts of anti-CR1 antibodies or soluble CR1, 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.

- Reviews

Wilson et al. (1987) reviewed CR1 and the other cell membrane proteins
that bind C3 and C4.

MOLECULAR GENETICS

- CR1 Polymorphisms

Nowak (1987) demonstrated polymorphism of CR1 using the hemagglutination
assay with human aggregated IgG and guinea pig complement. Among normal
men, 3 phenotypes were distinguished: a high phenotype corresponding to
strong agglutination, an intermediate phenotype producing weak
agglutination, and a low phenotype that gave no agglutination. In a
group of 517 normal men in Poland, these 3 phenotypes occurred in 63.8,
30.6, and 5.6%, respectively. These findings gave an estimated gene
frequency of 0.791 and 0.209 for the high and low CR1 alleles,
respectively.

Using monoclonal antibodies, Dykman et al. (1983) demonstrated
polymorphism of C3BR of red cells. In U.S. whites, the frequency of the
A and B alleles was found to be 0.83 and 0.17, respectively.
Heterozygotes showed differential expression of the 2 gene products in
different cell types. The A allele determines a 190-kD protein, whereas
the B allele determines a 220-kD protein. In red cells of heterozygotes,
the latter is preferentially expressed. The Bgb blood group, which was
raised in a multiparous woman, is an expression of this same protein.
Its genetics was always confusing because of the anomalous expression in
red cells in heterozygotes. There is cross-reactivity with HLA-B17.

Wilson et al. (1986) identified a HindIII-generated RFLP using a C1 cDNA
that correlated with the number of CR1 sites on erythrocytes. They
concluded that the genomic polymorphism linked to the CR1 gene was
associated with a cis-acting regulatory element for the expression of
CR1 on erythrocytes.

Holers et al. (1987) identified an mRNA size polymorphism that
correlated with the molecular weight polymorphism of the CR1 gene
product. This finding, in addition to the report of several homologous
repeats in CR1, is consistent with the hypothesis that the molecular
weight polymorphism is determined at the genomic level and was generated
by unequal crossing-over.

CR1 is a single-chain glycoprotein with 4 allotypic variants that differ
in molecular mass by increments of 40 to 50 kD. The 2 most common
variants are termed F and S (or A and B) allotypes and are 250 and 290
kD, respectively. The corresponding CR1 transcripts from various
allotypes show incremental differences of 1.3 to 1.5 kD. Wong et al.
(1989) described the organization of the S and F alleles of CR1.

- CR1 Polymorphisms and Systemic Lupus Erythematosus

The occurrence of excessive amounts of antigen-antibody complexes in
systemic lupus erythematosus (SLE; 152700) could be the consequence of
either overproduction of autoantibodies (as through polyclonal B-cell
activation or altered suppressor T-cell function) or impaired
catabolism. A defect in cellular C3b receptors involved in the clearance
of immune complexes that have activated the immune system and are coated
with C3b has been found and has been thought to be inherited (Miyakawa
et al., 1981). Both Miyakawa et al. (1981) and Iida et al. (1982) found
CR1 deficiency in systemic lupus erythematosus (SLE; 152700).

Wilson et al. (1982) showed that the number of C3b receptors on
erythrocytes is genetically regulated. Receptor sites on red cells were
decreased in SLE patients and their relatives; spouses of SLE patients
had normal values. Three phenotypes were demonstrated in the normal
population: HH (5,500-8,500 sites per cell), HL (3,000-5,499 sites per
cell) and LL (less than 3,000 sites per cell). Among normal subjects,
the 3 phenotypes were present in a frequency of 34, 54, and 12%,
respectively; the figures were 5, 42, and 53% for SLE patients.
Hardy-Weinberg and pedigree analyses were consistent with codominant
inheritance of high and low alleles. Wilson (1982) concluded that the
locus for the C3b receptor numerical phenotype is separate from the
structural locus for C3b receptor; of 6 pairs of HLA-identical sibs, 4
were discordant for the numerical phenotype.

Wilson et al. (1985) implicated autoantibodies to the C3b/C4b receptor
and absence of this receptor in the clinical manifestations of SLE.

In a review, Wilson et al. (1987) discussed the mechanism by which
inherited and acquired abnormalities of CR1 might participate in the
pathogenesis of SLE.

Moldenhauer et al. (1987) concluded that inherited deficiency of CR1
does not cause susceptibility to SLE. Deficiency of CR1 was found on red
cells of patients with SLE; however, the 2 alleles defined by the RFLP
identified using a cDNA probe for CR1 showed the same frequency in
normals and in patients with SLE.

Nath et al. (2005) performed a metaanalysis of several studies that had
tested the association of CR1 or interleukin-10 (IL10; 124092)
polymorphisms with SLE. The CR1 metaanalysis revealed the association of
the S structural variant of CR1 with SLE; the IL10 metaanalysis showed
the association of the IL10 G11 allele and SLE in whole populations and
of the promoter -1082A-G polymorphism and SLE in Asians.

- CR1 Polymorphisms 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 (see 611162),
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 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.

- CR1 Polymorphisms and Other Diseases

Ohi et al. (1986) found CR1 deficiency in 2 cases of mesangiocapillary
glomerulonephritis.

Eumycetoma is a tumorous fungal infection, typically of the hands or
feet, characterized by the infiltration of large numbers of neutrophils.
It is caused by Madurella mycetomatis, a pathogen that is abundant in
the soil and on the vegetation of Sudan, where the disease is common.
Van de Sande et al. (2007) noted that ELISA has shown near universal IgG
seropositivity in mycetoma patients and controls from endemic areas, but
no seropositivity in European controls, implying that most individuals
in endemic areas are exposed to the pathogen, but only a small
percentage develop disease. Van de Sande et al. (2007) studied 11 SNPs
in genes involved in neutrophil function in 125 Sudanese mycetoma
patients and 140 ethnically and geographically matched controls and
found significant differences in allele distributions for SNPs in IL8
(146930), IL8RB (146928), TSP4 (THBS4; 600715), NOS2 (163730), and CR1.
Serum IL8 was significantly higher in patients compared with controls,
while nitrite/nitrate levels were lower in patients and seemed to be
associated with delayed wound healing. Van de Sande et al. (2007)
concluded that there is a genetic predisposition toward susceptibility
to mycetoma.

For a discussion of a possible association between variation in the CR1
gene and Alzheimer disease, see 104300.

ANIMAL MODEL

Fairweather et al. (2006) found that mice deficient in both Cr1 and Cr2
had increased acute myocarditis and pericardial fibrosis due to
coxsackievirus B3 (CVB3), leading to early progression to dilated
cardiomyopathy and heart failure. Increased inflammation was not
associated with increased viral replication. Immunofluorescence
microscopy demonstrated increased numbers of macrophages, higher Il1b
(147720) levels, and immune complex deposition in the heart. The mouse
complement regulatory protein, Crry, was increased in cardiac
macrophages, while immature B cells were increased in mutant mice after
CVB3 infection. Fairweather et al. (2006) concluded that CR1/CR2
expression is not necessary for CVB3 clearance, but it is involved in
protection against immune-mediated damage to the heart.

*FIELD* AV
.0001
MALARIA, SEVERE, RESISTANCE TO
CR1, 3650A-G

Xiang et al. (1999) identified 3 single-nucleotide polymorphisms (SNPs)
in the CR1 gene that are associated with CR1 expression levels in
Caucasians. One of these, the CR1 exon 22 SNP (A/G at nucleotide 3650),
showed the strongest association with RBC CR1 levels in populations from
2 malaria-endemic sites in Papua New Guinea (PNG) and in Edinburgh, UK.
In all 3 populations the exon 22 genotype had a highly significant
effect on RBC CR1 level, with carriers of the G3650 low (L) expression
allele having significantly lower CR1 levels than HH individuals. The
RBC CR1 levels of HL individuals were intermediate between those of HH
and LL individuals, as expected for codominant alleles. The frequency of
the CR1 L allele in the malarious regions of PNG were the highest
described in the world. Its frequency in the nonmalarious Eastern
Highlands Province of PNG were significantly lower than in the malarious
regions. Cockburn et al. (2004) showed that RBC CR1 deficiency as
reflected by the LL genotype occurs in up to 80% of healthy individuals
from the malaria-endemic regions of PNG. Although the polymorphism in
the CR1 gene was associated with alpha-thalassemia, a common genetic
disorder in Melanesian populations, analysis of a case-control study
demonstrated that CR1 polymorphisms and alpha-thalassemia independently
confer protection against severe malaria (611162).

Tham et al. (2010) showed that levels of binding between the P.
falciparum merozoite ligand PfRh4 and CR1 correlated with CR1 expression
on the erythrocyte surface, as controlled by the CR1 exon 22 SNP.
Binding was reduced in individuals homozygous for the L allele compared
with those homozygous for the H allele.

*FIELD* SA
Dykman et al. (1983); Dykman et al. (1984); Gerdes et al. (1982);
Wong et al. (1985)
*FIELD* RF
1. Atkinson, J. P.: Personal Communication. St. Louis, Mo. 3/7/1983.

2. Cockburn, I. A.; Mackinnon, M. J.; O'Donnell, A.; Allen, S. J.;
Moulds, J. M.; Baisor, M.; Bockarie, M.; Reeder, J. C.; Rowe, J. A.
: A human complement receptor 1 polymorphism that reduces Plasmodium
falciparum rosetting confers protection against severe malaria. Proc.
Nat. Acad. Sci. 101: 272-277, 2004.

3. Curry, R. A.; Dierich, M. P.; Pellegrino, M. A.; Hoch, H. A.:
Evidence for linkage between HLA antigens and receptors for complement
components C3b and C3d in human-mouse hybrids. Immunogenetics 3:
465-471, 1976.

4. Dykman, T. R.; Cole, J. L.; Iida, K.; Atkinson, J. P.: Polymorphism
of human erythrocyte C3b/C4b receptor. Proc. Nat. Acad. Sci. 80:
1698-1702, 1983.

5. Dykman, T. R.; Cole, J. L.; Iida, K.; Atkinson, J. P.: Structural
heterogeneity of the C3b/C4b receptor (CR1) on human peripheral blood
cells. J. Exp. Med. 157: 2160-2165, 1983.

6. Dykman, T. R.; Hatch, J. A.; Atkinson, J. P.: Polymorphism of
the human C3b/C4b receptor: identification of a third allele and analysis
of receptor phenotypes in families and patients with systemic lupus
erythematosus. J. Exp. Med. 159: 691-703, 1984.

7. Fairweather, D.; Frisancho-Kiss, S.; Njoku, D. B.; Nyland, J. F.;
Kaya, Z.; Yusung, S. A.; Davis, S. E.; Frisancho, J. A.; Barrett,
M. A.; Rose, N. R.: Complement receptor 1 and 2 deficiency increases
coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and
heart failure by increasing macrophages, IL-1-beta, and immune complex
deposition in the heart. J. Immun. 176: 3516-3524, 2006.

8. Gerdes, J.; Hansmann, M.-L.; Stein, H.; Naiem, M.; Mason, D. Y.
: Ultrastructural localization of human complement C3b receptors in
the human kidney as determined by immunoperoxidase staining with the
monoclonal antibody C3RTo5. Virchows Arch. B Cell Path. Incl. Molec.
Path. 40: 1-7, 1982.

9. Hing, S.; Day, A. J.; Linton, S. J.; Ripoche, J.; Sim, R. B.; Reid,
K. B.; Solomon, E.: Assignment of complement components C4 binding
protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA
probes. Ann. Hum. Genet. 52: 117-122, 1988.

10. Holers, V. M.; Chaplin, D. D.; Leykam, J. F.; Gruner, B. A.; Kumar,
V.; Atkinson, J. P.: Human complement C3b/C4b receptor (CR1) mRNA
polymorphism that correlates with the CR1 allelic molecular weight
polymorphism. Proc. Nat. Acad. Sci. 84: 2459-2463, 1987.

11. Iida, K.; Momaghi, R.; Nussenzweig, V.: Complement receptor (CR1)
deficiency in erythrocytes from patients with systemic lupus erythematosus. J.
Exp. Med. 155: 1427-1438, 1982.

12. Jozsi, M.; Prechl, J.; Bajtay, Z.; Erdei, A.: Complement receptor
type 1 (CD35) mediates inhibitory signals in human B lymphocytes. J.
Immun. 168: 2782-2788, 2002.

13. Miyakawa, Y.; Yamada, A.; Kosaka, K.; Tsuda, F.; Kosugi, E.; Mayumi,
M.: Defective immune-adherence (C3b) receptor on erythrocytes from
patients with systemic lupus erythematosus. Lancet 318: 493-497,
1981. Note: Originally Volume II.

14. Moldenhauer, F.; David, J.; Fielder, A. H. L.; Lachmann, P. J.;
Walport, M. J.: Inherited deficiency of erythrocyte complement receptor
type 1 does not cause susceptibility to systemic lupus erythematosus. Arthritis
Rheum. 30: 961-966, 1987.

15. Moulds, J. M.; Moulds, J. J.: Blood group associations with parasites,
bacteria, and viruses. Transfus. Med. Rev. 14: 302-311, 2000.

16. Nath, S. K.; Harley, J. B.; Lee, Y. H.: Polymorphisms of complement
receptor 1 and interleukin-10 genes and systemic lupus erythematosus:
a meta-analysis. Hum. Genet. 118: 225-234, 2005.

17. Nelson, R. A.: The immune-adherence phenomenon: an immunologically
specific reaction between microorganisms and erythrocytes leading
to enhanced phagocytosis. Science 118: 733-737, 1953.

18. Nowak, J. S.: Genetic variability of complement receptor on human
erythrocytes. J. Genet. 66: 133-138, 1987.

19. Ohi, H.; Ikezawa, T.; Watanabe, S.; Seki, M.; Mizutani, Y.; Nawa,
N.; Hatano, M.: Two cases of mesangiocapillary glomerulonephritis
with CR1 deficiency. (Letter) Nephron 43: 307 only, 1986.

20. Rodriguez de Cordoba, S.; Lublin, D. M.; Rubinstein, P.; Atkinson,
J. P.: Human genes for three complement components that regulate
the activation of C3 are tightly linked. J. Exp. Med. 161: 1189-1195,
1985.

21. Rowe, J. A.; Moulds, J. M.; Newbold, C. I.; Miller, L. H.: P-falciparum
rosetting mediated by a parasite-variant erythrocyte membrane protein
and complement-receptor 1. Nature 388: 292-295, 1997.

22. Smith, B. O.; Mallin, R. L.; Krych-Goldberg, M.; Wang, X.; Hauhart,
R. E.; Bromek, K.; Uhrin, D.; Atkinson, J. P.; Barlow, P. N.: Structure
of the C3b binding site of CR1 (CD35), the immune adherence receptor. Cell 108:
769-780, 2002.

23. Tham, W.-H.; Wilson, D. W.; Lopaticki, S.; Schmidt, C. Q.; Tetteh-Quarcoo,
P. B.; Barlow, P. N.; Richard, D.; Corbin, J. E.; Beeson, J. G.; Cowman,
A. F.: Complement receptor 1 is the host erythrocyte receptor for
Plasmodium falciparum PfRh4 invasion ligand. Proc. Nat. Acad. Sci. 107:
17327-17332, 2010.

24. van de Sande, W. W. J.; Fahal, A.; Verbrugh, H.; van Belkum, A.
: Polymorphisms in genes involved in innate immunity predispose toward
mycetoma susceptibility. J. Immun. 179: 3065-3074, 2007.

25. Weis, J. H.; Morton, C. C.; Bruns, G. A. P.; Weis, J. J.; Klickstein,
L. B.; Wong, W. W.; Fearon, D. T.: A complement receptor locus: genes
encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map
to 1q32. J. Immun. 138: 312-315, 1987.

26. Wilson, J. G.: Personal Communication. Boston, Mass. 10/25/1982.

27. Wilson, J. G.; Andriopoulos, N. A.; Fearon, D. T.: CR1 and the
cell membrane proteins that bind C3 and C4: a basic and clinical review. Immun.
Res. 6: 192-209, 1987.

28. Wilson, J. G.; Jack, R. M.; Wong, W. W.; Schur, P. H.; Fearon,
D. T.: Autoantibody to the C3b/C4b receptor and absence of this receptor
from erythrocytes of a patient with systemic lupus erythematosus. J.
Clin. Invest. 76: 182-190, 1985.

29. Wilson, J. G.; Murphy, E. E.; Wong, W. W.; Klickstein, L. B.;
Weis, J. H.; Fearon, D. T.: Identification of a restriction fragment
length polymorphism by a CR1 cDNA that correlates with the number
of CR1 on erythrocytes. J. Exp. Med. 164: 50-59, 1986.

30. Wilson, J. G.; Wong, W. W.; Schur, P. H.; Fearon, D. T.: Mode
of inheritance of decreased C3b receptors on erythrocytes of patients
with systemic lupus erythematosus. New Eng. J. Med. 307: 981-986,
1982.

31. Wong, W. W.; Cahill, J. M.; Rosen, M. D.; Kennedy, C. A.; Bonaccio,
E. T.; Morris, M. J.; Wilson, J. G.; Klickstein, L. B.; Fearon, D.
T.: Structure of the human CR1 gene: molecular basis of the structural
and quantitative polymorphisms and identification of a new CR1-like
allele. J. Exp. Med. 169: 847-863, 1989.

32. Wong, W. W.; Klickstein, L. B.; Smith, J. A.; Weis, J. H.; Fearon,
D. T.: Identification of a partial cDNA clone for the human receptor
for complement fragments C3b/C4b. Proc. Nat. Acad. Sci. 82: 7711-7715,
1985.

33. Xiang, L.; Rundles, J. R.; Hamilton, D. R.; Wilson, J. G.: Quantitative
allele of CR1: coding sequence analysis and comparison of haplotypes
in two ethnic groups. J. Immun. 163: 4939-4945, 1999.

*FIELD* CN
Paul J. Converse - updated !$: 6/14/2012
Matthew B. Gross - updated: 9/3/2009
Paul J. Converse - updated: 5/5/2009
Paul J. Converse - updated: 4/4/2007
Victor A. McKusick - updated: 2/14/2006
Victor A. McKusick - updated: 2/6/2004
Victor A. McKusick - updated: 1/14/2003
Paul J. Converse - updated: 5/6/2002
Stylianos E. Antonarakis - updated: 5/6/2002
Victor A. McKusick - updated: 6/12/1997

*FIELD* CD
Victor A. McKusick: 6/23/1986

*FIELD* ED
mgross: 06/19/2012
mgross: 6/19/2012
terry: 6/14/2012
terry: 10/13/2010
carol: 9/17/2010
mgross: 5/3/2010
alopez: 3/26/2010
mgross: 9/3/2009
wwang: 6/2/2009
mgross: 5/5/2009
terry: 1/12/2009
carol: 5/30/2008
mgross: 7/5/2007
mgross: 4/6/2007
terry: 4/4/2007
alopez: 2/27/2006
terry: 2/14/2006
terry: 6/18/2004
cwells: 2/10/2004
terry: 2/6/2004
alopez: 1/16/2003
terry: 1/14/2003
mgross: 5/6/2002
mgross: 8/31/2000
carol: 9/10/1999
carol: 8/4/1998
mark: 6/16/1997
terry: 6/12/1997
davew: 6/27/1994
mimadm: 4/14/1994
warfield: 4/8/1994
supermim: 3/16/1992
carol: 3/2/1992
carol: 1/21/1992

MIM 607486
*RECORD*
*FIELD* NO
607486
*FIELD* TI
#607486 KNOPS BLOOD GROUP SYSTEM; KN
*FIELD* TX
A number sign (#) is used with this entry because the Knops blood group
read moresystem represents antigens carried by complement receptor-1 (CR1;
120620) of the erythrocyte cell membrane.

The Knops blood group system comprises 5 high-incidence antigens
designated KN1-KN5 (Daniels, 1995). The Knops system antigens are
carried on complement receptor-1. In humans, 4 CR1 allotypes of
different size are known and all of them express the Knops system
antigens. The extracellular domain of CR1, which has 25 potential
N-glycosylation sites, can be divided into 30 short consensus repeats
(SCRs), each having 60 to 70 amino acids with sequence homology between
SCRs ranging from 60 to 90%. The first 28 SCRs are further arranged into
4 longer regions termed long homologous repeats (LHRs), designated
LHR-A, LHR-B, LHR-C, and LHR-D and consisting of 7 SCRs each.
Tamasauskas et al. (2001) reported studies indicating that the
high-incidence Knops system antigens reside within LHR-D and to a lesser
extent within LHR-C. Sl(a) (KN4, or Swain-Langley) is involved in
malarial rosetting (Rowe et al., 1997), a process associated with
cerebral malaria (see 611162), which is the major cause of mortality
from Plasmodium falciparum. Reduction in rosette formation occurred with
Sl(a-) RBCs. Because the Sl(a-) phenotype is more common in persons of
African ancestry (Daniels, 1995), Moulds and Moulds (2000) suggested
that this phenotype provided protection against fatal falciparum
malaria. The studies of Tamasauskas et al. (2001) suggested that LHR-D
may represent an additional malaria interaction region in CR1.

*FIELD* RF
1. Daniels, G.: Human Blood Groups. Oxford: Blackwell , 1995.

2. Moulds, J. M.; Moulds, J. J.: Blood group associations with parasites,
bacteria, and viruses. Trans. Med. Rev. 14: 302-311, 2000.

3. Rowe, J. A.; Moulds, J. M.; Newbold, C. I.; Miller, L. H.: P-falciparum
rosetting mediated by a parasite-variant erythrocyte membrane protein
and complement-receptor 1. Nature 388: 292-295, 1997.

4. Tamasauskas, D.; Powell, V.; Schawalder, A.; Yazdanbakhsh, K.:
Localization of Knops system antigens in the long homologous repeats
of complement receptor 1. Transfusion 41: 1397-1404, 2001.

*FIELD* CD
Victor A. McKusick: 1/16/2003

*FIELD* ED
mgross: 07/05/2007
alopez: 1/16/2003

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