RBCC Red Blood Cell Collection

DARC (ACKR1, FY, GPD) [Confidence: high (a blood group or CD marker)]
Duffy antigen/chemokine receptor (Atypical chemokine receptor 1; Fy glycoprotein; GpFy; Glycoprotein D; Plasmodium vivax receptor; CD234)

hRBCD IPI00002940
IPI00002940 Splice isoform 2 of Q16570 Duffy antigen/chemokine receptor Splice isoform 2 of Q16570 Duffy antigen/chemokine receptor membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 1 n/a n/a n/a n/a n/a n/a integral membrane protein splice isoforms 1 and 2 found at its expected molecular weight found at molecular weight

BGMUT duffy
251 duffy DARC FYA 131G FYA 131A>G D44G FY(a+b-) common; Caucasians 42%; Blacks 10%; Chinese, 95%; Japanese 90%; Thai 92-100%; Australian aborigines 97% 8248172 Chaudhuri et al. "This allele illustrates the difference between FYB and FYA alleles, or FYB shows nt 131A and FYA shows nt.131G; here the reference sequence used is FYB acc. no U01839 the isoform showing 338 nt as compared to another frequently used as a reference, isoform of 336 nt.(see ""Introduction"" page). If the latter sequence were used as a reference the change of FYB to FYA allele would read nt.125A>G or res.D42A." Blumenfeld OO, curator 2011-12-19 15:49:57.510 NA

Comments
Isoform Q16570-2 was detected.

UniProt Q16570
ID ACKR1_HUMAN Reviewed; 336 AA.
AC Q16570; A8YPG5; O75898; Q16300; Q8WWE3; Q9UJP0; Q9UKZ5; Q9UKZ6;
read moreAC Q9UQE1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2005, sequence version 3.
DT 22-JAN-2014, entry version 131.
DE RecName: Full=Duffy antigen/chemokine receptor;
DE AltName: Full=Atypical chemokine receptor 1;
DE AltName: Full=Fy glycoprotein;
DE Short=GpFy;
DE AltName: Full=Glycoprotein D;
DE AltName: Full=Plasmodium vivax receptor;
DE AltName: CD_antigen=CD234;
GN Name=DARC; Synonyms=ACKR1, FY, GPD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PARTIAL PROTEIN SEQUENCE, AND
RP VARIANT ASP-42.
RC TISSUE=Bone marrow;
RX PubMed=8248172; DOI=10.1073/pnas.90.22.10793;
RA Chaudhuri A., Polyakova J., Zbrzezna V., Williams K., Gulati S.,
RA Pogo A.;
RT "Cloning of glycoprotein D cDNA, which encodes the major subunit of
RT the Duffy blood group system and the receptor for the Plasmodium vivax
RT malaria parasite.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:10793-10797(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ASP-42.
RC TISSUE=Blood;
RX PubMed=7663520; DOI=10.1038/ng0695-224;
RA Tournamille C., Colin Y., Cartron J.-P., Le van Kim C.;
RT "Disruption of a GATA motif in the Duffy gene promoter abolishes
RT erythroid gene expression in Duffy-negative individuals.";
RL Nat. Genet. 10:224-228(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=7833467;
RA Iwamoto S., Omi T., Kajii E., Ikemoto S.;
RT "Genomic organization of the glycoprotein D gene: Duffy blood group
RT Fya/Fyb alloantigen system is associated with a polymorphism at the
RT 44-amino acid residue.";
RL Blood 85:622-626(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2), AND VARIANTS ASP-42;
RP CYS-89 AND THR-100.
RC TISSUE=Blood;
RX PubMed=9731074;
RA Tournamille C., Le Van Kim C., Gane P., Le Pennec P.Y., Roubinet F.,
RA Babinet J., Cartron J.-P., Colin Y.;
RT "Arg89Cys substitution results in very low membrane expression of the
RT Duffy antigen/receptor for chemokines in Fy(x) individuals.";
RL Blood 92:2147-2156(1998).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANTS ASP-42; CYS-89
RP AND THR-100.
RX PubMed=9886340; DOI=10.1046/j.1365-2141.1998.01083.x;
RA Olsson M.L., Smythe J.S., Hansson C., Poole J., Mallinson G.,
RA Jones J., Avent N.D., Daniels G.;
RT "The Fy(x) phenotype is associated with a missense mutation in the
RT Fy(b) allele predicting Arg89Cys in the Duffy glycoprotein.";
RL Br. J. Haematol. 103:1184-1191(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PHE-326.
RC TISSUE=Peripheral blood;
RA Doescher A.;
RT "New polymorphisms in DARC.";
RL Submitted (SEP-2007) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT
RP PHE-326.
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-117 (ISOFORMS 1 AND 2).
RX PubMed=10570183; DOI=10.1073/pnas.96.24.13973;
RA Zimmerman P.A., Woolley I., Masinde G.L., Miller S.M., McNamara D.T.,
RA Hazlett F., Mgone C.S., Alpers M.P., Genton B., Boatin B.A.,
RA Kazura J.W.;
RT "Emergence of FY*A(null) in a Plasmodium vivax-endemic region of Papua
RT New Guinea.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:13973-13977(1999).
RN [10]
RP DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-16.
RX PubMed=12956774; DOI=10.1046/j.1365-2141.2003.04533.x;
RA Tournamille C., Filipe A., Wasniowska K., Gane P., Lisowska E.,
RA Cartron J.-P., Colin Y., Le Van Kim C.;
RT "Structure-function analysis of the extracellular domains of the Duffy
RT antigen/receptor for chemokines: characterization of antibody and
RT chemokine binding sites.";
RL Br. J. Haematol. 122:1014-1023(2003).
RN [11]
RP POLYMORPHISM, AND INVOLVEMENT IN RESISTANCE TO MALARIA.
RX PubMed=17389925; DOI=10.1371/journal.pone.0000336;
RA Kasehagen L.J., Mueller I., Kiniboro B., Bockarie M.J., Reeder J.C.,
RA Kazura J.W., Kastens W., McNamara D.T., King C.H., Whalen C.C.,
RA Zimmerman P.A.;
RT "Reduced Plasmodium vivax erythrocyte infection in PNG Duffy-negative
RT heterozygotes.";
RL PLoS ONE 2:E336-E336(2007).
RN [12]
RP REVIEW.
RX PubMed=20373092; DOI=10.1007/82_2010_19;
RA Bonecchi R., Savino B., Borroni E.M., Mantovani A., Locati M.;
RT "Chemokine decoy receptors: structure-function and biological
RT properties.";
RL Curr. Top. Microbiol. Immunol. 341:15-36(2010).
RN [13]
RP REVIEW.
RX PubMed=22912641; DOI=10.3389/fimmu.2012.00266;
RA Novitzky-Basso I., Rot A.;
RT "Duffy antigen receptor for chemokines and its involvement in
RT patterning and control of inflammatory chemokines.";
RL Front. Immunol. 3:266-266(2012).
RN [14]
RP REVIEW.
RX PubMed=22698181; DOI=10.1016/j.imlet.2012.04.004;
RA Graham G.J., Locati M., Mantovani A., Rot A., Thelen M.;
RT "The biochemistry and biology of the atypical chemokine receptors.";
RL Immunol. Lett. 145:30-38(2012).
RN [15]
RP REVIEW.
RX PubMed=23356288; DOI=10.1042/BST20120246;
RA Cancellieri C., Vacchini A., Locati M., Bonecchi R., Borroni E.M.;
RT "Atypical chemokine receptors: from silence to sound.";
RL Biochem. Soc. Trans. 41:231-236(2013).
RN [16]
RP VARIANT ASP-42.
RC TISSUE=Peripheral blood;
RX PubMed=7705836; DOI=10.1007/BF00208965;
RA Tournamille C., Le van Kim C., Gane P., Cartron J.-P., Colin Y.;
RT "Molecular basis and PCR-DNA typing of the Fya/fyb blood group
RT polymorphism.";
RL Hum. Genet. 95:407-410(1995).
RN [17]
RP VARIANT CYS-89.
RX PubMed=9746760;
RA Parasol N., Reid M., Rios M., Castilho L., Harari I., Kosower N.S.;
RT "A novel mutation in the coding sequence of the FY*B allele of the
RT Duffy chemokine receptor gene is associated with an altered
RT erythrocyte phenotype.";
RL Blood 92:2237-2243(1998).
RN [18]
RP INVOLVEMENT IN WBCQ1.
RX PubMed=18179887; DOI=10.1016/j.ajhg.2007.09.003;
RA Nalls M.A., Wilson J.G., Patterson N.J., Tandon A., Zmuda J.M.,
RA Huntsman S., Garcia M., Hu D., Li R., Beamer B.A., Patel K.V.,
RA Akylbekova E.L., Files J.C., Hardy C.L., Buxbaum S.G., Taylor H.A.,
RA Reich D., Harris T.B., Ziv E.;
RT "Admixture mapping of white cell count: genetic locus responsible for
RT lower white blood cell count in the Health ABC and Jackson Heart
RT Studies.";
RL Am. J. Hum. Genet. 82:81-87(2008).
RN [19]
RP ERRATUM.
RA Nalls M.A., Wilson J.G., Patterson N.J., Tandon A., Zmuda J.M.,
RA Huntsman S., Garcia M., Hu D., Li R., Beamer B.A., Patel K.V.,
RA Akylbekova E.L., Files J.C., Hardy C.L., Buxbaum S.G., Taylor H.A.,
RA Reich D., Harris T.B., Ziv E.;
RL Am. J. Hum. Genet. 82:532-532(2008).
CC -!- FUNCTION: Atypical chemokine receptor that controls chemokine
CC levels and localization via high-affinity chemokine binding that
CC is uncoupled from classic ligand-driven signal transduction
CC cascades, resulting instead in chemokine sequestration,
CC degradation, or transcytosis. Also known as interceptor
CC (internalizing receptor) or chemokine-scavenging receptor or
CC chemokine decoy receptor. Has a promiscuous chemokine-binding
CC profile, interacting with inflammatory chemokines of both the CXC
CC and the CC subfamilies but not with homeostatic chemokines. Acts
CC as a receptor for chemokines including CCL2, CCL5, CCL7, CCL11,
CC CCL13, CCL14, CCL17, CXCL5, CXCL6, IL8/CXCL8, CXCL11, GRO, RANTES,
CC MCP-1, TARC and also for the malaria parasites P.vivax and
CC P.knowlesi. May regulate chemokine bioavailability and,
CC consequently, leukocyte recruitment through two distinct
CC mechanisms: when expressed in endothelial cells, it sustains the
CC abluminal to luminal transcytosis of tissue-derived chemokines and
CC their subsequent presentation to circulating leukocytes; when
CC expressed in erythrocytes, serves as blood reservoir of cognate
CC chemokines but also as a chemokine sink, buffering potential
CC surges in plasma chemokine levels.
CC -!- SUBCELLULAR LOCATION: Early endosome. Recycling endosome.
CC Membrane; Multi-pass membrane protein. Note=Predominantly
CC localizes to endocytic vesicles, and upon stimulation by the
CC ligand is internalized via caveolae. Once internalized, the ligand
CC dissociates from the receptor, and is targeted to degradation
CC while the receptor is recycled back to the cell membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=2;
CC IsoId=Q16570-1; Sequence=Displayed;
CC Name=1;
CC IsoId=Q16570-2; Sequence=VSP_001323;
CC -!- TISSUE SPECIFICITY: Found in adult kidney, adult spleen, bone
CC marrow and fetal liver. In particular, it is expressed along
CC postcapillary venules throughout the body, except in the adult
CC liver. Erythroid cells and postcapillary venule endothelium are
CC the principle tissues expressing duffy. Fy(-A-B) individuals do
CC not express duffy in the bone marrow, however they do, in
CC postcapillary venule endothelium.
CC -!- POLYMORPHISM: DARC is responsible for the Duffy blood group system
CC (FY) [MIM:110700]. The molecular basis of the Fy(A)=Fy1/Fy(B)=Fy2
CC blood group antigens is a single variation in position 42; Gly-42
CC corresponds to Fy(A) and Asp-42 to Fy(B). Individuals that do not
CC produce the Duffy antigen (FY(A-B-)) are more resistant to
CC infection by the malarial parasite Plasmodium vivax. This allele
CC is found predominantly in population of African origin
CC [MIM:611162].
CC -!- POLYMORPHISM: Genetic variations in DARC define the white blood
CC cell count quantitative trait locus 1 (WBCQ1) [MIM:611862].
CC Peripheral white blood cell count (WBC) is a common clinical
CC measurement, used to determine evidence of acute infammation or
CC infection. Peripheral WBC is the sum of several cell types
CC including neutrophils and lymphocytes, which are the most common
CC types of WBC, as well as less common cell types such as
CC eosinophils, basophils, and monocytes. Elevated WBC has been
CC associated with risk of coronary heart disease, cancer, and all-
CC cause mortality. White blood cell levels have widespread clinical
CC applications including assessment of patients undergoing
CC chemotherapy and evaluation of infection.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC Atypical chemokine receptor subfamily.
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;=duffy";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/DARC";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Duffy antigen entry;
CC URL="http://en.wikipedia.org/wiki/Duffy_antigen";
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DR EMBL; U01839; AAC50055.1; -; mRNA.
DR EMBL; X85785; CAA59770.1; -; Genomic_DNA.
DR EMBL; S76830; AAB33239.1; -; Genomic_DNA.
DR EMBL; AF055992; AAC72301.1; -; Genomic_DNA.
DR EMBL; AF030521; AAD20435.1; -; mRNA.
DR EMBL; AM887935; CAP12644.1; -; Genomic_DNA.
DR EMBL; AL035403; CAB56228.1; -; Genomic_DNA.
DR EMBL; BC017817; AAH17817.1; -; mRNA.
DR EMBL; AF100634; AAF02415.1; -; Genomic_DNA.
DR EMBL; AF100634; AAF02416.1; -; Genomic_DNA.
DR PIR; I52608; I52608.
DR RefSeq; NP_001116423.1; NM_001122951.2.
DR RefSeq; NP_002027.2; NM_002036.3.
DR UniGene; Hs.153381; -.
DR ProteinModelPortal; Q16570; -.
DR DIP; DIP-3783N; -.
DR ChEMBL; CHEMBL2321626; -.
DR PhosphoSite; Q16570; -.
DR DMDM; 67476970; -.
DR PRIDE; Q16570; -.
DR DNASU; 2532; -.
DR Ensembl; ENST00000368121; ENSP00000357103; ENSG00000213088.
DR Ensembl; ENST00000368122; ENSP00000357104; ENSG00000213088.
DR Ensembl; ENST00000537147; ENSP00000441985; ENSG00000213088.
DR GeneID; 2532; -.
DR KEGG; hsa:2532; -.
DR UCSC; uc001fto.3; human.
DR CTD; 2532; -.
DR GeneCards; GC01P159173; -.
DR HGNC; HGNC:4035; DARC.
DR HPA; HPA016421; -.
DR HPA; HPA017672; -.
DR MIM; 110700; phenotype.
DR MIM; 611162; phenotype.
DR MIM; 611862; phenotype.
DR MIM; 613665; gene.
DR neXtProt; NX_Q16570; -.
DR PharmGKB; PA28451; -.
DR eggNOG; NOG28176; -.
DR HOVERGEN; HBG051419; -.
DR KO; K06574; -.
DR OMA; HCVATPL; -.
DR OrthoDB; EOG7RFTHW; -.
DR PhylomeDB; Q16570; -.
DR Reactome; REACT_111102; Signal Transduction.
DR ChiTaRS; DARC; human.
DR GeneWiki; Duffy_antigen_system; -.
DR GenomeRNAi; 2532; -.
DR NextBio; 9987; -.
DR PRO; PR:Q16570; -.
DR ArrayExpress; Q16570; -.
DR Bgee; Q16570; -.
DR CleanEx; HS_DARC; -.
DR Genevestigator; Q16570; -.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0055037; C:recycling endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0004950; F:chemokine receptor activity; NAS:UniProtKB.
DR GO; GO:0006952; P:defense response; NAS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:Ensembl.
DR GO; GO:0032642; P:regulation of chemokine production; IEA:Ensembl.
DR InterPro; IPR005384; Duffy_chemokine_rcpt.
DR PANTHER; PTHR14181; PTHR14181; 1.
DR PRINTS; PR01559; DUFFYANTIGEN.
PE 1: Evidence at protein level;
KW Alternative splicing; Blood group antigen; Complete proteome;
KW Direct protein sequencing; Disulfide bond; Endosome;
KW G-protein coupled receptor; Glycoprotein; Membrane; Polymorphism;
KW Receptor; Reference proteome; Transducer; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1 336 Duffy antigen/chemokine receptor.
FT /FTId=PRO_0000152585.
FT TOPO_DOM 1 63 Extracellular (Potential).
FT TRANSMEM 64 84 Helical; Name=1; (Potential).
FT TOPO_DOM 85 95 Cytoplasmic (Potential).
FT TRANSMEM 96 116 Helical; Name=2; (Potential).
FT TOPO_DOM 117 129 Extracellular (Potential).
FT TRANSMEM 130 153 Helical; Name=3; (Potential).
FT TOPO_DOM 154 166 Cytoplasmic (Potential).
FT TRANSMEM 167 187 Helical; Name=4; (Potential).
FT TOPO_DOM 188 207 Extracellular (Potential).
FT TRANSMEM 208 228 Helical; Name=5; (Potential).
FT TOPO_DOM 229 244 Cytoplasmic (Potential).
FT TRANSMEM 245 265 Helical; Name=6; (Potential).
FT TOPO_DOM 266 287 Extracellular (Potential).
FT TRANSMEM 288 308 Helical; Name=7; (Potential).
FT TOPO_DOM 309 336 Cytoplasmic (Potential).
FT CARBOHYD 16 16 N-linked (GlcNAc...).
FT CARBOHYD 33 33 N-linked (GlcNAc...) (Potential).
FT DISULFID 51 276
FT DISULFID 129 195
FT VAR_SEQ 1 7 MGNCLHR -> MASSGYVLQ (in isoform 1).
FT /FTId=VSP_001323.
FT VARIANT 42 42 G -> D (antigen Fy(b); dbSNP:rs12075).
FT /FTId=VAR_003480.
FT VARIANT 89 89 R -> C (antigen Fy(x); dbSNP:rs34599082).
FT /FTId=VAR_015068.
FT VARIANT 100 100 A -> T (in dbSNP:rs13962).
FT /FTId=VAR_015069.
FT VARIANT 203 203 L -> Q (in dbSNP:rs3027020).
FT /FTId=VAR_044116.
FT VARIANT 326 326 S -> F (in dbSNP:rs17851570).
FT /FTId=VAR_044117.
SQ SEQUENCE 336 AA; 35553 MW; C3F2A3E71D972E2D CRC64;
MGNCLHRAEL SPSTENSSQL DFEDVWNSSY GVNDSFPDGD YGANLEAAAP CHSCNLLDDS
ALPFFILTSV LGILASSTVL FMLFRPLFRW QLCPGWPVLA QLAVGSALFS IVVPVLAPGL
GSTRSSALCS LGYCVWYGSA FAQALLLGCH ASLGHRLGAG QVPGLTLGLT VGIWGVAALL
TLPVTLASGA SGGLCTLIYS TELKALQATH TVACLAIFVL LPLGLFGAKG LKKALGMGPG
PWMNILWAWF IFWWPHGVVL GLDFLVRSKL LLLSTCLAQQ ALDLLLNLAE ALAILHCVAT
PLLLALFCHQ ATRTLLPSLP LPEGWSSHLD TLGSKS
//

MIM 110700
*RECORD*
*FIELD* NO
110700
*FIELD* TI
#110700 BLOOD GROUP, DUFFY SYSTEM; FY
;;DUFFY BLOOD GROUP SYSTEM
PLASMODIUM VIVAX, RESISTANCE TO, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because the Duffy blood group
system is based on variation in the DARC gene (613665). Complete
resistance to infection by the malarial parasite Plasmodium vivax (see
611162) is associated with the Duffy phenotype Fy(a-b-), which results
from a polymorphism in the DARC promoter (613665.0002).

DESCRIPTION

The Duffy blood group system, which consists of 4 alleles, 5 phenotypes,
and 5 antigens, is important in clinical medicine because of transfusion
incompatibilities and hemolytic disease of the newborn. Duffy antigens
are located on DARC (613665), an acidic glycoprotein found on
erythrocytes and other cells throughout the body. The 2 principal
antigens, Fy(a) and Fy(b), are produced by the FYA and FYB codominant
alleles (see 613665.0001). Four phenotypes are defined by the
corresponding antibodies, anti-Fy(a) and anti-Fy(b): Fy(a+b-), Fy(a-b+),
Fy(a+b+), and Fy(a-b-). Fy(a-b-), or Duffy null, is the major phenotype
in African and American blacks and is characterized by the presence of
Fy(b) on nonerythroid cells, but an absence of Fy(b) on erythrocytes.
The Fy(a-b-) phenotype is associated with complete resistance to
infection by the malarial parasite Plasmodium vivax (see 611162).
Individuals with the Fy(a-b-) phenotype have the FYB-erythroid silent
(FYB-ES) allele with a mutation in the DARC promoter (613665.0002). A
fifth phenotype, Fy(bwk), or Fy(x), is characterized by weak Fy(b)
expression on erythrocytes due to a reduced amount of protein.
Individuals with the Fy(bwk) phenotype have the FYB-weak (FYB-WK)
allele, also called the FYX allele, with a missense mutation in DARC
(613665.0003). Other Duffy antigens include Fy3, Fy4, Fy5, and Fy6
(reviews by Pogo and Chaudhuri (2000), Langhi and Bordin (2006), and
Meny (2010)).

CLINICAL FEATURES

An association between sickle cell trait (603903) and Duffy-null blood
group was demonstrated in Saudi Arabs (Gelpi and King, 1976). Neither
linkage nor association of the usual type was the basis, but rather a
protection against malaria provided by both traits.

BIOCHEMICAL FEATURES

Nichols et al. (1987) reported a new Duffy specificity, Fy6, defined by
a murine monoclonal antibody. Fy6 is related to susceptibility to
invasion of red cells by P. vivax.

DIAGNOSIS

Maternal allo-immunization to antigens of the Duffy blood group system
can result in hemolytic disease of the newborn (HDN). Hessner et al.
(1999) evaluated the use of allele-specific PCR for prenatal genotyping
of the Duffy antigen system to identify pregnancies at risk for HDN.
Oligonucleotide primers were designed for FYA, FYB, and null-FY alleles.
The authors found a perfect match between results of serotyping and
detection by molecular methods. They suggested that this assay is
particularly useful for rapid genotyping of fetal amniotic cells to
identify pregnancies at risk for HDN due to maternal-fetal
incompatibilities within the Duffy blood group system.

MAPPING

The Duffy system enjoys the distinction of being the first blood group
whose genetic locus was assigned to a specific autosome, i.e.,
chromosome 1 (Donahue et al., 1968). Duffy and the locus for a form of
hereditary cataract (116200) are closely linked. From extensive family
studies, Robson et al. (1973) arrived at a tentative map of chromosome
1.

Palmer et al. (1977) studied a parent with transposition of segment
1q31-1q32 from the long arm to the short arm of chromosome 1 and a child
in whom crossing-over had resulted in duplication of this segment. The
Duffy type in the father and a normal son with the same transposition
was Fy(ab), while in the mother it was Fy(b). In the proband with the
duplication it was Fy(b), suggesting that the Duffy locus is situated at
1q2.

The demonstration of close linkage to alpha-spectrin (SPTA1; 182860)
suggests the location of Fy in the q21 band (Raeymaekers et al., 1988).
McAlpine et al. (1989) concluded that Fy lies distal to SPTA1.

By fluorescence in situ hybridization, Chaganti (1993) mapped the Fy
gene, DARC, to chromosome 1q22-q23.

MOLECULAR GENETICS

- FYA/FYB Polymorphism

Tournamille et al. (1995) found that a single amino acid difference
(G42D; 613665.001) in DARC accounts for the difference between the FYA
and FYB alleles at the Duffy blood group locus. Mallinson et al. (1995)
also reported the basis for the FYA/FYB polymorphism.

For further information on the FYA/FYB polymorphism, see MOLECULAR
GENETICS in 613665.

- Fy(a-b-) Phenotype

The Fy(a-b-) phenotype is rare among white and Asian populations,
whereas it is the predominant phenotype among populations of black
people, especially those originating in West Africa. Tournamille et al.
(1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype
is a point mutation, -67T-C (613665.0002), in a consensus binding site
for GATA1 (305371), a transcription factor active in erythroid cells.
The Fy(a-b-) phenotype provides complete protection from Plasmodium
vivax infection (see 611162).

Mallinson et al. (1995) presented evidence for 2 different genetic
backgrounds giving rise to the Fy(a-b-) phenotype. The Duffy gene from a
very rare Caucasian individual (AZ) with the Fy(a-b-) phenotype had a
14-bp deletion (613665.0004) that resulted in a frameshift that
introduced a stop codon and produced a putative truncated DARC protein.
The only known examples of the Fy(a-b-) phenotype in Caucasians were AZ
and Czech gypsies.

For further information on the molecular genetics underlying the
Fy(a-b-) phenotype, see MOLECULAR GENETICS in 613665.

- Fy(bwk) Phenotype

Tournamille et al. (1998) and Olsson et al. (1998) described a Duffy
allele, FYB-WK, or FYX, in approximately 3.5% of the population that,
because of an arg89-to-cys (R89C; 613665.0003) substitution in the first
cytoplasmic domain of DARC, results in reduced levels of protein, lower
antigen expression, and reduced ability to bind chemokines. The
phenotype is called Fy(bwk), Fy(x), or either Fy(a-b+(weak)) or
Fy(a+b+(weak))

For further information on the molecular genetics underlying the Fy(bwk)
phenotype, see MOLECULAR GENETICS in 613665.

HISTORY

On the basis of families studied in Rochester, N.Y., Weitkamp (1972)
could demonstrate no linkage of Duffy and the HBB locus (141900), as had
been suggested by Nance et al. (1970). An earlier suspicion of
localization to chromosome 16 (Crawford et al., 1967) was apparently in
error.

From study of a family with a pericentric inversion of chromosome 1, Lee
et al. (1974) suggested that the most probable location of the Fy locus
is close to the centromere on the short arm (favored) or near the distal
end of the centric heterochromatin on the long arm. Assuming that each
arm of chromosome 1 is 140 male cM in length, Cook et al. (1974)
concluded that, measured from the centromere, map positions are as
follows: PGD (172200) 1p124--Rh (see 111700) 1p109--PGM1 (171900)
1p079--Fy 1p010--PEPC (170000) 1q030.

In the course of paternity testing, Herbich et al. (1985) found an
apparent maternal exclusion by the PGM1 enzyme system--mother's PGM1
type, 1; child's PGM1 type, 2; and by the Duffy blood group
system--mother, Fy(a-b+); child, Fy(a+b-). The father was not available
for testing. The karyotype of the child showed a 'new fragile site' at
1p31. The authors concluded that the PGM1 and Duffy loci are located in
the 1p31 band, which they stated to be 'a position supposed to carry the
PGM1 and the Duffy loci.' The last statement is incorrect and the
assignment to 1p31 is inconsistent with previous well-established
assignments of PGM1 and Fy to 1p22.1 and 1q12-q21, respectively.

*FIELD* SA
Cook et al. (1978); Howard et al. (1975); Miller et al. (1975); Pasvol
and Wilson (1982); Ritter (1967)
*FIELD* RF
1. Chaganti, R. S. K.: Personal Communication. New York, N. Y.
10/22/1993.

2. Cook, P. J. L.; Page, B. M.; Johnston, A. W.; Stanford, W. K.;
Gavin, J.: Four further families informative for 1q and the Duffy
blood group. Cytogenet. Cell Genet. 22: 378-380, 1978.

3. Cook, P. J. L.; Robson, E. B.; Buckton, K. E.; Jacobs, P. A.; Polani,
P. E.: Segregation of genetic markers in families with chromosome
polymorphisms and structural rearrangements involving chromosome no.
1. Ann. Hum. Genet. 37: 261-274, 1974.

4. Crawford, M. N.; Punnett, H. H.; Carpenter, G. G.: Deletion of
the long arm of chromosome 16 and an unexpected Duffy blood group
phenotype reveal a possible autosomal linkage. Nature 215: 1075-1076,
1967.

5. Donahue, R. P.; Bias, W. B.; Renwick, J. H.; McKusick, V. A.:
Probable assignment of the Duffy blood group locus to chromosome 1
in man. Proc. Nat. Acad. Sci. 61: 949-955, 1968.

6. Gelpi, A. P.; King, M. C.: Association of Duffy blood groups with
the sickle cell trait. Hum. Genet. 32: 65-68, 1976.

7. Herbich, J.; Szilvassy, J.; Schnedl, W.: Gene localisation of
the PGM-1 enzyme system and the Duffy blood groups on chromosome no.
1 by means of a new fragile site at 1p31. Hum. Genet. 70: 178-180,
1985.

8. Hessner, M. J.; Pircon, R. A.; Johnson, S. T.; Luhm, R. A.: Prenatal
genotyping of the Duffy blood group system by allele-specific polymerase
chain reaction. Prenatal Diag. 19: 41-45, 1999.

9. Howard, P. N.; Stoddard, G. R.; Goddard, M. W.; Seely, J. R.:
Giemsa banding of chromosome 1qh+ and linkage analysis. J. Med. Genet. 12:
44-48, 1975.

10. Langhi, D. M., Jr.; Bordin, J. O.: Duffy blood group and malaria. Hematology 11:
389-398, 2006.

11. Lee, C. S. N.; Ying, K. L.; Bowen, P.: Position of the Duffy
locus on chromosome 1 in relation to breakpoints for structural rearrangements. Am.
J. Hum. Genet. 26: 93-102, 1974.

12. Mallinson, G.; Soo, K. S.; Schall, T. J.; Pisacka, M.; Anstee,
D. J.: Mutations in the erythrocyte chemokine receptor (Duffy) gene:
the molecular basis of the Fy(a)/Fy(b) antigens and identification
of a deletion in the Duffy gene of an apparently healthy individual
with the Fy(a-b-) phenotype. Brit. J. Haemat. 90: 823-829, 1995.

13. McAlpine, P. J.; Coopland, G.; Guy, C.; James, S.; Komarnicki,
L.; MacDonald, M.; Stranc, L.; Lewis, M.; Philipps, S.; Coghlan, G.;
Kaita, H.; Cox, D. W.; Guinto, E. R.; MacGillivray, R.: Mapping the
genes for erythrocytic alpha-spectrin 1 (SPTA1) and coagulation factor
V (F5). (Abstract) Cytogenet. Cell Genet. 51: 1042, 1989.

14. Meny, G. M.: The Duffy blood group system: a review. Immunohematology 26:
51-56, 2010.

15. Miller, L. H.; Mason, S. J.; Dvorak, J. A.: Erythrocyte receptors
of Plasmodium knowlesi malaria: Duffy blood group determinants. Science 189:
561-562, 1975.

16. Nance, W. E.; Conneally, M.; Kang, K. W.; Reed, T. E.; Schroder,
J.; Rose, S.: Genetic linkage analysis of human hemoglobin variants. Am.
J. Hum. Genet. 22: 453-459, 1970.

17. Nichols, M. E.; Rubinstein, P.; Barnwell, J.; Rodriguez de Cordoba,
S.; Rosenfield, R. E.: A new human Duffy blood group specificity
defined by a murine monoclonal antibody: immunogenetics and association
with susceptibility to Plasmodium vivax. J. Exp. Med. 166: 776-785,
1987.

18. Olsson, M. L.; Smythe, J. S.; Hansson, C.; Poole, J.; Mallinson,
G.; Jones, J.; Avent, N. D.; Daniels, G.: The Fy(x) phenotype is
associated with a missense mutation in the Fy(b) allele predicting
Arg89Cys in the Duffy glycoprotein. Brit. J. Haemat. 103: 1184-1191,
1998.

19. Palmer, C. G.; Christian, J. C.; Merritt, A. D.: Partial trisomy
1 due to a 'shift' and probable location of the Duffy (Fy) locus. Am.
J. Hum. Genet. 29: 371-377, 1977.

20. Pasvol, G.; Wilson, R. J. M.: The interaction of malaria parasites
with red blood cells. Brit. Med. Bull. 38: 133-140, 1982.

21. Pogo, A. O.; Chaudhuri, A.: The Duffy protein: a malarial and
chemokine receptor. Seminars Hemat. 37: 122-129, 2000.

22. Raeymaekers, P.; Van Broeckhoven, C.; Backhovens, H.; Wehnert,
A.; Muylle, L.; De Jonghe, P.; Gheuens, J.; Vandenberghe, A.: The
Duffy blood group is linked to the alpha-spectrin locus in a large
pedigree with autosomal dominant inheritance of Charcot-Marie-Tooth
disease type 1. Hum. Genet. 78: 76-78, 1988.

23. Ritter, H.: Zur formalen Genetik des Duffy-systems. Untersuchung
von 247 Familien. Humangenetik 4: 59-61, 1967.

24. Robson, E. B.; Cook, P. J. L.; Corney, G.; Hopkinson, D. A.; Noades,
J.; Cleghorn, T. E.: Linkage data on Rh, PGM, PGD, peptidase C and
Fy from family studies. Ann. Hum. Genet. 36: 393-399, 1973.

25. Tournamille, C.; Colin, Y.; Cartron, J. P.; Le Van Kim, C.: Disruption
of a GATA motif in the Duffy gene promoter abolishes erythroid gene
expression in Duffy-negative individuals. Nature Genet. 10: 224-228,
1995.

26. Tournamille, C.; Le Van Kim, C.; Gane, P.; Cartron, J.-P.; Colin,
Y.: Molecular basis and PCR-DNA typing of the Fya/fyb blood group
polymorphism. Hum. Genet. 95: 407-410, 1995.

27. Tournamille, C.; Le Van Kim, C.; Gane, P.; Le Pennec, P. Y.; Roubinet,
F.; Babinet, J.; Cartron, J. P.; Colin, Y.: Arg89Cys substitution
results in very low membrane expression of the Duffy antigen/receptor
for chemokines in Fy(x) individuals. Blood 92: 2147-2156, 1998.
Note: Erratum: Blood 95: 2753 only, 2000.

28. Weitkamp, L. R.: Personal Communication. Rochester, N. Y.
1972.

*FIELD* CS
Immune:
Duffy negative blacks are more resistant to vivax malaria

Lab:
Duffy blood group

Inheritance:
Autosomal dominant

*FIELD* ED
joanna: 02/07/2011

*FIELD* CN
Matthew B. Gross - updated: 12/21/2010
Paul J. Converse - updated: 8/13/2009
Paul J. Converse - updated: 7/7/2009
Paul J. Converse - updated: 8/20/2008
Paul J. Converse - updated: 8/8/2008
Victor A. McKusick - updated: 2/19/2008
Victor A. McKusick - updated: 8/8/2007
Paul J. Converse - updated: 7/3/2007
Marla J. F. O'Neill - updated: 8/18/2006
Paul J. Converse - updated: 5/15/2006
Victor A. McKusick - updated: 2/21/2002
Victor A. McKusick - updated: 9/17/2001
Victor A. McKusick - updated: 5/18/2000
Victor A. McKusick - updated: 3/22/2000
Victor A. McKusick - updated: 12/8/1999
Victor A. McKusick - updated: 11/2/1999
Victor A. McKusick - updated: 6/18/1999
Victor A. McKusick - updated: 11/16/1998
Victor A. McKusick - updated: 9/12/1997
Ada Hamosh - updated: 7/10/1997
Victor A. McKusick - updated: 2/3/1997

*FIELD* CD
Victor A. McKusick: 6/16/1986

*FIELD* ED
mgross: 12/22/2010
mgross: 12/21/2010
mgross: 8/13/2009
terry: 8/13/2009
mgross: 7/8/2009
terry: 7/7/2009
wwang: 5/4/2009
mgross: 8/20/2008
terry: 8/8/2008
alopez: 4/11/2008
alopez: 2/26/2008
terry: 2/19/2008
alopez: 8/27/2007
terry: 8/8/2007
mgross: 7/10/2007
mgross: 7/5/2007
terry: 7/3/2007
wwang: 2/15/2007
wwang: 8/28/2006
terry: 8/18/2006
terry: 6/23/2006
mgross: 6/2/2006
terry: 5/15/2006
joanna: 3/17/2004
carol: 7/9/2003
joanna: 5/15/2003
tkritzer: 5/8/2003
terry: 6/27/2002
carol: 2/28/2002
cwells: 2/27/2002
terry: 2/21/2002
mcapotos: 9/19/2001
mcapotos: 9/17/2001
mcapotos: 6/7/2000
mcapotos: 6/1/2000
terry: 5/18/2000
mgross: 4/3/2000
terry: 3/22/2000
mcapotos: 12/15/1999
mcapotos: 12/13/1999
mcapotos: 12/10/1999
terry: 12/8/1999
carol: 11/11/1999
terry: 11/2/1999
jlewis: 6/24/1999
terry: 6/18/1999
terry: 11/19/1998
terry: 11/16/1998
jenny: 9/19/1997
terry: 9/12/1997
alopez: 7/10/1997
alopez: 4/21/1997
mark: 2/3/1997
terry: 2/3/1997
mark: 10/3/1996
terry: 9/17/1996
mark: 3/4/1996
mark: 2/20/1996
mark: 12/13/1995
mark: 11/17/1995
terry: 10/30/1995
pfoster: 4/25/1994
warfield: 4/7/1994
mimadm: 2/11/1994
carol: 12/9/1993

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

DESCRIPTION

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

PATHOGENESIS

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

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

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

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

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

MAPPING

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

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

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

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

- Associations Pending Confirmation

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

MOLECULAR GENETICS

- Variation in HBB and Resistance to Malaria

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

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

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

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

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

- Thalassemia and Resistance to Malaria

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

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

- Variation in FY and Resistance to P. Vivax Infection

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

- G6PD Deficiency and Resistance to Malaria

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

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

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

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

- Variation in GYPA and Resistance to Malaria

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

- Variation in GYPB and Resistance to Malaria

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

- Variation in GYPC and Resistance to Malaria

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

- Southeast Asian Ovalocytosis and Resistance to Cerebral
Malaria

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

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

- Variation in CD36 and Susceptibility or Resistance to Cerebral
Malaria

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

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

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

- Variation in CR1 and Resistance to Malaria

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

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

- Variation in ICAM1 and Susceptibility to Cerebral Malaria

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

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

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

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

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

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

- Variation in TNF and Susceptibility to Cerebral Malaria

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

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

- Variation in NOS2A and Resistance to Malaria

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

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

- Variation in TIRAP and Resistance to Malaria

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

- Variation in FCGR2B and Resistance to Malaria

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

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

- Blood Group O and Resistance to Severe Malaria

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

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

- Variation in GNAS and Susceptibility to Severe Malaria

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

- Variation in TIM1 and Resistance to Cerebral Malaria

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

- Variation in IL12B and Susceptibility to Cerebral Malaria

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

- Variation in FUT9 and Susceptibility to Placental Malaria
Infection

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

- Variation in FCGR2A and Susceptibility to Severe Malaria

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

- Resistance Versus Tolerance

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

- Reviews

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

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

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

ANIMAL MODEL

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

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

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37. Nuchnoi, P.; Ohashi, J.; Kimura, R.; Hananantachai, H.; Naka,
I.; Krudsood, S.; Looareesuwan, S.; Tokunaga, K.; Patarapotikul, J.
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38. Omi, K.; Ohashi, J.; Patarapotikul, J.; Hananantachai, H.; Naka,
I.; Looareesuwan, S.; Tokunaga, K.: CD36 polymorphism is associated
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39. Pasvol, G.; Wainscoat, J. S.; Weatherall, D. J.: Erythrocytes
deficient in glycophorin resist invasion by the malarial parasite
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41. Patel, S. S.; Mehlotra, R. K.; Kastens, W.; Mgone, C. S.; Kazura,
J. W.; Zimmerman, P. A.: The association of the glycophorin C exon
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42. Raberg, L.; Sim, D.; Read, A. F.: Disentangling genetic variation
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43. Rihet, P.; Flori, L.; Tall, F.; Traore, A. S.; Fumoux, F.: Hemoglobin
C is associated with reduced Plasmodium falciparum parasitemia and
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44. Rihet, P.; Traore, Y.; Abel, L.; Aucan, C.; Traore-Leroux, T.;
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45. Roth, E. F., Jr.; Raventos-Suarez, C.; Rinaldi, A.; Nagel, R.
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1983.

46. Rowe, J. A.; Handel, I. G.; Thera, M. A.; Deans, A.-M.; Lyke,
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C. V.; Doumbo, O. K.; Moulds, J. M.: Blood group O protects against
severe Plasmodium falciparum malaria through the mechanism of reduced
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47. Rowe, J. A.; Moulds, J. M.; Newbold, C. I.; Miller, L. H.: P-falciparum
rosetting mediated by a parasite-variant erythrocyte membrane protein
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48. Ruwando, C.; Khea, S. C.; Snow, R. W.; Yates, S. N. R.; Kwiatkoweld,
D.; Gupta, S.; Warn, P.; Alisopp, G. E. M.; Gilbert, S. C.; Peschu,
N.; Newbold, C. I.; Greenwood, S. M.; Marsh, K.; Hill, A. V. S.:
Natural selection of hemi- and heterozygotes for G6PD deficiency in
Africa by resistance to severe malaria. Nature 376: 246-249, 1995.

49. Schuldt, K.; Esser, C.; Evans, J.; May, J.; Timmann, C.; Ehmen,
C.; Loag, W.; Ansong, D.; Ziegler, A.; Agbenyega, T.; Meyer, C. G.;
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50. Serjeantson, S. W.; White, B. S.; Bhatia, K.; Trent, R. J.: A
3.5 kb deletion in the glycophorin C gene accounts for the Gerbich-negative
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51. Sikora, M.; Ferrer-Admetlla, A.; Laayouni, H.; Menendez, C.; Mayor,
A.; Bardaji, A.; Sigauque, B.; Mandomando, I.; Alonso, P. L.; Bertranpetit,
J.; Casals, F.: A variant in the gene FUT9 is associated with susceptibility
to placental malaria infection. Hum. Molec. Genet. 18: 3136-3144,
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52. Sjoberg, K.; Lepers, J. P.; Raharimalala, L.; Larsson, A.; Olerup,
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53. Tham, W.-H.; Wilson, D. W.; Lopaticki, S.; Schmidt, C. Q.; Tetteh-Quarcoo,
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54. Timmann, C.; Evans, J. A.; Konig, I. R.; Kleensang, A.; Ruschendorf,
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57. Turner, L.; Lavstsen, T.; Berger, S. S.; Wang, C. W.; Petersen,
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59. Williams, T. N.; Maltland, K.; Bennett, S.; Ganczakowski, M.;
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Clegg, J. S.: High incidence of malaria in alpha-thalassaemic children. Nature 383:
522-525, 1996.

*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

MIM 611862
*RECORD*
*FIELD* NO
611862
*FIELD* TI
#611862 WHITE BLOOD CELL COUNT QUANTITATIVE TRAIT LOCUS 1; WBCQ1
*FIELD* TX
A number sign (#) is used with this entry because white blood cell count
read moreas a quantitative trait is associated with a single-nucleotide
polymorphism in the DARC gene (613665), which encodes the Duffy blood
group antigen.

MAPPING

Peripheral white blood cell count (WBC) is a clinical measurement, used
to determine evidence of acute inflammation or infection. In addition to
elevation or depression of white blood cell levels with clinical
disorders, peripheral WBC is known to vary among different racial and
ethnic groups. Specifically, WBC is lower among African Americans than
among European Americans (Bain et al., 1984; Reed and Diehl, 1991).
Using admixture mapping, Nalls et al. (2008) analyzed data from African
American participants in 2 population studies. Participants of both
studies were genotyped across more than 1,322 SNPs that were preselected
to be informative for African versus European ancestry and span the
entire genome. Nalls et al. (2008) used these markers to estimate
genetic ancestry in each chromosomal region and then tested the
association between WBC and genetic ancestry at each locus. They found a
locus on chromosome 1q strongly associated with WBC (p less than
10(-12)). The strongest association was with a single-nucleotide
polymorphism (SNP) in the DARC gene, dbSNP rs2814778, a marker known to
eliminate expression of the Duffy blood group antigen (DARC; see
613665.0002). Participants who had both copies of the common West
African allele had a mean WBC of 4.9 (standard deviation 1.3);
participants who had both common European alleles had a mean WBC of 7.1
(standard deviation 1.3). This variant explained approximately 20% of
population variation in WBC.

MOLECULAR GENETICS

By quadrupling the sample size from the Nalls et al. (2008) study, Reich
et al. (2009) showed that low WBC in African Americans, which they
referred to as benign ethnic neutropenia, primarily results from reduced
neutrophil count due to homozygosity for the Duffy-null SNP, dbSNP
rs2814778, rather than to ancestry alone. Reich et al. (2009) noted the
clinical significance of the lower neutrophil counts in individuals
homozygous for the Duffy-null variant in medical decision making, as WBC
is a marker of immunocompetence, infection, and inflammation, and they
proposed the potential utility of dbSNP rs2814778 genotyping.

*FIELD* RF
1. Bain, B.; Seed, M.; Godsland, I.: Normal values for peripheral
blood white cell counts in women of four different ethnic origins. J.
Clin. Path. 37: 188-193, 1984.

2. Nalls, M. A.; Wilson, J. G.; Patterson, N. J.; Tandon, A.; Zmuda,
J. M.; Huntsman, S.; Garcia, M.; Hu, D.; Li, R.; Beamer, B. A.; Patel,
K. V.; Akylbekova, E. L.; Files, J. C.; Hardy, C. L.; Buxbaum, S.
G.; Taylor, H. A.; Reich, D.; Harris, T. B.; Ziv, E.: Admixture mapping
of white cell count: genetic locus responsible for lower white blood
cell count in the Health ABC and Jackson Heart studies. Am. J. Hum.
Genet. 82: 81-87, 2008. Note: Erratum: Am. J. Hum. Genet. 82: 532
only, 2008.

3. Reed, W. W.; Diehl, L. F.: Leukopenia, neutropenia, and reduced
hemoglobin levels in healthy American blacks. Arch. Intern. Med. 151:
501-505, 1991.

4. Reich, D.; Nalls, M. A.; Kao, W. H. L.; Akylbekova, E. L.; Tandon,
A.; Patterson, N.; Mullikin, J.; Hsueh, W.-C.; Cheng, C.-Y.; Coresh,
J.; Boerwinkle, E.; Li, M.; and 12 others: Reduced neutrophil count
in people of African descent is due to a regulatory variant in the
Duffy antigen receptor for chemokines gene. PLoS Genet. 5: e1000360,
2009. Note: Electronic Article.

*FIELD* CN
Paul J. Converse - updated: 7/8/2009

*FIELD* CD
Victor A. McKusick: 2/26/2008

*FIELD* ED
mgross: 12/21/2010
alopez: 3/12/2010
mgross: 7/8/2009
alopez: 4/11/2008
alopez: 2/26/2008

MIM 613665
*RECORD*
*FIELD* NO
613665
*FIELD* TI
*613665 DUFFY ANTIGEN RECEPTOR FOR CHEMOKINES; DARC
;;DUFFY CHEMOKINE RECEPTOR;;
FY GLYCOPROTEIN;;
read moreGLYCOPROTEIN D; GPD
*FIELD* TX

DESCRIPTION

DARC is an acidic glycoprotein that spans the transmembrane domain 7
times and has an extracellular N terminus and an intracellular C
terminus. It is expressed on erythrocytes, endothelial cells of
capillary and postcapillary venules, epithelial cells of kidney
collecting ducts and lung alveoli, and Purkinje cells of cerebellum.
DARC is a promiscuous chemokine receptor that binds chemokines of both
CXC (e.g., IL8; 146930) and CC (e.g., CCL5; 187011) classes, suggesting
that it plays a role in inflammatory reactions. In addition, DARC serves
as the erythroid receptor for the human malarial parasite Plasmodium
vivax and the monkey malarial parasite Plasmodium knowlesi, which
occasionally infects humans (see 611162). Variation in DARC forms the
basis of the Duffy blood group system (110700) (reviews by Pogo and
Chaudhuri (2000), Langhi and Bordin (2006), and Meny (2010)).

CLONING

Hadley et al. (1984) found that the red cell component that carries
Duffy antigen is a 35- to 43-kD protein. Some unusual physical
properties distinguished it from previously described red cell membrane
proteins.

Duffy antigens appear to be multimeric erythrocyte-membrane proteins
composed of different subunits. A glycoprotein of 35 to 45 kD, named
GPD, is the major subunit of the protein complex and has the antigenic
determinants defined by anti-Fy(a), anti-Fy(b), and anti-Fy6 antibodies.
Chaudhuri et al. (1993) isolated cDNA clones encoding the major subunit
of the Duffy blood group from a human bone marrow cDNA library using a
PCR-amplified DNA fragment encoding an internal peptide sequence of the
GPD protein. The ORF of the 1,267-bp cDNA clone indicated that GPD
protein is composed of 338 amino acids, predicting a molecular mass of
35,733, which is the same as a deglycosylated GPD protein. In Southern
blot analysis, Chaudhuri et al. (1993) used a GPD cDNA probe to identify
a single gene in Duffy-positive and -negative individuals.
Duffy-negative individuals, therefore, have the GPD gene, but it is not
expressed in bone marrow. The same or a similar gene is active in adult
kidney, adult spleen, and fetal liver of Duffy-positive individuals.
Chaudhuri et al. (1993) found a significant protein sequence homology to
human and rabbit interleukin-8 receptors (see IL8RA; 146929).

The Duffy glycoprotein is expressed along postcapillary venules
throughout the body, except in liver. Erythroid cells and postcapillary
venule endothelium are the principal tissues expressing Duffy
transcripts. Fy(a-b-) individuals do not produce Duffy mRNA in bone
marrow, in accordance with the absence of Duffy glycoprotein on their
erythrocytes. However, in organs other than bone marrow of
Duffy-negative individuals, mRNA of the same size but less quantity than
those of Duffy-positive individuals is expressed. Chaudhuri et al.
(1995) demonstrated Duffy glycoprotein on endothelial cells of Fy(a-b-)
individuals.

By 5-prime and 3-prime RACE of erythroblast and lung RNA, Iwamoto et al.
(1996) cloned a DARC splice variant containing a novel first exon. This
novel exon encodes 7 amino acids, including an initiating methionine,
and is spiced in-frame to nucleotide 203 of the cDNA reported by
Chaudhuri et al. (1993). Downstream of nucleotide 203, the sequences
reported by Chaudhuri et al. (1993) and Iwamoto et al. (1996) are
identical. Thus, the variant reported by Iwamoto et al. (1996) encodes a
336-amino acid protein with 7 novel N-terminal amino acids instead of
the 9 N-terminal amino acids of the 338-amino acid protein reported by
Chaudhuri et al. (1993). Northern blot analysis and RT-PCR, followed by
Southern blot analysis, revealed that the spliced DARC transcript
identified by Iwamoto et al. (1996) showed a predominance of about 50-
to 200-fold compared with the unspliced transcript reported by Chaudhuri
et al. (1993) in every organ and erythroid lineage cell line studied.

In their review, Pogo and Chaudhuri (2000) noted that the nucleotide and
amino acid sequences of DARC had to be renumbered after the discovery by
Iwamoto et al. (1996) that the spliced mRNA is the major product of the
DARC gene. They proposed that the first nucleotide of the translation
initiation codon of the major spliced mRNA be numbered nucleotide 1.
This numbering convention avoids inconsistencies created by different
lengths of the 5-prime UTR due to alternative transcription initiation
sites.

By PCR of a pancreas cDNA library, Lee et al. (2003) obtained a cDNA
encoding the Duffy Fy(b) epitope. The predicted 336-amino acid
7-transmembrane domain receptor lacks the DRY motif required for G
protein coupling and signal transduction.

Tang et al. (1999) cloned a mouse gene with a predicted amino acid
sequence homology of approximately 63% to human DARC. Northern blot
analysis demonstrated that the mouse DARC mRNA was highly expressed in
adult mouse spleen and skeletal muscle and in whole embryos between
embryonic days 8.5 to 12.

GENE STRUCTURE

Iwamoto et al. (1996) determined that the DARC gene contains 2 exons.
The region upstream of the initiator ATG codon in exon 1 lacks TATA or
CCAAT boxes, but it includes short GC stretches. Primer extension
analysis in human erythroleukemia cell RNA and ribonuclease protection
analysis in human bone marrow RNA identified a major transcriptional
start site 34 bp upstream from the initiator ATG codon. In lung and
kidney RNA, transcription started 82 bp upstream of the initiator ATG
codon. A GATA1 (305371)-binding motif is located between the 2
transcriptional starts sites and likely plays the core role for the
promoter in erythroid cells, but not in postcapillary venule
endothelium.

Tang et al. (1999) demonstrated that, like the human DARC gene, the
mouse Darc gene exhibits a single intron of 462 bp, which interrupts the
open reading frame between the codons for the seventh and eighth amino
acid residues.

MAPPING

By fluorescence in situ hybridization, Chaganti (1993) mapped the GPD
gene to chromosome 1q22-q23.

Tang et al. (1999) localized the mouse Darc gene to chromosome 1.

GENE FUNCTION

Resistance to vivax malaria and Duffy negativity (see 110700) occurs in
blacks. Miller et al. (1976) presented evidence that Duffy determinants
are directly involved as receptors for the second stage of red cell
invasion by the Plasmodium.

Horuk et al. (1993) presented evidence indicating that the Duffy blood
group antigen is the erythrocyte receptor for the chemokines
interleukin-8 (IL8; 146930) and melanoma growth stimulatory activity
(MGSA, or CXCL1; 155730). IL8 bound minimally to Duffy-negative
erythrocytes. A monoclonal antibody to the Duffy blood group antigen
blocked binding of IL8 in other chemokines to Duffy-positive
erythrocytes. Both MGSA and IL8 blocked binding of the malaria parasite
ligand and invasion of human erythrocytes by Plasmodium knowlesi,
suggesting the possibility of receptor blockade for anti-malarial
therapy.

Szabo et al. (1995) demonstrated that the Duffy chemokine-binding
junction is conserved between mouse and man.

Peiper et al. (1995) found that the Duffy antigen-erythrocyte chemokine
receptor was also expressed by endothelial cells lining postcapillary
venules and splenic sinusoids, suggesting additional unelucidated roles
for this protein.

By Northern blot analysis of hemangiosarcomas, which developed
spontaneously in the spleen of the Eker rat, Tang et al. (1999) found
expression of mRNAs that hybridized with both Darc and Cxcr2 (IL8RB;
146928) probes, suggesting a potential role of these receptors in the
angiogenesis associated with tumor formation.

Lee et al. (2003) found that, when expressed on endothelial cells, the
Duffy antigen bound a number of chemokines, including CXCL1 and CXCL8
(IL8). Duffy antigen expression facilitated movement of CXCL1 across an
endothelial monolayer and enhanced CXCL1- and CXCL8-mediated neutrophil
transendothelial migration. Mice lacking Duffy antigen showed a marked
attenuation of Cxcl8-driven neutrophil recruitment into lungs. Lee et
al. (2003) concluded that Duffy antigen has a role in enhancing
leukocyte recruitment to sites of inflammation by facilitating movement
of chemokines across the endothelium.

Using a yeast 2-hybrid screen, Bandyopadhyay et al. (2006) identified
DARC as an interacting partner of KAI1 (CD82; 600623). They demonstrated
that cancer cells expressing KAI1 attach to vascular endothelial cells
through direct interaction between KAI1 and DARC, leading to inhibition
of tumor cell proliferation and induction of senescence by modulating
the expression of TBX2 (600747) and CDKN1A (116889). In DARC knockout
mice, the metastasis-suppression activity of Kai1 was significantly
compromised, whereas Kai1 completely abrogated pulmonary metastasis in
wildtype and heterozygous littermates. Bandyopadhyay et al. (2006)
concluded that DARC is essential for the function of KAI1 as a
suppressor of metastasis.

Mayr et al. (2008) used a human endotoxemia model of systemic,
self-limited inflammation to investigate the influence of DARC on
inflammation in Duffy-negative and -positive subjects. ELISA, RT-PCR,
and flow cytometric analyses demonstrated similar increases in plasma
levels of TNF (191160), IL6 (147620), and IL10 (124092) and whole-blood
GRO1 (CXCL1), MCP1 (CCL2; 158105), and IL8 mRNA in both Duffy-negative
and -positive groups after lipopolysaccharide (LPS) infusion. MCP1 peak
plasma levels were about 2-fold higher in Duffy-positive individuals
compared with Duffy-negative individuals, and GRO1 levels were about
2.5-fold higher in Duffy-positive individuals 2 hrs after LPS infusion.
Red blood cell (RBC)-bound MCP1, GRO1, and IL8 increased 20- to 50-fold
in Duffy-positive individuals. Mayr et al. (2008) concluded that DARC
substantially alters chemokine concentrations in blood, but it does not
have a protective effect during human endotoxemia.

By incubating DARC-positive and DARC-negative RBCs with HIV-1 and using
flow cytometry, He et al. (2008) showed that DARC bound the virus to
RBCs and, after cell washing, could mediate transfer of the virus,
particularly strains using the CXCR4 coreceptor (162643), to susceptible
target cells. HIV-1 binding to DARC could be inhibited by the DARC
ligands CCL5 (187011) and CXCL8 (IL8), but not by the nonligand CCL3
(182283). He et al. (2008) proposed that the interplay between DARC and
chemokines may influence the amount of free versus DARC-bound virus
available for eventual transfer from RBCs to target cells.

- Reviews

Hadley and Peiper (1997) provided a review of the physiologic role of
the Duffy blood group antigen. They summarized advances in knowledge
from the recognition of Duffy as a receptor on the RBC for the malarial
parasite, Plasmodium vivax, to its identification as a receptor for
chemoattractant cytokines, or chemokines. Duffy blood group antigen is
expressed by endothelial cells of postcapillary venules and by Purkinje
cells of the cerebellum. In these sites it is referred to by the acronym
DARC (Duffy antigen receptor for chemokines). The importance of DARC is
evidenced by the conservation of this gene across species. For those
wishing to assign physiologic significance to DARC, a problem is
presented by the conservation of DARC function and primary structure
across species with, at the same time, a large population of individuals
of African ancestry lacking expression of this receptor on their RBCs
without any detectable adverse consequences. Hadley and Peiper (1997)
stated that further work is required to understand the molecular basis
for maintenance of expression of DARC on endothelial cells and Purkinje
cells, even in individuals who are Duffy negative.

Pogo and Chaudhuri (2000), Langhi and Bordin (2006), and Meny (2010)
provided reviews of DARC and the Duffy blood group system.

MOLECULAR GENETICS

- Duffy Blood Group System: FYA/FYB Polymorphism

Tournamille et al. (1995) found that a single amino acid difference,
gly44-to-asp (G44D; 613665.001), accounts for the difference between the
FYA and FYB alleles at the Duffy blood group locus (see 110700). This is
the result of a G-to-A transition at nucleotide 131 (131G-A), which also
correlates with a BanI restriction site polymorphism. Mallinson et al.
(1995) likewise found G44D as the basis of the FYA/FYB polymorphism.

In their review, Pogo and Chaudhuri (2000) referred to the FYA/FYB
polymorphism as 125G-A, with 125G defining the FYA allele and 125A
defining the FYB allele. The resulting substitution is gly42 to asp
(G42D), with gly42 defining the Fy(a) antigen and asp42 defining the
Fy(b) antigen. The nucleotide and amino acid sequences of DARC were
renumbered due to the discovery by Iwamoto et al. (1996) that a spliced
mRNA, encoding a 336-amino acid protein, is the major product of the
DARC gene.

- Duffy Blood Group System: Fy(a-b-) Phenotype

Chaudhuri et al. (1995) found that Duffy glycoprotein mRNA was present
in lung, spleen, and colon, but not bone marrow, of African American
individuals with the Fy(a-b-) phenotype (see 110700), supporting an
erythroid-specific downregulation of Duffy GP mRNA as the basis of this
phenotype.

Based on the presence of an intact gene and a tissue-specific expression
defect in bone marrow, it was postulated that loss of expression in
erythroid cells of Duffy-negative individuals could be due to a
promoter/enhancer defect. Indeed, Tournamille et al. (1995) demonstrated
that Duffy-negative individuals have a point mutation, -67T-C
(613665.0002), which they called -46T-C, in a consensus binding site for
GATA1 (305371), a transcription factor active in erythroid cells. This
point mutation abolished erythroid promoter activity in reporter gene
assays.

Iwamoto et al. (1996) reported the same DARC promoter mutation as
Tournamille et al. (1995). The mutation, which Iwamoto et al. (1996)
called -365T-C, was found in the proximal GATA motif from 3 black
Fy(a-b-) individuals. Their studies indicated that the black-type
mutation abolishes Duffy gene expression in erythroid but not in
postcapillary venule endothelium, which is compatible with the Northern
blot and immunohistochemical observations in black Fy(a-b-) individuals.

Mallinson et al. (1995) presented evidence for 2 different genetic
backgrounds giving rise to the Fy(a-b-) phenotype. The most likely
genetic mechanism in most individuals is downregulation of Duffy
glycoprotein mRNA. However, the Duffy gene from a very rare Caucasian
individual (AZ) with the Fy(a-b-) phenotype had a 14-bp deletion
(613665.0004), resulting in a frameshift that introduced a stop codon
and produced a putative truncated 118-amino acid protein. The occurrence
of this mutation in an apparently healthy individual raised questions
about the functional importance of the Duffy glycoprotein, not only in
normal erythrocytes, but also in all human cells and tissues. The only
known examples of the Fy(a-b-) phenotype in Caucasians were AZ and Czech
gypsies.

In a P. vivax-endemic region of Papua New Guinea where the resident
Abelam-speaking population is characterized by a frequency of
alpha(+)-thalassemia of 98% or greater, Zimmerman et al. (1999)
discovered that the mutation responsible for erythrocyte Duffy
antigen-negativity, Fy(a-b-), is located on the FY*A allele. In this
study population, there were 23 heterozygous and no homozygous
individuals bearing the new allele, giving an allele frequency of
23/1062, or 0.022. Flow cytometric analysis illustrated a 2-fold
difference in erythroid-specific Fy-antigen expression between
heterozygous-null and homozygous-normal individuals, suggesting a gene
dosage effect. In further comparisons, Zimmerman et al. (1999) observed
a higher prevalence of P. vivax infection in homozygous normals (83/508,
or 0.163) compared with heterozygous FY*A/FY*A(null) (2/23, or 0.087)
individuals, giving an odds ratio of 2.05. Emergence of FY*A(null) in
this population suggests that P. vivax is involved in selection of this
erythroid polymorphism. This mutation would ultimately compromise the
alpha(+)-thalassemia/P. vivax-mediated protection against severe P.
falciparum malaria.

- Duffy Blood Group System: Fy(bwk) Phenotype

Tournamille et al. (1998) and Olsson et al. (1998) described a Duffy
allele, FYB-weak (FYB-WK), or FYX, in approximately 3.5% of the
population that, because of an arg89-to-cys (R89C; 613665.0003)
substitution in the first cytoplasmic domain of DARC, results in reduced
levels of protein, lower antigen expression, and reduced ability to bind
chemokines. The phenotype is called Fy(bwk), Fy(x), or either
Fy(a-b+(weak)) or Fy(a+b+(weak)) (see 110700). The R89C substitution
results from a C-to-T change at nucleotide 286 of the DARC gene.

- White Blood Cell Count Quantitative Trait Locus 1

Using the method of admixture mapping in a genetic association study,
Nalls et al. (2008) found a strong association between a marker known to
affect the expression of the Duffy blood group antigen (-67T-C;
613665.0002) and the presence of lower white blood cell count (611862)
characteristic of African Americans as contrasted with European
Americans.

By quadrupling the sample size from the Nalls et al. (2008) study, Reich
et al. (2009) showed that low white blood cell count in African
Americans, which they referred to as benign ethnic neutropenia,
primarily results from reduced neutrophil count due to homozygosity for
the Duffy-null SNP, dbSNP rs2814778, rather than to ancestry alone.
Reich et al. (2009) noted the clinical significance of the lower
neutrophil counts in individuals homozygous for the Duffy-null variant
in medical decision making, as white blood cell count is a marker of
immunocompetence, infection, and inflammation, and they proposed the
potential utility of dbSNP rs2814778 genotyping.

POPULATION GENETICS

Livingstone (1984) examined the seeming paradox that the Duffy-negative
allele (see 110700.0002) is most frequent in areas where there is no
vivax malaria. Most red cell polymorphisms that have been considered to
be due to malaria selection are found in high frequencies in populations
with endemic malaria. Possible explanations are that vivax malaria was
eliminated from West Africa by genetic adaptations to the organism or
that a prior-existing high frequency of the Duffy-negative allele
prevented vivax malaria from becoming endemic in West Africa.
Livingstone (1984) suggested that 'the temperate climate adaptations of
the vivax parasite and its probable primate malaria ancestor point to
the latter possibility.'

Whereas mechanisms governing 'balanced polymorphism' presumably
constrain the increase in frequency of mutations conferring homozygous
lethal phenotypes, e.g., that of hemoglobin S in sickle cell anemia,
other mutations have increased to fixation, including the Duffy blood
group negativity, Fy(a-b-), in Africans, and alpha(+)-thalassemia in
Melanesians. The Duffy-negative phenotype, due to a promoter mutation at
a GATA1-binding site, is haplotypically associated in Africans with the
Fy(b) allele. Because Fy(a-b-) prevents Plasmodium vivax from invading
host erythrocytes and completing its complex life cycle, it is not
surprising that vast regions of Africa inhabited by Fy(a-b-) human
populations are devoid of this malaria parasite. Although the
specificity of the parasite-receptor interaction suggests that selective
pressure by the pathogen drove the allele to fixation, the apparent lack
of significant mortality from P. vivax infection counters this
hypothesis. Alternatively, debates suggest that preexisting high
frequency of Fy(a-b-) prevented P. vivax from becoming established in
Africa (Livingstone, 1984). In contrast to Duffy-null, the mechanism by
which alpha(+)-thalassemia protects against malaria is unknown.
Epidemiologic surveys (Allen et al., 1997) demonstrated that
alpha(+)-thalassemia is associated with increased susceptibility to
uncomplicated malaria among young children; see 141800. It was proposed
that alpha(+)-thalassemia may facilitate so-called 'benign' P. vivax
infection to act later in life as a 'natural vaccine' against severe
Plasmodium falciparum malaria.

Lautenberger et al. (2000) used the -46T-C FY polymorphism to study
linkage disequilibrium with other markers in the region of the FY gene.
They found evidence of strong and consistent linkage disequilibrium with
3 such loci (D1S303, D1S484, and the SPTA1 gene (182860)) spanning 8 cM.
Lautenberger et al. (2000) also observed significant linkage
disequilibrium signals over a 30-cM region for short tandem repeats and
at 26.4 cM for the AT3 gene (107300), which, by admixture linkage
disequilibrium (MALD) assessment in African American
population-association analyses, provided quantitative estimates of
centimorgan limits of 5 to 10 cM.

The Duffy blood group locus provides a unique opportunity to
characterize the impact of selection on patterns of sequence variation,
as a function of the distance from a targeted mutation. Hamblin and Di
Rienzo (2000) focused on variation around the FY*O mutation (-67T-C) in
sub-Saharan African populations in which the FY*O allele is virtually
fixed, and they compared the empirical data with theoretical
expectations based on a simple selective-sweep model. They found that
the F(ST) value for the FY*O allele is the highest observed in any
allele in humans, providing strong evidence for the action of natural
selection at this locus. Homozygosity for the null allele confers
complete resistance to vivax malaria. To characterize the signature of
directional selection at this locus, they surveyed DNA sequence
variation, both in a 1.9-kb region centered on the FY*O mutation site,
and in a 1-kb region 5 to 6 kb away from it, in 17 Italians and in a
total of 24 individuals from 5 sub-Saharan African populations. The
level of variation across both regions was 2- to 3-fold lower in the
Africans than in the Italians. As a result, the pooled African sample
showed a significant departure from the neutral expectation for the
number of segregating sites, whereas the Italian sample did not. The
FY*O allele occurred on 2 major haplotypes in 3 of the 5 African
populations. This finding could be due to recombination, recurrent
mutation, population structure, and/or mutation accumulation and drift.
Although the authors were unable to distinguish among these alternative
hypotheses, it was considered likely that the 2 major haplotypes
originated before the operation of selection on the FY*O mutation.

The Duffy blood group locus has been considered a likely target of
natural selection because of the extreme pattern of geographic
differentiation of its 3 major alleles, FY*B, FY*A, and FY*O. Hamblin et
al. (2002) resequenced the FY region in samples of Hausa from Cameroon
(fixed for FY*O), Han Chinese (fixed for FY*A), Italians, and
Pakistanis. The data from the FY region were compared with the patterns
of variation observed in 10 unlinked, putatively neutral loci from the
same populations, as well as with theoretical expectations from the
neutral-equilibrium model. The FY region in the Hausa showed evidence of
directional selection in 2 independent properties of the data, i.e.,
level of sequence variation and frequency spectrum; these observations
were consistent with the FY*O mutation being the target. The Italian and
Chinese FY data showed patterns of variation that were very unusual,
particularly with regard to frequency spectrum and linkage
disequilibrium, but did not fit the predictions of any simple model of
selection. These patterns may represent a more complex and previously
unrecognized signature of positive selection.

EVOLUTION

Li et al. (1997) found a polymorphism of a dinucleotide (GT)-repeat
sequence, designated FyGT/C, in the 3-prime untranslated region of the
Duffy gene. They typed the frequency of the polymorphic variants in
chimpanzee and humans of African and Japanese origin to trace the origin
of the FY, FYA, and FYB alleles. The chimpanzee sequence had a single
substituted GC at the eleventh repeat from the 3-prime end similar to
the FyGT14C1 or FyGT15C1 alleles associated with the FYB allele, but did
not contain the -365T-to-C substitution observed in Africans with the FY
allele, who had 2 different alleles at the FyGT/C locus: FY-GT15C1B and
FY-GT14C1B. Thus, the authors postulated that the FYB allele is the
ancestral human allele, and that the African FY allele diverged from the
FYB along with the divergence of Africans from non-Africans. In the
Japanese FYA cluster of 110 random individuals, 3 different
polymorphisms were observed in the expected Hardy-Weinberg distribution.

ANIMAL MODEL

By fine mapping bone mineral density (BMD) quantitative trait loci (QTL)
in chromosome 1 of intercrossed mouse strains, expression profiling of
genes in the QTL region, and SNP analysis, Edderkaoui et al. (2007)
identified Darc as a candidate mouse chromosome 1 BMD QTL gene. Mice
lacking Darc had increased femur volumetric BMD, smaller trabecular
volume, and decreased endosteal circumference. Darc -/- mice also had
reduced osteoclast formation and activity. Edderkaoui et al. (2007)
concluded that DARC plays an important role in regulating femur BMD via
control of osteoclastogenesis and suggested that DARC may have a role in
osteoporosis. They noted that human chromosome 1q21-q43, which is
syntenic to the region on mouse chromosome 1 containing the BMD QTL,
also contains a BMD QTL (BMND2; 605833).

Hepatocystis kochi is a malaria-like pathogen common in baboons that
produces anemia and merocyst formation, but not the cyclical fever
spikes typical of malaria in humans. Tung et al. (2009) identified
variation in the cis regulatory region of Fy in wild Kenyan baboons that
was associated with susceptibility to Hepatocystis kochi. Genetic
variation in the region also influenced gene expression in vivo, and
this finding was confirmed by reporter analysis in vitro.

HISTORY

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

*FIELD* AV
.0001
DUFFY BLOOD GROUP SYSTEM, FYA/FYB POLYMORPHISM
DARC, GLY42ASP

Tournamille et al. (1995) found that a single amino acid difference,
gly44-to-asp (GLY44ASP; G44D), accounts for the difference between the
FYA and FYB alleles at the Duffy blood group locus. This is the result
of a G-to-A transition at nucleotide 131 (131G-A), which also correlates
with a BanI restriction site polymorphism. This polymorphism allowed
them to develop a method for the DNA typing of the main Duffy blood
group antigens by means of PCR/restriction fragment length
polymorphisms. Mallinson et al. (1995) likewise found G44D as the basis
of the FYA/FYB polymorphism.

In their review, Pogo and Chaudhuri (2000) referred to this SNP as
125G-A, with 125G defining the FYA allele and 125A defining the FYB
allele. The resulting substitution is gly42 to asp (G42D), with gly42
defining the Fy(a) antigen and asp42 defining the Fy(b) antigen. The
nucleotide and amino acid sequences of DARC were renumbered due to the
discovery by Iwamoto et al. (1996) that a spliced mRNA, encoding a
336-amino acid protein, is the major product of the DARC gene.

.0002
DUFFY BLOOD GROUP SYSTEM, FY(a-b-) PHENOTYPE
PLASMODIUM VIVAX, RESISTANCE TO, INCLUDED;;
WHITE BLOOD CELL COUNT QUANTITATIVE TRAIT LOCUS 1, INCLUDED
DARC, -67T-C (dbSNP rs2814778)

The Fy(a-b-) phenotype is rare among white and Asian populations,
whereas it is the predominant phenotype among populations of black
people, especially those originating in West Africa. Tournamille et al.
(1995) demonstrated that the molecular basis of the Fy(a-b-) phenotype
is a T-to-C transition at nucleotide -46, numbering relative to the
erythroid transcriptional start site, in the GATA box of the FYB
promoter. This mutation disrupts the binding site for the GATA1 (305371)
erythroid transcription factor, results in a silent FYB allele in
erythroid cells, and is considered to be responsible for most cases of
Fy(a-b-) erythrocytes in black populations. The GATA mutation generates
a StyI restriction site, allowing the identification of this mutation by
RFLP. The Fy(a-b-) phenotype provides complete protection from
Plasmodium vivax infection (see 611162).

Iwamoto et al. (1996) reported the same DARC promoter mutation as
Tournamille et al. (1995). The mutation, which Iwamoto et al. (1996)
called -365T-C, was found in the proximal GATA motif from 3 black
Fy(a-b-) individuals. Iwamoto et al. (1996) found that the black-type
mutation abolished chloramphenicol acetyltransferase transcription in
human erythroleukemia cells but not in human microvascular endothelial
cells. Deletion mutagenesis studies revealed that the proximal GATA
motif represents the erythroid regulatory core region for the Duffy
gene. Gel shift assay showed that the proximal GATA motif is the target
sequence of GATA1 (305371). These studies indicated that the black-type
mutation abolishes Duffy gene expression in erythroid but not in
postcapillary venule endothelium, which is compatible with the Northern
blot and immunohistochemical observation in black Fy(a-b-) individuals.

In their review, Pogo and Chaudhuri (2000) referred to this SNP as
-33T-C, numbering relative to the major erythroid transcriptional start
site reported by Iwamoto et al. (1996), which is located 34 nucleotides
upstream of the translation initiation codon for the major DARC isoform.
Pogo and Chaudhuri (2000) referred to the allele as FYB-erythroid
silent, or FYB-ES. In another review, Meny (2010) referred to this SNP
as -67T-C, numbering relative to the translational start site of the
major DARC isoform.

In a P. vivax-endemic region of Papua New Guinea where the resident
Abelam-speaking population is characterized by a frequency of
alpha(+)-thalassemia of 98% or greater, Zimmerman et al. (1999)
discovered that the mutation responsible for erythrocyte Duffy
antigen-negativity, Fy(a-b-), is located on the FY*A allele. In this
study population, there were 23 heterozygous and no homozygous
individuals bearing the new allele, giving an allele frequency of
23/1062, or 0.022. Flow cytometric analysis illustrated a 2-fold
difference in erythroid-specific Fy-antigen expression between
heterozygous-null and homozygous-normal individuals, suggesting a gene
dosage effect. In further comparisons, Zimmerman et al. (1999) observed
a higher prevalence of P. vivax infection in homozygous normals (83/508,
or 0.163) compared with heterozygous FY*A/FY*A(null) (2/23, or 0.087)
individuals, giving an odds ratio of 2.05. Emergence of FY*A(null) in
this population suggests that P. vivax is involved in selection of this
erythroid polymorphism. This mutation would ultimately compromise the
alpha(+)-thalassemia/P. vivax-mediated protection against severe P.
falciparum malaria.

In a review of the evolutionary significance of cis-regulatory
mutations, Wray (2007) listed a common polymorphism of DARC resulting in
resistance to infection with malaria. They argued that changes in
cis-regulatory sequences constitute an important part of the genetic
basis for adaptation. The claim was empirically well supported by
studies, such as those of DARC, identifying cis-regulatory mutations
that have functionally significant consequences for morphology,
physiology, and behavior.

The -46T-C promoter SNP in DARC is widely prevalent in populations of
African descent, and -46CC genotype results in selective loss of DARC
expression on RBCs. He et al. (2008) found that, in the admixed
African-American population, the DARC -46C allele was in Hardy-Weinberg
equilibrium in human immunodeficiency virus (HIV; see 609423)-negative
subjects, but it was in disequilibrium in HIV-positive patients.
Genotype analysis indicated that the prevalence of -46CC was greater in
HIV-positive patients, and -46CC individuals had a 50% higher risk of
acquiring HIV. Calculation of the population attributable fraction for
excess HIV burden was estimated to be 11% for DARC -46CC in African
settings. In contrast, DARC -46CC was associated with slower disease
progression in terms of death or development of dementia.

Kulkarni et al. (2009) found that ethnic leukopenia present in healthy
African Americans was also present in the setting of HIV infection. The
disease course among HIV+ African Americans with low WBC was slower than
that of HIV+ European Americans with low WBC. DARC -46CC was present
nearly exclusively in African Americans (69.1%) compared to European
Americans (0.2%), and there was a trend toward a survival advantage for
HIV+ African Americans with -46 CC compared to HIV+ European Americans
or to African Americans with DARC -46CT or -46TT. However, the survival
advantage associated with -46CC was highly dependent on WBC counts, as
this association was greatly magnified in subjects with low WBC and
muted in those with high WBC. Overall, the observations indicated that
ethnic leukopenia in HIV-infected African Americans may be associated
with a more benign phenotype, despite HIV-induced immunodeficiency.

White blood cell count is lower among African Americans compared to
European Americans (see 611862). In a study of 2 African American
populations using admixture mapping to identify loci that influence
white blood cell count, Nalls et al. (2008) found a significant
association of low white blood cell count with a higher proportion of
African ancestry, and identified the strongest association with the DARC
single-nucleotide polymorphism dbSNP rs2814778, which controls
expression of the Duffy blood group antigen. Nalls et al. (2008) noted
that this is one of the alleles in the genome with the largest allele
frequency difference between West Africans and European Americans.

By quadrupling the sample size from the Nalls et al. (2008) study, Reich
et al. (2009) showed that low white blood cell count in African
Americans primarily results from reduced neutrophil count due to
homozygosity for the Duffy-null SNP, dbSNP rs2814778, rather than to
ancestry alone. Reich et al. (2009) noted the clinical significance of
the lower neutrophil counts in individuals homozygous for the Duffy-null
variant in medical decision making, as white blood cell count is a
marker of immunocompetence, infection, and inflammation, and they
proposed the potential utility of dbSNP rs2814778 genotyping.

.0003
DUFFY BLOOD GROUP SYSTEM, FY(bwk) PHENOTYPE
DARC, ARG89CYS

Tournamille et al. (1998) and Olsson et al. (1998) described a Duffy
allele, FYB-weak (FYB-WK), or FYX, in approximately 3.5% of the
population that, because of an arg89-to-cys (R89C) substitution in the
first cytoplasmic domain of DARC, results in reduced levels of protein,
lower antigen expression, and reduced ability to bind chemokines. The
phenotype is called Fy(bwk), Fy(x), or either Fy(a-b+(weak)) or
Fy(a+b+(weak)). The R89C substitution results from a C-to-T change at
nucleotide 286 of the DARC gene.

Parasol et al. (1998) noted that, in addition to West African blacks,
the Duffy-null phenotype also occurs in non-Ashkenazi Jews, being found,
for example, in approximately 20% of Jews from Yemen. They found that in
some of these cases Fy(b-) individuals had the wildtype FY*B GATA but
carried 271C-T and 304G-A mutations. The 271C-T substitution resulted in
an R91C amino acid substitution (R89C in the predominant DARC isoform
reported by Iwamoto et al. (1996)), which represented a considerable
change of chemical nature, one that may affect the antigenic
determinants of DARC, and thus may be of clinical significance. Parasol
et al. (1998) noted that further studies were needed to determine
whether erythrocytes carrying these mutations behave as Fy(bwk)
variants.

Carrington et al. (1997) described a CCR5 (601373) allele that carries a
single amino acid substitution (R60S; 601373.0008) in the first
intracellular domain of the protein that in heterozygous state appears
to protect against human immunodeficiency virus (HIV) infection (see
609423). Tamasauskas et al. (2001) showed that in both the CCR5 R60S and
DARC R89C alleles, the loss of a positive charge from the intracellular
loop leads to reduced surface expression, thereby identifying a novel
mechanism that may be protective against disease: against malarial
infection by Plasmodium vivax in the case of the DARC gene and against
AIDS in the case of the CCR5 gene.

.0004
DUFFY BLOOD GROUP SYSTEM, FY(a-b-) PHENOTYPE
DARC, 14-BP DEL, NT286

Mallinson et al. (1995) presented evidence for 2 different genetic
backgrounds giving rise to the Fy(a-b-) phenotype. The most likely
genetic mechanism in most individuals is downregulation of Duffy
glycoprotein mRNA (see 613665.0002). However, the Duffy gene from a very
rare Caucasian individual (AZ) with the Fy(a-b-) phenotype had a 14-bp
deletion that resulted in a frameshift. In the Abstract and Results
sections of their paper, Mallinson et al. (1995) reported that the
deletion removed nucleotides 287 to 301 of DARC. However, their Figure 4
showed that the deletion involved nucleotides 292 to 305, which appeared
to be correct. The DARC cDNA sequence used by Mallinson et al. (1995)
was identical to that of the minor DARC variant reported by Chaudhuri et
al. (1993). The frameshift resulting from the deletion introduced a stop
codon 23 amino acids downstream and produced a putative truncated
118-amino acid protein. The occurrence of this mutation in an apparently
healthy individual raised questions about the functional importance of
the Duffy glycoprotein, not only in normal erythrocytes, but also in all
human cells and tissues. The only known examples of the Fy(a-b-)
phenotype in Caucasians were AZ and Czech gypsies.

Using the sequence of the major DARC variant reported by Iwamoto et al.
(1996), as was recommended by Pogo and Chaudhuri (2000), this 14-bp
deletion occurs at nucleotide 286.

*FIELD* SA
Howard et al. (1975)
*FIELD* RF
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*FIELD* CN
Cassandra L. Kniffin - updated: 6/13/2011

*FIELD* CD
Matthew B. Gross: 12/10/2010

*FIELD* ED
carol: 02/26/2013
wwang: 6/24/2011
ckniffin: 6/13/2011
mgross: 12/22/2010
mgross: 12/21/2010