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'''Duffy antigen/chemokine receptor''' ('''DARC'''), also known as '''Fy glycoprotein''' ('''FY''') or '''CD234''' ('''C'''luster of '''D'''ifferentiation 234), is a [[protein]] that in humans is encoded by the ''DARC'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: DARC Duffy blood group, chemokine receptor| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2532| accessdate = }}</ref><ref name="pmid8248172">{{cite journal | vauthors = Chaudhuri A, Polyakova J, Zbrzezna V, Williams K, Gulati S, Pogo AO | title = Cloning of glycoprotein D cDNA, which encodes the major subunit of the Duffy blood group system and the receptor for the Plasmodium vivax malaria parasite | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 90 | issue = 22 | pages = 10793–7 | date = November 1993 | pmid = 8248172 | pmc = 47864 | doi = 10.1073/pnas.90.22.10793 | bibcode = 1993PNAS...9010793C }}</ref><ref name="pmid7663520">{{cite journal | vauthors = Tournamille C, Colin Y, Cartron JP, Le Van Kim C | title = Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals | journal = Nat. Genet. | volume = 10 | issue = 2 | pages = 224–8 | date = June 1995 | pmid = 7663520 | doi = 10.1038/ng0695-224 }}</ref> | |||
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The Duffy antigen is located on the surface of [[red blood cell]]s, and is named after the patient in which it was discovered. The protein encoded by this gene is a [[glycoprotein|glycosylated]] [[membrane protein]] and a non-specific [[receptor (biochemistry)|receptor]] for several [[chemokine]]s. The protein is also the receptor for the human malarial parasites ''[[Plasmodium vivax]]'', ''[[Plasmodium knowlesi]]'' and simian malarial parasite ''[[Plasmodium cynomolgi]]''.<ref>{{cite journal| pmid=28698207 | doi=10.1182/blood-2017-02-764787 | title=Strict Tropism for CD71+/ CD234+ Human Reticulocytes Limits ''Plasmodium cynomolgi'''s Zoonotic Potential | year=2017 | author=Kosaisavee V, Suwanarusk R, Chua ACY, Kyle DE, Malleret B, Zhang R, Imwong M, Imerbsin R, Ubalee R, Sámano-Sánchez H, Yeung BKS, Ong J, Lombardini E, Nosten F, Tan KSW, Bifani P, Snounou G, Rénia L, Russell B | journal=Blood}}</ref> [[Polymorphism (biology)|Polymorphisms]] in this gene are the basis of the Duffy blood group system.<ref name="entrez_2532">{{cite web | title = Entrez Gene: Duffy antigen| url =https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2532 | accessdate = }}</ref> | |||
== History == | |||
It was noted in the 1920s that black Africans had some intrinsic resistance to malaria, but the basis for this remained unknown. The Duffy antigen gene was the fourth gene associated with the resistance after the genes responsible for [[sickle cell anaemia]], [[thalassemia]] and [[glucose-6-phosphate dehydrogenase]]. | |||
In 1950, the Duffy [[antigen]] was discovered in a multiply-transfused [[hemophiliac]] whose serum contained the first example of anti-Fya [[antibody]].<ref> | |||
<ref> {{cite journal|title=A New Human Blood Group|journal=Nature|date= | {{cite journal | title = A New Human Blood Group | journal = Nature | date = 4 February 1950 | vauthors = Cutbush M, Mollison PL, Parkin DM | volume = 165 | issue = 188–189 | pages = 188–189 | doi = 10.1038/165188b0 | url = http://www.nature.com/nature/journal/v165/n4188/pdf/165188b0.pdf | bibcode = 1950Natur.165..188C }} | ||
</ref> | |||
In 1951, the antibody to a second antigen, Fyb, was discovered in [[blood plasma|serum]]. Using these two antibodies, three common [[phenotypes]] were defined: Fy(a+b+), Fy(a+b-), and Fy(a-b+). | |||
Several other types were later discovered bringing the current total up to 6: Fya, Fyb, Fy3, Fy4, Fy5 and Fy6. Only Fya, Fyb and Fy3 are considered clinically important. Reactions to Fy5 have also rarely been reported. | |||
== Genetics and genomics == | |||
== | The Duffy antigen/chemokine [[receptor (biochemistry)|receptor]] gene (gp-Fy; CD234) is located on the long arm of [[chromosome 1]] (1.q22-1.q23) and was cloned in 1993.<ref name="pmid8248172"/> The gene was first localised to chromosome 1 in 1968, and was the first blood system antigen to be localised. It is a single copy gene spanning over 1500 bases and is in two [[exon]]s. The gene encodes a 336 amino acid acidic [[glycoprotein]]. It carries the antigenic determinants of the Duffy blood group system which consist of four codominant [[allele]]s—FY*A and FY*B—coding for the Fy-a and Fy-b antigens respectively, FY*X and FY*Fy, five [[phenotype]]s (Fy-a, Fy-b, Fy-o, Fy-x and Fy-y) and five antigens. Fy-x is a form of Fy-b where the Fy-b gene is poorly expressed. Fy-x is also known as Fy-b<sup>weak</sup> or Fy-b<sup>Wk</sup>. | ||
Fy-a and Fy-b differ by in a single [[amino acid]] at position 42: [[glycine]] in Fy-a and [[aspartic acid]] in Fy-b ([[guanine]] in Fy-a and [[adenosine]] in Fy-b at position 125). A second mutation causing a Duffy negative phenotype is known: the responsible mutation is G -> A at position 298. The genetic basis for the Fy(a-b-) phenotype is a [[point mutation]] in the erythroid specific [[promoter (biology)|promoter]] (a T -> C mutation at position -33 in the [[GATA box]]).<ref>{{cite journal |vauthors=Tournamille C, Colin Y, Cartron JP, Le Van KC | date = Jun 1995 | title = Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals | url = | journal = Nat Genet | volume = 10 | issue = 2| pages = 224–8 | doi=10.1038/ng0695-224 | pmid=7663520}}</ref> This mutation occurs in the Fy-b allele and has been designated Fy-b<sup>Es</sup> (erythroid silent). Two isotypes have been identified. The Fy-x allele is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate [[Transition (genetics)|transitions]]: [[Cytosine]]265[[Threonine]] ([[Arginine]]89[[Cysteine]]) and [[Guanine]]298[[Adenosine]] ([[Alanine]]100[[Threonine]]). A third mutation (a [[transversion (genetics)|transversion]]) in this gene has also been described - G145T ([[Alanine]]49[[Serine]]) - that has been associated with the Fy-x phenotype. | |||
Most Duffy negative blacks carry a silent Fy-b [[allele]] with a single T to C substitution at [[nucleotide]] -46, impairing the [[promoter (biology)|promoter]] activity in erythroid cells by disrupting a binding site for the [[GATA1]] erythroid [[transcription factor]]. The gene is still transcribed in non erythroid cells in the presence of this [[mutation]]. | |||
The Duffy | The Duffy negative phenotype occurs at low frequency among whites (~3.5%) and is due to a third mutation that results in an unstable protein (Arg89Cys: [[cytosine]] -> [[thymidine]] at position 265).<ref name="pmid10738032">{{cite journal | vauthors = Yazdanbakhsh K, Rios M, Storry JR, Kosower N, Parasol N, Chaudhuri A, Reid ME | title = Molecular mechanisms that lead to reduced expression of duffy antigens | journal = Transfusion | volume = 40 | issue = 3 | pages = 310–20 | date = March 2000 | pmid = 10738032 | doi = 10.1046/j.1537-2995.2000.40030310.x }}</ref> | ||
The silent allele has evolved at least twice in the black population of Africa and evidence for selection for this allele has been found.<ref name="pmid10762551">{{cite journal | vauthors = Hamblin MT, Di Rienzo A | title = Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus | journal = American Journal of Human Genetics | volume = 66 | issue = 5 | pages = 1669–79 | date = May 2000 | pmid = 10762551 | pmc = 1378024 | doi = 10.1086/302879 }}</ref> The selection pressure involved here appears to be more complex than many text books might suggest.<ref name="pmid11753822">{{cite journal | vauthors = Hamblin MT, Thompson EE, Di Rienzo A | title = Complex Signatures of Natural Selection at the Duffy Blood Group Locus | journal = American Journal of Human Genetics | volume = 70 | issue = 2 | pages = 369–83 | date = February 2002 | pmid = 11753822 | pmc = 419988 | doi = 10.1086/338628 }}</ref> An independent evolution of this phenotype occurred in [[Papua New Guinea]] has also been documented.<ref name="pmid10570183">{{cite journal | vauthors = Zimmerman PA, Woolley I, Masinde GL, Miller SM, McNamara DT, Hazlett F, Mgone CS, Alpers MP, Genton B, Boatin BA, Kazura JW | title = Emergence of FY*Anull in a Plasmodium vivax-endemic region of Papua New Guinea | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 24 | pages = 13973–7 | date = November 1999 | pmid = 10570183 | pmc = 24175 | doi = 10.1073/pnas.96.24.13973 | bibcode = 1999PNAS...9613973Z }}</ref> | |||
A comparative study of this gene in seven mammalian species revealed significant differences between species.<ref name="pmid19724088">{{cite journal | vauthors = Awasthi G, Dashb AP, Dasa A | title = Evolutionary insights into duffy gene in mammalian taxa with comparative genetic analysis | journal = J Vector Borne Dis | volume = 46 | issue = 3 | pages = 230–6 | date = September 2009 | pmid = 19724088 | doi = }}</ref> The species examined included ''[[Pan troglodytes]]'' (chimpanzee), ''[[Macaca mulatta]]'' (rhesus monkey), ''[[Pongo pygmaeus]]'' (orangutan), ''[[Rattus norvegicus]]'' (brown rat), ''[[Mus musculus]]'' (mouse), ''[[Monodelphis domestica]]'' (opossum), ''[[Bos taurus]]'' (cow) and ''[[Canis familiaris]]'' (dog). | |||
This | Three exons are present in humans and chimpanzees, whereas only two exons occur in the other species. This additional exon is located at the 5' end and is entirely non coding. Both intron and exon size vary considerably between the species examined. Between the chimpanzee and the human, 24 differences in the nucleotide sequence were noted. Of these 18 occurred in non coding regions. Of the remaining 6, 3 were synonymous and 3 non synonymous mutations. The significance of these mutations if any is not known. | ||
The | The mouse ortholog has been cloned and exhibits 63% homology to the human gene at the amino acid level. The mouse gene is located on chromosome 1 between the genetic markers Xmv41 and D1Mit166. The mouse gene has two exons (100 and 1064 nucleotides in length respectively), separated by a 461 base pair intron. In the mouse DARC is expressed during embryonic development between days 9.5 and 12. | ||
In | In yellow baboons (''[[Papio cynocephalus]]'') mutations in this gene have been associated with protection from infection with species of the genus ''[[Hepatocystis]]''.<ref name="pmid19553936">{{cite journal | vauthors = Tung J, Primus A, Bouley AJ, Severson TF, Alberts SC, Wray GA | title = Evolution of a malaria resistance gene in wild primates | journal = Nature | volume = 460 | issue = 7253 | pages = 388–91 | date = July 2009 | pmid = 19553936 | doi = 10.1038/nature08149 | bibcode = 2009Natur.460..388T }}</ref> | ||
The ancestral form of extant DARC alleles in humans appears to be the FY*B allele.<ref name=Schmid2011>Schmid P, Ravenell KR, Sheldon SL, Flegel WA (2011) DARC alleles and Duffy phenotypes in African Americans. Transfusion {{doi|10.1111/j.1537-2995.2011.03431.x}}.</ref> | |||
The gene appears to be under strong purifying selection.<ref name=Oliveira_2012>{{cite journal | vauthors = Oliveira TY, Harris EE, Meyer D, Jue CK, Silva WA | title = Molecular evolution of a malaria resistance gene (DARC) in primates | journal = Immunogenetics | volume = 64 | issue = 7 | pages = 497–505 | year = 2012 | pmid = 22395823 | doi = 10.1007/s00251-012-0608-2 }}</ref> The cause of this selective pressure has not yet been identified. | |||
== Molecular biology == | == Molecular biology == | ||
Duffy has | Biochemical analysis of the Duffy antigen has shown that it has a high content of α-helical secondary structure - typical of chemokine receptors.<ref name=Grodecka_2012>{{cite journal | vauthors = Grodecka M, Bertrand O, Karolak E, Lisowski M, Waśniowska K | title = One-step immunopurification and lectinochemical characterization of the Duffy atypical chemokine receptor from human erythrocytes | journal = Glycoconj. J. | volume = 29 | issue = 2–3 | pages = 93–105 | year = 2012 | pmid = 22246380 | pmc = 3311851 | doi = 10.1007/s10719-011-9367-9 }}</ref> Its N-glycans are mostly of the triantennary complex type terminated with α2-3- and α2-6-linked sialic acid residues with bisecting GlcNAc and α1-6-linked fucose at the core. | ||
The Duffy antigen is expressed in greater quantities on [[reticulocyte]]s than on mature erythrocytes.<ref name="pmid10960522">{{cite journal | vauthors = Woolley IJ, Hotmire KA, Sramkoski RM, Zimmerman PA, Kazura JW | title = Differential expression of the duffy antigen receptor for chemokines according to RBC age and FY genotype | journal = Transfusion | volume = 40 | issue = 8 | pages = 949–53 | date = August 2000 | pmid = 10960522 | doi = 10.1046/j.1537-2995.2000.40080949.x }}</ref> While the Duffy antigen is expressed on [[erythrocytes]] it is also found on some epithelial cells, [[Purkinje cells]] of the [[cerebellum]],<ref name="Horuk1997">{{cite journal | vauthors = Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC | title = Expression of chemokine receptors by subsets of neurons in the central nervous system | journal = Journal of Immunology | volume = 158 | issue = 6 | pages = 2882–90 | year = 1997 | pmid = 9058825 | doi = }}</ref> endothelial cells of [[thyroid]] [[capillaries]], the post-capillary [[venule]]s of some organs including the spleen, liver and kidney<ref name="Hadley1994">{{cite journal | vauthors = Hadley TJ, Lu ZH, Wasniowska K, Martin AW, Peiper SC, Hesselgesser J, Horuk R | title = Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen | journal = J. Clin. Invest. | volume = 94 | issue = 3 | pages = 985–91 | year = 1994 | pmid = 8083383 | pmc = 295143 | doi = 10.1172/JCI117465 }}</ref> and the large pulmonary venules. | |||
In some people who lack the Duffy antigen on their erythrocytes it may still be expressed in some cells.<ref name="Peiper1995">{{cite journal | vauthors = Peiper SC, Wang ZX, Neote K, Martin AW, Showell HJ, Conklyn MJ, Ogborne K, Hadley TJ, Lu ZH, Hesselgesser J, Horuk R | title = The Duffy antigen/receptor for chemokines (DARC) is expressed in endothelial cells of Duffy negative individuals who lack the erythrocyte receptor | journal = J. Exp. Med. | volume = 181 | issue = 4 | pages = 1311–7 | date = April 1995 | pmid = 7699323 | pmc = 2191961 | doi = 10.1084/jem.181.4.1311 }}</ref> It has two potential N-linked glycosylation sites at [[asparagine]] (Asn) 16 and Asn27. | |||
The Duffy antigen has been found to act as a multispecific receptor for chemokines of both the C-C and C-X-C families, including: | |||
* monocyte chemotatic protein-1 (MCP-1) - [[CCL2]]<ref name="Chadhuri1994">{{cite journal | vauthors = Chaudhuri A, Zbrzezna V, Polyakova J, Pogo AO, Hesselgesser J, Horuk R | title = Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor | journal = J. Biol. Chem. | volume = 269 | issue = 11 | pages = 7835–8 | year = 1994 | pmid = 8132497 | doi = }}</ref> | |||
* regulated upon activation normal T expressed and secreted (RANTES) - [[CCL5]]<ref name="Horuk1994">{{cite journal | vauthors = Horuk R, Wang ZX, Peiper SC, Hesselgesser J | title = Identification and characterization of a promiscuous chemokine-binding protein in a human erythroleukemic cell line | journal = J. Biol. Chem. | volume = 269 | issue = 26 | pages = 17730–3 | year = 1994 | pmid = 7517400 | doi = }}</ref> | |||
* melanoma growth stimulatory activity (MSGA-α), KC, neutrophil-activating protein 3 (NAP-3) - [[CXCL1]]/[[CXCL2]]<ref name="Huruk1993">{{cite journal | vauthors = Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, Miller LH | title = A receptor for the malarial parasite ''Plasmodium vivax'': the erythrocyte chemokine receptor | journal = Science | volume = 261 | issue = 5125 | pages = 1182–4 | date = August 1993 | pmid = 7689250 | doi = 10.1126/science.7689250 | url = http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=7689250 | bibcode = 1993Sci...261.1182H }}</ref> | |||
and the angiogenic CXC chemokines: | |||
* Growth related gene alpha (GRO-α) - [[CXCL1]] | |||
* Platelet factor 4 - [[CXCL4]]<ref name=McMorran2012>{{cite journal | vauthors = McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ | title = Platelet factor 4 and Duffy antigen required for platelet killing of ''Plasmodium falciparum'' | journal = Science | volume = 338 | issue = 6112 | pages = 1348–51 | year = 2012 | pmid = 23224555 | doi = 10.1126/science.1228892 |bibcode = 2012Sci...338.1348M }}</ref> | |||
* ENA-78 - [[CXCL5]] | |||
* Neutrophil activating peptide-2 (NAP-2) - [[CXCL7]] | |||
* Interleukin-8 (IL-8) - [[interleukin 8|CXCL8]] | |||
Consequently, the Fy protein is also known as DARC (Duffy Antigen Receptor for Chemokines). The chemokine binding site on the receptor appears to be localised to the [[N-terminus|amino terminus]].<ref name="Lu1995">{{cite journal | vauthors = Lu ZH, Wang ZX, Horuk R, Hesselgesser J, Lou YC, Hadley TJ, Peiper SC | title = The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain | journal = J. Biol. Chem. | volume = 270 | issue = 44 | pages = 26239–45 | year = 1995 | pmid = 7592830 | doi = 10.1074/jbc.270.44.26239 }}</ref> The antigen is predicted to have 7 transmembrane domains, an exocellular N-terminal domain and an endocellular C-terminal domain. Alignment with other seven transmembrane [[G-protein-coupled receptor]]s shows that DARC lacks the highly conserved DRY motif in the second intracellular loop of the [[protein]] that is known to be associated with G-protein signaling. Consistent with this finding ligand binding by DARC does not induce G-protein coupled signal transduction nor a Ca2+ flux unlike other chemokine receptors. Based on these alignments the Duffy antigen is considered to be most similar to the [[interleukin 8 receptor, beta|interleukin-8B receptor]]s. | |||
[[Scatchard analysis]] of competition binding studies has shown high affinity binding to the Duffy antigen with dissociation constants (KD) binding values of 24 ± 4.9, 20 ± 4.7, 41.9 ± 12.8, and 33.9 ± 7 nanoMoles for MGSA, interleukin-8, RANTES and monocyte chemotactic peptide-1 respectively.<ref name="Chaudhuri1994">{{cite journal | vauthors = Chaudhuri A, Zbrzezna V, Polyakova J, Pogo AO, Hesselgesser J, Horuk R | title = Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor | journal = J. Biol. Chem. | volume = 269 | issue = 11 | pages = 7835–8 | date = March 1994 | pmid = 8132497 | doi = }}</ref> | |||
In DARC-transfected cells, DARC is internalized following ligand binding and this led to the hypothesis that expression of DARC on the surface of erythrocytes, [[endothelial]], neuronal cells and [[epithelial]] cells may act as a sponge and provide a mechanism by which inflammatory chemokines may be removed from circulation as well as their concentration modified in the local environment.<ref name="Fukuma2003">{{cite journal | vauthors = Fukuma N, Akimitsu N, Hamamoto H, Kusuhara H, Sugiyama Y, Sekimizu K | title = A role of the Duffy antigen for the maintenance of plasma chemokine concentrations | journal = Biochem. Biophys. Res. Commun. | volume = 303 | issue = 1 | pages = 137–9 | year = 2003 | pmid = 12646177 | doi = 10.1016/S0006-291X(03)00293-6 }}</ref> This hypothesis has also been questioned after [[Gene knockout|knock out]] mice were created. These animals appeared healthy and had normal responses to infection. While the function of the Duffy antigen remains presently (2006) unknown, evidence is accumulating that suggests a role in [[neutrophil]] migration from the blood into the tissues<ref name="Lee_2003a">{{cite journal | vauthors = Lee JS, Frevert CW, Wurfel MM, Peiper SC, Wong VA, Ballman KK, Ruzinski JT, Rhim JS, Martin TR, Goodman RB | title = Duffy antigen facilitates movement of chemokine across the endothelium in vitro and promotes neutrophil transmigration in vitro and in vivo | journal = Journal of Immunology | volume = 170 | issue = 10 | pages = 5244–51 | year = 2003 | pmid = 12734373 | doi = 10.4049/jimmunol.170.10.5244 }}</ref> and in modulating the inflammatory response.<ref name="Dawson2000">{{cite journal | vauthors = Dawson TC, Lentsch AB, Wang Z, Cowhig JE, Rot A, Maeda N, Peiper SC | title = Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC) | journal = Blood | volume = 96 | issue = 5 | pages = 1681–4 | year = 2000 | pmid = 10961863 | doi = }}</ref><ref name="Patterson2002">{{cite journal | vauthors = Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J | title = Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium | journal = J. Pathol. | volume = 197 | issue = 1 | pages = 108–16 | year = 2002 | pmid = 12081195 | doi = 10.1002/path.1100 }}</ref><ref name="Liu1999">{{cite journal | vauthors = Liu XH, Hadley TJ, Xu L, Peiper SC, Ray PE | title = Up-regulation of Duffy antigen receptor expression in children with renal disease | journal = Kidney Int. | volume = 55 | issue = 4 | pages = 1491–500 | year = 1999 | pmid = 10201015 | doi = 10.1046/j.1523-1755.1999.00385.x }}</ref><ref name="Rot2005">{{cite journal | vauthors = Rot A | title = Contribution of Duffy antigen to chemokine function | journal = Cytokine Growth Factor Rev. | volume = 16 | issue = 6 | pages = 687–94 | year = 2005 | pmid = 16054417 | doi = 10.1016/j.cytogfr.2005.05.011 }}</ref><ref name="Segerer2000">{{cite journal | vauthors = Segerer S, Regele H, MacK M, Kain R, Cartron JP, Colin Y, Kerjaschki D, Schlöndorff D | title = The Duffy antigen receptor for chemokines is up-regulated during acute renal transplant rejection and crescentic glomerulonephritis | journal = Kidney Int. | volume = 58 | issue = 4 | pages = 1546–56 | year = 2000 | pmid = 11012889 | doi = 10.1046/j.1523-1755.2000.00316.x }}</ref><ref name="Segerer2001">{{cite journal | vauthors = Segerer S, Cui Y, Eitner F, Goodpaster T, Hudkins KL, Mack M, Cartron JP, Colin Y, Schlondorff D, Alpers CE | title = Expression of chemokines and chemokine receptors during human renal transplant rejection | journal = Am. J. Kidney Dis. | volume = 37 | issue = 3 | pages = 518–31 | year = 2001 | pmid = 11228176 | doi = 10.1016/S0272-6386(01)80009-3 }}</ref><ref name="Bruhl2005">{{cite journal | vauthors = Brühl H, Vielhauer V, Weiss M, Mack M, Schlöndorff D, Segerer S | title = Expression of DARC, CXCR3 and CCR5 in giant cell arteritis | journal = Rheumatology (Oxford, England) | volume = 44 | issue = 3 | pages = 309–13 | year = 2005 | pmid = 15572394 | doi = 10.1093/rheumatology/keh485 }}</ref><ref name="Middleton2005">{{cite journal | vauthors = Middleton J, Americh L, Gayon R, Julien D, Mansat M, Mansat P, Anract P, Cantagrel A, Cattan P, Reimund JM, Aguilar L, Amalric F, Girard JP | title = A comparative study of endothelial cell markers expressed in chronically inflamed human tissues: MECA-79, Duffy antigen receptor for chemokines, von Willebrand factor, CD31, CD34, CD105 and CD146 | journal = J. Pathol. | volume = 206 | issue = 3 | pages = 260–8 | year = 2005 | pmid = 15887283 | doi = 10.1002/path.1788 }}</ref><ref name="Segerer2003">{{cite journal | vauthors = Segerer S, Böhmig GA, Exner M, Colin Y, Cartron JP, Kerjaschki D, Schlöndorff D, Regele H | title = When renal allografts turn DARC | journal = Transplantation | volume = 75 | issue = 7 | pages = 1030–4 | year = 2003 | pmid = 12698093 | doi = 10.1097/01.TP.0000054679.91112.6F }}</ref><ref name="Pruenster2006">{{cite journal | vauthors = Pruenster M, Rot A | title = Throwing light on DARC | journal = Biochem. Soc. Trans. | volume = 34 | issue = Pt 6 | pages = 1005–8 | year = 2006 | pmid = 17073738 | doi = 10.1042/BST0341005 }}</ref> | |||
The protein is also known to interact with the protein KAI1 ([[CD82]]) a surface glycoprotein of [[leukocyte]]s and may have a role in the control of cancer. | |||
The Duffy antigen has been shown to exist as a constitutive homo-oligomer and that it hetero-oligomerizes with the CC chemokine receptor CCR5 ([[CD195]]). The formation of this heterodimer impairs chemotaxis and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding remains unchanged.<ref name="Chakera2008">{{cite journal | vauthors = Chakera A, Seeber RM, John AE, Eidne KA, Greaves DR | title = The duffy antigen/receptor for chemokines exists in an oligomeric form in living cells and functionally antagonizes CCR5 signaling through hetero-oligomerization | journal = Mol. Pharmacol. | volume = 73 | issue = 5 | pages = 1362–70 | date = May 2008 | pmid = 18230715 | doi = 10.1124/mol.107.040915 }}</ref> | |||
DARC has been shown to internalise chemokines but does not scavenge them.<ref name="Pruenster2008">{{cite journal | vauthors = Pruenster M, Mudde L, Bombosi P, Dimitrova S, Zsak M, Middleton J, Richmond A, Graham GJ, Segerer S, Nibbs RJ, Rot A | title = The Duffy antigen receptor for chemokines transports chemokines and supports their promigratory activity | journal = Nat. Immunol. | volume = 10 | issue = 1 | pages = 101–8 | date = January 2009 | pmid = 19060902 | pmc = 3205989 | doi = 10.1038/ni.1675 }}</ref> It mediates chemokine transcytosis, which leds to apical retention of intact chemokines and more leukocyte migration. | |||
Binding melanoma growth-stimulating activity inhibits the binding of ''[[Plasmodium knowlesi|P. knowlesi]]'' to DARC. | |||
== Population genetics == | |||
Differences in the racial distribution of the Duffy antigens were discovered in 1954, when it was found that the overwhelming majority of blacks had the [[erythrocyte]] phenotype Fy(a-b-): 68% in [[African American]]s and 88-100% in African blacks (including more than 90% of [[West Africa]]n blacks).<ref name="isbn0-07-143199-3">{{cite book | author = Levinson, Warren | title = Medical microbiology & immunology: examination & board review | edition = | language = | publisher = Lange Medical Books/McGraw-Hill | location = New York | year = 2004 | origyear = | pages = | quote = | isbn = 0-07-143199-3 | oclc = | doi = | url = | accessdate = }}</ref> This phenotype is exceedingly rare in Caucasians. Because the Duffy antigen is uncommon in those of [[Black people|Black African]] descent, the presence of this antigen has been used to detect genetic [[Genetic admixture|admixture]]. In a sample of unrelated African Americans (n = 235), Afro-Caribbeans (n = 90) and Colombians (n = 93), the frequency of the -46T (Duffy positive) allele was 21.7%, 12.2% and 74.7% respectively.<ref name="pmid10439320">{{cite journal | vauthors = Nickel RG, Willadsen SA, Freidhoff LR, Huang SK, Caraballo L, Naidu RP, Levett P, Blumenthal M, Banks-Schlegel S, Bleecker E, Beaty T, Ober C, Barnes KC | title = Determination of Duffy genotypes in three populations of African descent using PCR and sequence-specific oligonucleotides | journal = Hum. Immunol. | volume = 60 | issue = 8 | pages = 738–42 | date = August 1999 | pmid = 10439320 | doi = 10.1016/S0198-8859(99)00039-7 }}</ref> | |||
Overall the frequencies of Fya and Fyb antigens in Caucasians are 66% and 83% respectively, in Asians 99% and 18.5% respectively and in blacks 10% and 23% respectively. The frequency of Fy3 is 100% Caucasians, 99.9% Asians and 32% Blacks. Phenotype frequencies are: | |||
* Fy(a+b+): 49% Caucasians, 1% Blacks, 9% Chinese | |||
* Fy(a-b+): 34% Caucasians, 22% Blacks, <1% Chinese | |||
* Fy(a+b-): 17% Caucasians, 9% Blacks, 91% Chinese | |||
While a possible role in the protection of humans from malaria had been previously suggested, this was only confirmed clinically in 1976.<ref name="pmid778616">{{cite journal | vauthors = Miller LH, Mason SJ, Clyde DF, McGinniss MH | title = The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy | journal = N. Engl. J. Med. | volume = 295 | issue = 6 | pages = 302–4 | date = August 1976 | pmid = 778616 | doi = 10.1056/NEJM197608052950602 }}</ref> Since then many surveys have been carried out to elucidate the prevalence of Duffy antigen alleles in different populations including: | |||
* The mutation Ala100Thr (G -> A in the first [[codon]] position—base number 298) within the FY*B allele was thought to be purely a [[Caucasian race|Caucasian]] genotype, but has since been described in Brazilians. However, the study's authors point out that the Brazilian population has arisen from intermarriage between Portuguese, Black Africans, and Indians, which accounts for the presence of this mutation in a few members of Brazil's non-Caucasian groups. Two of the three Afro-Brazilian test subjects that were found to have the mutation (out of a total of 25 Afro-Brazilians tested) were also related to one another, as one was a mother and the other her daughter.<ref name="pmid16110438">{{cite journal | vauthors = Estalote AC, Proto-Siqueira R, Silva WA, Zago MA, Palatnik M | title = The mutation G298A-->Ala100Thr on the coding sequence of the Duffy antigen/chemokine receptor gene in non-caucasian Brazilians | journal = Genet. Mol. Res. | volume = 4 | issue = 2 | pages = 166–73 | year = 2005 | pmid = 16110438 | doi = | url = http://www.funpecrp.com.br/gmr/year2005/vol2-4/gmr0122_abstract.htm }}</ref> | |||
* This antigen along with other blood group antigens was used to identify the [[Basque people]] as a genetically separate group.<ref name="pmid16596943">{{cite journal | vauthors = Bauduer F, Feingold J, Lacombe D | title = The Basques: review of population genetics and Mendelian disorders | journal = Hum. Biol. | volume = 77 | issue = 5 | pages = 619–37 | date = October 2005 | pmid = 16596943 | doi = 10.1353/hub.2006.0001 }}</ref> Its use in forensic science is under consideration.<ref name="pmid16566771">{{cite journal | vauthors = Ferri G, Bini C, Ceccardi S, Ingravallo F, Lugaresi F, Pelotti S | title = Minisequencing-based genotyping of Duffy and ABO blood groups for forensic purposes | journal = J. Forensic Sci. | volume = 51 | issue = 2 | pages = 357–60 | date = March 2006 | pmid = 16566771 | doi = 10.1111/j.1556-4029.2006.00058.x }}</ref> | |||
* The [[Andaman Islands|Andaman]] and [[Nicobar Islands|Nicobar]] Islands, now part of India, were originally inhabited by 14 aboriginal tribes. Several of these have gone extinct. One surviving tribe—the [[Jarawa (Andaman Islands)|Jarawas]]—live in three jungle areas of [[South Andaman]] and one jungle area in [[Middle Andaman]]. The area is endemic for [[malaria]]. The causative species is ''[[Plasmodium falciparum]]'': there is no evidence for the presence of ''Plasmodium vivax''. Blood grouping revealed an absence of both Fy(a) and Fy(b) antigens in two areas and a low prevalence in two others.<ref name="pmid15943709">{{cite journal | vauthors = Das MK, Singh SS, Adak T, Vasantha K, Mohanty D | title = The Duffy blood groups of Jarawas - the primitive and vanishing tribe of Andaman and Nicobar Islands of India | journal = Transfus Med | volume = 15 | issue = 3 | pages = 237–40 | date = June 2005 | pmid = 15943709 | doi = 10.1111/j.1365-3148.2005.00583.x }}</ref> | |||
* In the [[Yemen]]ite [[Jew]]s the frequency of the Fy allele is 0.5879<ref name="pmid7346047">{{cite journal | vauthors = Kobyliansky E, Micle S, Goldschmidt-Nathan M, Arensburg B, Nathan H | title = Duffy, Kell and P blood group systems in some Jewish populations of Israel | journal = Acta Anthropogenet | volume = 4 | issue = 3–4 | pages = 173–9 | year = 1980 | pmid = 7346047 | doi = }}</ref> The frequency of this allele varies from 0.1083 to 0.2191 among Jews from the Middle East, North Africa and [[Southern Europe]]. The incidence of Fya among Ashkenazi Jews is 0.44 and among the non-Ashkenazi Jews it is 0.33. The incidence of Fyb is higher in both groups with frequencies of 0.53 and 0.64 respectively.<ref name="Parasol2001">{{cite journal | vauthors = Parasol N, Cohen N, Zemishlany Z, Lerer B, Kosower NS | title = Duffy antigen/receptor for chemokines (DARC): genotypes in Ashkenazi and non-Ashkenazi Jews in Israel | journal = Hum. Biol. | volume = 73 | issue = 2 | pages = 307–13 | date = April 2001 | pmid = 11446431 | doi = 10.1353/hub.2001.0024 }}</ref> | |||
* In the [[Chinese people|Chinese]] ethnic populations—the [[Han (people)|Han]] and the [[She people]]—the frequencies of Fya and Fyb alleles were 0.94 and 0.06 and 0.98 and 0.02 respectively.<ref name="pmid15783300">{{cite journal | vauthors = Yan L, Zhu F, Fu Q, He J | title = ABO, Rh, MNS, Duffy, Kidd, Yt, Scianna, and Colton blood group systems in indigenous Chinese | journal = Immunohematology | volume = 21 | issue = 1 | pages = 10–4 | year = 2005 | pmid = 15783300 | doi = }}</ref> | |||
* The frequency of the Fya allele in most Asian populations is ~95%. | |||
* In [[Grande Comore]] (also known as [[Ngazidja]]) the frequency of the Fy(a- b-) phenotype is 0.86.<ref name="pmid15754970">{{cite journal | vauthors = Chiaroni J, Touinssi M, Frassati C, Degioanni A, Gibert M, Reviron D, Mercier P, Boëtsch G | title = Genetic characterization of the population of Grande Comore Island (Njazidja) according to major blood groups | journal = Hum. Biol. | volume = 76 | issue = 4 | pages = 527–41 | date = August 2004 | pmid = 15754970 | doi = 10.1353/hub.2004.0053 }}</ref> | |||
* The incidence of Fy(a+b-) in northern India among blood donors is 43.85%.<ref name="Thakral2010">{{cite journal | vauthors = Thakral B, Saluja K, Sharma RR, Marwaha N | title = Phenotype frequencies of blood group systems (Rh, Kell, Kidd, Duffy, MNS, P, Lewis, and Lutheran) in north Indian blood donors | journal = Transfus Apher Sci | volume = 43 | issue = 1 | pages = 17–22 | date = June 2010 | pmid = 20558108 | doi = 10.1016/j.transci.2010.05.006 }}</ref> | |||
* In the [[Maghreb]], [[Horn of Africa]] and the [[Nile Valley]], the [[Afroasiatic languages|Afroasiatic]] (Hamitic-Semitic) speaking populations are largely Duffy-positive.<ref>{{cite journal|last1=Rosenberg|first1=Ronald|title=Plasmodium vivax in Africa: hidden in plain sight?|journal=Trends in Parasitology|date=May 2007|volume=23|issue=5|pages=193–196|url=http://www.sciencedirect.com/science/article/pii/S1471492207000554|accessdate=1 June 2016|doi=10.1016/j.pt.2007.02.009}}</ref> Between 70%-98% of Hamito-Semitic groups in Ethiopia were found to be Duffy-positive.<ref>{{cite journal|last1=H. M. Mathews, J. C. Armstrong|title=Duffy Blood Types and Vivax Malaria in Ethiopia|journal=American Journal of Tropical Medicine and Hygiene|date=March 1981|volume=30|pages=299–303|pmid=7015888}}</ref> Serological and DNA based analysis of 115 unrelated [[Tunis]]ians also found an FY*X frequency of 0.0174; FY*1 = 0.291 (expressed 0.260, silent 0.031); FY*2 = 0.709 (expressed 0.427; silent 0.282). Since the FY*2 silent is the most common allele in West Africa, its minor occurrence in the sample probably represents recent diffusion from the latter region.<ref name="pmid18608113">{{cite journal | vauthors = Sellami MH, Kaabi H, Midouni B, Dridi A, Mojaat N, Boukef MK, Hmida S | title = Duffy blood group system genotyping in an urban Tunisian population | journal = Annals of Human Biology | volume = 35 | issue = 4 | pages = 406–15 | year = 2008 | pmid = 18608113 | doi = 10.1080/03014460802082127 }}</ref> | |||
* In [[Nouakchott]], [[Mauritania]] overall 27% of the population are Duffy-positive. 54% of [[Moors|Moor]]s are Duffy antigen positive, while only 2% of black ethnic groups (mainly [[Poular]], [[Soninke people|Soninke]] and [[Wolof people|Wolof]]) are Duffy positive.<ref name="Lepers_1986">{{cite journal | vauthors = Lepers JP, Simonneau M, Charmot G | title = [The Duffy blood group system in the population of Nouakchott (Mauritania)] | language = French | journal = Bull Soc Pathol Exot Filiales | volume = 79 | issue = 3 | pages = 417–20 | year = 1986 | pmid = 3769126 | doi = }}</ref> | |||
* A map of the Duffy antigen distribution has been produced.<ref name="Howes_2011">{{cite journal | vauthors = Howes RE, Patil AP, Piel FB, Nyangiri OA, Kabaria CW, Gething PW, Zimmerman PA, Barnadas C, Beall CM, Gebremedhin A, Ménard D, Williams TN, Weatherall DJ, Hay SI | title = The global distribution of the Duffy blood group | journal = Nat Commun | volume = 2 | issue = 4 | pages = 266 | date = April 2011 | pmid = 21468018 | pmc = 3074097 | doi = 10.1038/ncomms1265 | bibcode = 2011NatCo...2E.266H }}</ref> The most prevalent allele globally is FY*A. Across sub-Saharan Africa the predominant allele is the silent FY*B<sup>ES</sup> variant. | |||
* In [[Iran]] the Fy (a-b-) phenotype was found in 3.4%.<ref name="pmid21840761">{{cite journal | vauthors = Keramati MR, Shakibaei H, Kheiyyami MI, Ayatollahi H, Badiei Z, Samavati M, Sadeghian MH | title = Blood group antigens frequencies in the northeast of Iran | journal = Transfus. Apher. Sci. | volume = 45 | issue = 2 | pages = 133–6 | date = October 2011 | pmid = 21840761 | doi = 10.1016/j.transci.2011.07.006 }}</ref> | |||
There appears to have been a selective sweep in Africa which reduced the incidence of this antigen there. This sweep appears to have occurred between 6,500 and 97,200 years ago (95% confidence interval)<ref name="pmid10762551"/> | |||
The distribution within India has been studied in some detail.<ref name="pmid23028857">{{cite journal | vauthors = Chittoria A, Mohanty S, Jaiswal YK, Das A | title = Natural Selection Mediated Association of the Duffy (FY) Gene Polymorphisms with Plasmodium vivax Malaria in India | journal = PLoS ONE | volume = 7 | issue = 9 | pages = e45219 | year = 2012 | pmid = 23028857 | pmc = 3448599 | doi = 10.1371/journal.pone.0045219 | bibcode = 2012PLoSO...745219C }}</ref> | |||
== Clinical significance == | |||
Historically the role of this antigen other than its importance as a receptor for [[Plasmodium]] protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein. | |||
=== Asthma === | |||
[[Asthma]] is more common and tends to be more severe in those of African descent. There appears to be a correlation with both total [[IgE]] levels and asthma and mutations in the Duffy antigen.<ref name="pmid18827265">{{cite journal | vauthors = Vergara C, Tsai YJ, Grant AV, Rafaels N, Gao L, Hand T, Stockton M, Campbell M, Mercado D, Faruque M, Dunston G, Beaty TH, Oliveira RR, Ponte EV, Cruz AA, Carvalho E, Araujo MI, Watson H, Schleimer RP, Caraballo L, Nickel RG, Mathias RA, Barnes KC | title = Gene Encoding Duffy Antigen/Receptor for Chemokines Is Associated with Asthma and IgE in Three Populations | journal = Am. J. Respir. Crit. Care Med. | volume = 178 | issue = 10 | pages = 1017–22 | date = November 2008 | pmid = 18827265 | pmc = 2582596 | doi = 10.1164/rccm.200801-182OC }}</ref> | |||
=== Hematopoiesis === | |||
Duffy antigen plays a fundamental role on [[hematopoiesis]].<ref name="Duchene2017">{{cite journal | vauthors = Duchene J, Novitzky-Basso I, Thiriot A, Casanova-Acebes M, Bianchini M, Etheridge SL, Hub E, Nitz K, Artinger K, Eller K, Caamaño J, Rülicke T, Moss P, Megens RT, von Andrian UH, Hidalgo A, Weber C, Rot A | title = Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis | journal = Nature Immunology | date = May 2017 | doi = 10.1038/ni.3763 | volume=18 | pages=753–761}}</ref> Indeed, [[nucleated red blood cells]] present in the bone marrow have high expression of DARC, which facilitates their direct contact with [[hematopoietic stem cells]]. The absence of erythroid DARC alters hematopoiesis including stem and progenitor cells, which ultimately gives rise to phenotypically distinct neutrophils. As a result, mature neutrophils of Duffy-negative individuals carry more molecular “weapons” against infectious pathogens.<ref name="Rigby2017">{{cite article | vauthors = Rigby A | title= How Ancestry Shapes Our Immune Cells | url =http://www.zmescience.com/medicine/ancestry-shapes-immune-cells-07052017}}</ref> Therefore, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of DARC in the erythroid lineage.<ref name="Duchene2017"/> | |||
=== Benign ethnic neutropenia === | |||
A significant proportion (25–50%) of otherwise healthy African Americans are known to have a persistently lower white blood cell count than the normal range defined for individuals of European ancestry—a condition known as benign ethnic [[neutropenia]]. This condition is also found in [[Arab]] [[Jordan]]ians, [[Negev Bedouin|Black Bedouin]], [[Falashah Jews]], [[Yemenite Jews]] and [[West Indian]]s. This condition is associated with a reduced capacity to mobilize bone marrow [[neutrophil]] reserves in response to corticosteroids, despite normal cellularity and maturation of all cell lines in bone marrow aspirates. Strongly suggestive evidence has been found that links condition to a mutation in the Duffy gene.<ref name="Reich2009">{{cite journal | vauthors = Reich D, Nalls MA, Kao WH, Akylbekova EL, Tandon A, Patterson N, Mullikin J, Hsueh WC, Cheng CY, Coresh J, Boerwinkle E, Li M, Waliszewska A, Neubauer J, Li R, Leak TS, Ekunwe L, Files JC, Hardy CL, Zmuda JM, Taylor HA, Ziv E, Harris TB, Wilson JG | title = Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene | journal = PLoS Genet. | volume = 5 | issue = 1 | pages = e1000360 | date = January 2009 | pmid = 19180233 | pmc = 2628742 | doi = 10.1371/journal.pgen.1000360 | editor1-last = Visscher | editor1-first = Peter M. }}</ref> The distinctive neutrophils that are formed in the absence of DARC on erythroid lineage (see above - role of DARC on hematopoieisis) readily leave the blood stream, which explains the apparent lower numbers of neutrophils in the blood of Duffy-negative individuals.<ref name="Duchene2017"/><ref name="Rigby2017"/> | |||
=== Cancer === | |||
Interactions between the metastasis suppressor [[CD82 (gene)|KAI1]] on tumor cells and the cytokine receptor DARC on adjacent vascular cells suppresses tumor [[metastasis]].<ref name="pmid16959609">{{cite journal | vauthors = Zijlstra A, Quigley JP | title = The DARC side of metastasis: shining a light on KAI1-mediated metastasis suppression in the vascular tunnel | journal = Cancer Cell | volume = 10 | issue = 3 | pages = 177–8 | date = September 2006 | pmid = 16959609 | doi = 10.1016/j.ccr.2006.08.012 }}</ref> In human breast cancer samples low expression of the DARC protein is significantly associated with estrogen receptor status, both lymph node and distant metastasis and poor survival.<ref name="pmid16785997">{{cite journal | vauthors = Wang J, Ou ZL, Hou YF, Luo JM, Shen ZZ, Ding J, Shao ZM | title = Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential | journal = Oncogene | volume = 25 | issue = 54 | pages = 7201–11 | date = November 2006 | pmid = 16785997 | doi = 10.1038/sj.onc.1209703 }}</ref> | |||
=== Endotoxin response === | |||
The procoagulant response to lipopolysaccaride (bacterial endotoxin) is reduced in Duffy antigen negative Africans compared with Duffy positive Caucasians.<ref name="pmid19187081">{{cite journal | vauthors = Mayr FB, Spiel AO, Leitner JM, Firbas C, Jilma-Stohlawetz P, Chang JY, Key NS, Jilma B | title = Racial differences in endotoxin-induced tissue factor-triggered coagulation | journal = J. Thromb. Haemost. | volume = 7 | issue = 4 | pages = 634–40 | date = April 2009 | pmid = 19187081 | doi = 10.1111/j.1538-7836.2009.03307.x }}</ref> This erence is likely to involve additional genes. | |||
=== HIV infection === | |||
A connection has been found between [[HIV]] susceptibility and the expression of the Duffy antigen. The absence of the DARC receptor appears to increase the susceptibility to infection by HIV. However once established, the absence of the DARC receptor appears to slow down the progression of the disease.<ref name="pmid18621010">{{cite journal | vauthors = He W, Neil S, Kulkarni H, Wright E, Agan BK, Marconi VC, Dolan MJ, Weiss RA, Ahuja SK | title = Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility | journal = Cell Host Microbe | volume = 4 | issue = 1 | pages = 52–62 | date = July 2008 | pmid = 18621010 | pmc = 2562426 | doi = 10.1016/j.chom.2008.06.002 }}</ref> | |||
HIV-1 appears to be able to attach to erythrocytes via DARC.<ref name="pmid18621010"/> | |||
The association between the Duffy antigen and HIV infection appears to be complex. [[Leukopenia]] (a low total white cell count) is associated with relatively poor survival in HIV infection and this association is more marked in [[White people|caucasians]] than in [[Black people|people of Black African descent]], despite the (on average) lower white cell counts found in black Africans. This difference appears to correlate with a particular genotype (-46C/C) associated with the absence of the Duffy antigen.<ref name="pmid19620399">{{cite journal | vauthors = Kulkarni H, Marconi VC, He W, Landrum ML, Okulicz JF, Delmar J, Kazandjian D, Castiblanco J, Ahuja SS, Wright EJ, Weiss RA, Clark RA, Dolan MJ, Ahuja SK | title = The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry | journal = Blood | volume = 114 | issue = 13 | pages = 2783–92 | date = July 2009 | pmid = 19620399 | pmc = 2927046 | doi = 10.1182/blood-2009-04-215186 }}</ref> This genotype has only been found in black Africans and their descendants. The strength of this association increases inversely with the total white cell count. The basis for this association is probably related to the role of the Duffy antigen in [[cytokine]] binding but this has yet to be verified. | |||
A study of 142 black South African high-risk female sex workers over 2 years revealed a seroconversion rate of 19.0%.<ref name = "Ramsuran_2011">{{cite journal | vauthors = Ramsuran V, Kulkarni H, He W, Mlisana K, Wright EJ, Werner L, Castiblanco J, Dhanda R, Le T, Dolan MJ, Guan W, Weiss RA, Clark RA, Karim SS, Ahuja SK, Ndung'u T | title = Duffy-Null–Associated Low Neutrophil Counts Influence HIV-1 Susceptibility in High-Risk South African Black Women | journal = Clin. Infect. Dis. | volume = 52 | issue = 10 | pages = 1248–56 | date = May 2011 | pmid = 21507922 | pmc = 3115278 | doi = 10.1093/cid/cir119 }}</ref> Risk of seroconversion appeared to be correlated with Duffy-null-associated low neutrophil counts. | |||
===Inflammation=== | |||
An association with the levels [[CCL2|monocyte chemoattractant protein-1]] has been reported.<ref name="Voruganti_2012">{{cite journal | vauthors = Voruganti VS, Laston S, Haack K, Mehta NR, Smith CW, Cole SA, Butte NF, Comuzzie AG | title = Genome-wide association replicates the association of Duffy antigen receptor for chemokines (DARC) polymorphisms with serum monocyte chemoattractant protein-1 (MCP-1) levels in Hispanic children | journal = Cytokine | volume = 60 | issue = 3 | pages = 634–8 | date = September 2012 | pmid = 23017229 | doi = 10.1016/j.cyto.2012.08.029 }}</ref> | |||
In the [[Sardinian people|Sardinian population]], an association of several variants in the DARC gene (coding and non-coding) correlates with increased serum levels of monocyte chemoattractant protein (MCP -1). A new variant in this population, consisting of the amino acid substitution of arginine for a cysteine at position 89 of the protein diminishes the ability to bind chemokines.<ref name="pmid26366554">{{cite journal | vauthors = Sidore C, Busonero F, Maschio A, Porcu E, Naitza S, Zoledziewska M, Mulas A, Pistis G, Steri M, Danjou F, Kwong A, Ortega Del Vecchyo VD, Chiang CW, Bragg-Gresham J, Pitzalis M, Nagaraja R, Tarrier B, Brennan C, Uzzau S, Fuchsberger C, Atzeni R, Reinier F, Berutti R, Huang J, Timpson NJ, Toniolo D, Gasparini P, Malerba G, Dedoussis G, Zeggini E, Soranzo N, Jones C, Lyons R, Angius A, Kang HM, Novembre J, Sanna S, Schlessinger D, Cucca F, Abecasis GR | display-authors = 6 | title = Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers | journal = Nature Genetics | volume = 47 | issue = 11 | pages = 1272–81 | year = 2015 | pmid = 26366554 | doi = 10.1038/ng.3368 | pmc=4627508}}</ref> | |||
DARC has also been linked to rheumatoid arthritis (RA), possibly displaying chemokines such as CXCL5 on the surface of endothelial cells within the synovium, increasing the recruitment of neutrophils in the disease state.<ref>{{cite journal | vauthors = Smith E, McGettrick HM, Stone MA, Shaw JS, Middleton J, Nash GB, Buckley CD, Ed Rainger G | title = Duffy antigen receptor for chemokines and CXCL5 are essential for the recruitment of neutrophils in a multicellular model of rheumatoid arthritis synovium | journal = Arthritis and Rheumatism | volume = 58 | issue = 7 | pages = 1968–73 | date = July 2008 | pmid = 18576313 | pmc = 2821686 | doi = 10.1002/art.23545 }}</ref> | |||
=== Lung transplantation === | |||
The Duffy antigen has been implicated in lung transplantation rejection.<ref name="Geleff2009">{{cite journal | vauthors = Geleff S, Draganovici D, Jaksch P, Segerer S | title = The role of chemokine receptors in acute lung allograft rejection | journal = Eur. Respir. J. | volume = 35 | issue = 1 | pages = 167–75 | date = July 2009 | pmid = 19608592 | doi = 10.1183/09031936.00042309 }}</ref> | |||
=== Malaria === | |||
On erythrocytes, the Duffy antigen acts as a [[receptor (biochemistry)|receptor]] for invasion by the human [[malaria]]l parasites ''P. vivax'' and ''[[Plasmodium knowlesi|P. knowlesi]]''. This was first shown in 1980. Duffy negative individuals whose erythrocytes do not express the receptor are believed to be resistant to merozoite invasion<ref name="Ryan_2006">{{cite journal | vauthors = Ryan JR, Stoute JA, Amon J, Dunton RF, Mtalib R, Koros J, Owour B, Luckhart S, Wirtz RA, Barnwell JW, Rosenberg R | title = Evidence for transmission of Plasmodium vivax among a duffy antigen negative population in Western Kenya | journal = Am. J. Trop. Med. Hyg. | volume = 75 | issue = 4 | pages = 575–81 | date = October 2006 | pmid = 17038676 | url = http://www.ajtmh.org/content/75/4/575.long }}</ref> although ''P. vivax'' infection has been reported in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection.<ref name="Ryan_2006"/> This antigen may also play a role in [[erythrocyte]] invasion in the rodent malarial parasite ''[[Plasmodium yoelii|P. yoelii]]''. The [[epitope]] Fy6 is required for ''P. vivax'' invasion.<ref name="pmid10960522"/> | |||
The protection to ''P. vivax'' malaria conferred by the absence of the Duffy antigen appears to be very limited at best in [[Madagascar]]. Although 72% of the population are Duffy antigen negative, 8.8% of the Duffy antigen negative individuals were [[asymptomatic carrier]]s of ''P. vivax''.<ref name="Ménard2010">{{cite journal | vauthors = Ménard D, Barnadas C, Bouchier C, Henry-Halldin C, Gray LR, Ratsimbasoa A, Thonier V, Carod JF, Domarle O, Colin Y, Bertrand O, Picot J, King CL, Grimberg BT, Mercereau-Puijalon O, Zimmerman PA | title = Plasmodium vivax clinical malaria is commonly observed in Duffy-negative Malagasy people | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 13 | pages = 5967–71 | date = March 2010 | pmid = 20231434 | pmc = 2851935 | doi = 10.1073/pnas.0912496107 | bibcode = 2010PNAS..107.5967M }}</ref> Malaria has also been found in [[Angola]] and [[Equatorial Guinea]] in Duffy negative individuals.<ref name="Mendes2011">{{cite journal | vauthors = Mendes C, Dias F, Figueiredo J, Mora VG, Cano J, de Sousa B, do Rosário VE, Benito A, Berzosa P, Arez AP | title = Duffy Negative Antigen Is No Longer a Barrier to Plasmodium vivax – Molecular Evidences from the African West Coast (Angola and Equatorial Guinea) | journal = PLoS Negl Trop Dis | volume = 5 | issue = 6 | pages = e1192 | date = June 2011 | pmid = 21713024 | pmc = 3119644 | doi = 10.1371/journal.pntd.0001192 | editor1-last = Franco-Paredes | editor1-first = Carlos }}</ref> ''P. vivax'' malaria in a Duffy antigen negative individual in [[Mauritania]] has also been reported.<ref name=Wurtz2011>{{cite journal | vauthors = Wurtz N, Mint Lekweiry K, Bogreau H, Pradines B, Rogier C, Ould Mohamed Salem Boukhary A, Hafid JE, Ould Ahmedou Salem MS, Trape JF, Basco LK, Briolant S | title = Vivax malaria in Mauritania includes infection of a Duffy-negative individual | journal = Malar. J. | volume = 10 | issue = | pages = 336 | year = 2011 | pmid = 22050867 | pmc = 3228859 | doi = 10.1186/1475-2875-10-336 }}</ref> Similar infections have been reported in Brazil<ref name="Cavasini_2007a">{{cite journal | vauthors = Cavasini CE, de Mattos LC, Couto AA, Couto VS, Gollino Y, Moretti LJ, Bonini-Domingos CR, Rossit AR, Castilho L, Machado RL | title = Duffy blood group gene polymorphisms among malaria vivax patients in four areas of the Brazilian Amazon region | journal = Malar. J. | volume = 6 | issue = | pages = 167 | year = 2007 | pmid = 18093292 | pmc = 2244634 | doi = 10.1186/1475-2875-6-167 }}</ref><ref name="Cavasini_2007b">{{cite journal | vauthors = Cavasini CE, Mattos LC, Couto AA, Bonini-Domingos CR, Valencia SH, Neiras WC, Alves RT, Rossit AR, Castilho L, Machado RL | title = Plasmodium vivax infection among Duffy antigen-negative individuals from the Brazilian Amazon region: an exception? | journal = Trans. R. Soc. Trop. Med. Hyg. | volume = 101 | issue = 10 | pages = 1042–4 | date = October 2007 | pmid = 17604067 | doi = 10.1016/j.trstmh.2007.04.011 }}</ref> and [[Kenya]].<ref name="Ryan_2006"/> Additional cases of infection in Duffy antigen negative individuals have been reported from the Congo<ref name="pmid19803728">{{cite journal | vauthors = Culleton R, Ndounga M, Zeyrek FY, Coban C, Casimiro PN, Takeo S, Tsuboi T, Yadava A, Carter R, Tanabe K | title = Evidence for the transmission of Plasmodium vivax in the Republic of the Congo, West Central Africa | journal = J. Infect. Dis. | volume = 200 | issue = 9 | pages = 1465–9 | date = November 2009 | pmid = 19803728 | doi = 10.1086/644510 }}</ref> and Uganda.<ref name="pmid21603649">{{cite journal | vauthors = Dhorda M, Nyehangane D, Rénia L, Piola P, Guerin PJ, Snounou G | title = Transmission of Plasmodium vivax in south-western Uganda: report of three cases in pregnant women | journal = PLoS ONE | volume = 6 | issue = 5 | pages = e19801 | year = 2011 | pmid = 21603649 | pmc = 3094453 | doi = 10.1371/journal.pone.0019801 |bibcode = 2011PLoSO...619801D }}</ref> A study in [[Brazil]] of the protection against ''P. vivax'' offered by the lack of the Duffy antigen found no differential resistance to malaria vivax between Duffy antigen positive and negative individuals.<ref name="Carvalho_2012">{{cite journal | vauthors = Carvalho TA, Queiroz MG, Cardoso GL, Diniz IG, Silva AN, Pinto AY, Guerreiro JF | title = Plasmodium vivax infection in Anajas, State of Para: no differential resistance profile among Duffy-negative and Duffy-positive individuals | journal = Malar. J. | volume = 11 | issue = 1 | pages = 430 | date = December 2012 | pmid = 23259672 | pmc = 3544589 | doi = 10.1186/1475-2875-11-430 }}</ref> | |||
Nancy Ma's night monkey (''[[Aotus nancymaae|A. nancymaae]]'') is used as an animal model of ''P. vivax'' infection. This species' erythrocytes possess the Duffy antigen and this antigen is used as the receptor for ''P. vivax'' on the erythrocytes in this species.<ref name="pmid19799492">{{cite journal | vauthors = McHenry AM, Barnwell JW, Adams JH | title = Plasmodium vivax DBP binding to Aotus nancymaae erythrocytes is Duffy antigen dependent | journal = J. Parasitol. | volume = 96 | issue = 1 | pages = 1–7 | date = October 2009 | pmid = 19799492 | pmc = 2883003 | doi = 10.1645/GE-2281.1 }}</ref> | |||
Examination of this gene in 497 patients in the [[Amazonas (Brazilian state)|Amazonas State]], Brazil, made by the doctor Sérgio Albuquerque, suggests that the genotypes FY*A/FY*B-33 and FY*B/FY*B-33 (where -33 refers to the null mutation at position -33 in the GATA box) may have an advantage over the genotypes FY*A/FY*B and FY*A/FY*A, FY*A/FY*B, FY*A/FY*X and FY*B/FY*X.<ref name="pmid20162434">{{cite journal | vauthors = Albuquerque SR, Cavalcante Fde O, Sanguino EC, Tezza L, Chacon F, Castilho L, dos Santos MC | title = FY polymorphisms and vivax malaria in inhabitants of Amazonas State, Brazil | journal = Parasitol Res | volume = 106 | issue = 5 | pages = 1049–53 | date = February 2010 | pmid = 20162434 | doi = 10.1007/s00436-010-1745-x }}</ref> FY*A/FY*B and FY*A/FY*A genotypes showed to be associated with increased rates of ''P. vivax'' infection and FY*B/FY*X and FY*A/FY*X were shown to be associated with the low levels of parasitism. | |||
A difference between the susceptibility to ''Plasmodium vivax'' malaria has been reported.<ref name=King2011>{{cite journal | vauthors = King CL, Adams JH, Xianli J, Grimberg BT, McHenry AM, Greenberg LJ, Siddiqui A, Howes RE, da Silva-Nunes M, Ferreira MU, Zimmerman PA | title = Fya/Fyb antigen polymorphism in human erythrocyte Duffy antigen affects susceptibility to Plasmodium vivax malaria | journal = Proc Natl Acad Sci U S A | volume = 108 | issue = 50 | pages = 20113–8 | date = November 2011 | pmid = 22123959 | doi = 10.1073/pnas.1109621108 | bibcode = 2011PNAS..10820113K }}</ref> Erythrocytes expressing Fya had 41-50% lower binding of ''P. vivax'' compared with Fyb cells. Individuals with the Fy(a+b-) phenotype have a 30-80% reduced risk of clinical vivax but not falciparum malaria. | |||
The binding of platelet factor 4 ([[CXCL4]]) appears to be critical for the platelet induced killing of ''[[Plasmodium falciparum|P. falciparum]].<ref name=McMorran_2012>{{cite journal | vauthors = McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ | title = Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum | journal = Science | volume = 338 | issue = 6112 | pages = 1348–51 | date = December 2012 | pmid = 23224555 | doi = 10.1126/science.1228892 | bibcode = 2012Sci...338.1348M }}</ref> | |||
The Duffy antigen binding protein in ''P. vivax'' is composed of three subdomains and is thought to function as a dimer.<ref name=Sampath_2013>{{cite journal | vauthors = Sampath S, Carrico C, Janes J, Gurumoorthy S, Gibson C, Melcher M, Chitnis CE, Wang R, Schief WR, Smith JD | title = Glycan Masking of Plasmodium vivax Duffy Binding Protein for Probing Protein Binding Function and Vaccine Development | journal = PLoS Pathog. | volume = 9 | issue = 6 | pages = e1003420 | date = June 2013 | pmid = 23853575 | doi = 10.1371/journal.ppat.1003420 | pmc=3681752}}</ref> The critical DARC binding residues are concentrated at the dimer interface and along a relatively flat surface spanning portions of two subdomains. | |||
=== Multiple myeloma === | |||
An increased incidence of Duffy antigen has been reported in patients with multiple myeloma compared with healthy controls.<ref name="Guler2009">{{cite journal | vauthors = Guler N, Turgut M, Ozatli D, Turgut Y, Gokce AK, Koc S, Albayrak D | title = High ratio of Duffy (a+b+) phenotype in patients with multiple myeloma compared to healthy controls | journal = Hematol Oncol | volume = 27 | issue = 1 | pages = 50–1 | date = March 2009 | pmid = 19206111 | doi = 10.1002/hon.887 }}</ref> | |||
=== Pneumonia === | |||
The Duffy antigen is present in the normal pulmonary vascular bed. Its expression is increased in the vascular beds and alveolar septa of the lung parenchyma during suppurative pneumonia.<ref name="Lee_2003b">{{cite journal | vauthors = Lee JS, Frevert CW, Thorning DR, Segerer S, Alpers CE, Cartron JP, Colin Y, Wong VA, Martin TR, Goodman RB | title = Enhanced expression of Duffy antigen in the lungs during suppurative pneumonia | journal = J. Histochem. Cytochem. | volume = 51 | issue = 2 | pages = 159–66 | date = February 2003 | pmid = 12533524 | doi = 10.1177/002215540305100204 }}</ref> | |||
=== Pregnancy === | |||
Duffy antigen has been implicated in haemolytic disease of the newborn. | |||
=== Prostate cancer === | |||
Experimental work has suggested that DARC expression inhibits prostate tumor growth. Men of black African descent are at greater risk of prostate cancer than are men of either Causcasian or Asian descendant (60% greater incidence and double the mortality compared to Caucasians). The reasons for this increased risk are not known. The contribution of DARC to this increased risk has been tested in [[Jamaica]]n males of black African descent.<ref name="pmid20596779">{{cite journal | vauthors = Elson JK, Beebe-Dimmer JL, Morgenstern H, Chilkuri M, Blanchard J, Lentsch AB | title = The Duffy Antigen/Receptor for Chemokines (DARC) and Prostate-Cancer Risk among Jamaican Men | journal = J Immigr Minor Health | volume = 13 | issue = 1 | pages = 36–41 | date = July 2010 | pmid = 20596779 | pmc = 3017736 | doi = 10.1007/s10903-010-9330-z }}</ref> It was found that none of the increased risk could be attributed to the DARC gene. | |||
=== Renal transplantion === | |||
Antibodies and a cellular response to the Duffy antigen have been associated with renal transplant rejection.<ref name="Watorek2008">{{cite journal | vauthors = Watorek E, Boratyńska M, Hałoń A, Klinger M | title = Anti-Fya antibodies as the cause of an unfortunate post-transplant course in renal transplant recipient | journal = Ann. Transplant. | volume = 13 | issue = 1 | pages = 48–52 | year = 2008 | pmid = 18344944 | doi = }}</ref> | |||
=== Sickle cell anaemia === | |||
Duffy antigen-negative individuals with [[sickle cell anaemia]] tend to suffer from more severe organ damage than do those with the Duffy antigen.<ref name="Afenyi-Annan2008">{{cite journal | vauthors = Afenyi-Annan A, Kail M, Combs MR, Orringer EP, Ashley-Koch A, Telen MJ | title = Lack of Duffy antigen expression is associated with organ damage in patients with sickle cell disease | journal = Transfusion | volume = 48 | issue = 5 | pages = 917–24 | date = May 2008 | pmid = 18248572 | doi = 10.1111/j.1537-2995.2007.01622.x }}</ref> Duffy-positive patients exhibit higher counts of white blood cells, polynuclear neutrophils, higher plasma levels of IL-8 and RANTES than Duffy-negative patients.<ref name="Nebor2010">{{cite journal | vauthors = Nebor D, Durpes MC, Mougenel D, Mukisi-Mukaza M, Elion J, Hardy-Dessources MD, Romana M | title = Association between Duffy antigen receptor for chemokines expression and levels of inflammation markers in sickle cell anemia patients | journal = Clin. Immunol. | volume = 136 | issue = 1 | pages = 116–22 | date = July 2010 | pmid = 20347396 | doi = 10.1016/j.clim.2010.02.023 }}</ref> | |||
=== Southeast Asian ovalocytosis === | |||
There is a ~10% increase in Fy expression in Southeast Asian ovalocytosis erythocytes.<ref name="Woolley2009">{{cite journal | vauthors = Woolley IJ, Hutchinson P, Reeder JC, Kazura JW, Cortés A | title = Southeast Asian ovalocytosis is associated with increased expression of Duffy antigen receptor for chemokines (DARC) | journal = Immunohematology | volume = 25 | issue = 2 | pages = 63–6 | year = 2009 | pmid = 19927622 | doi = }}</ref> | |||
=== Transfusion medicine === | |||
A Duffy negative blood recipient may have a transfusion reaction if the donor is Duffy positive.<ref name="pmid10439320" /> Since most Duffy-negative people are of African descent, blood donations from people of black African origin are important to transfusion banks. | |||
==Transfusion data== | |||
International Society for Blood Transfusion (ISBT) symbol: FY | |||
ISBT number: 008 | |||
Gene symbol: FY | |||
Gene name: Duffy blood group | |||
Number of Duffy antigens: 6 | |||
===Antibody type=== | |||
Almost entirely IgG. IgG1 usually predominates. IgM does occur but is rare. | |||
===Antibody behavior=== | |||
Anti-Fy<sup>a</sup> is a common antibody while anti-Fy<sup>b</sup> is approximately 20 times less common.,<ref name="Roback JD 2008">Roback JD et al. AABB Technical Manual, 16th Ed. Bethesda: AABB Press, 2008.</ref><ref>Klein HG, Anstee DJ. Mollison's Blood Transfusion in Clinical Medicine. 11th Ed. Oxford: Blackwell Publishing, 2005.</ref> They are reactive at body temperature and are therefore clinically significant, although they do not typically bind complement. Antibodies are acquired through exposure (pregnancy or history of blood transfusion) and subsequent alloimmunization. They display dosage (react more strongly to homozygous cells versus heterozygous cells).<ref name="Roback JD 2008"/> | |||
===Transfusion reactions=== | |||
Typically mild but may be serious, even fatal. Although these usually occur immediately they may occur after a delay (up to 24 hours). These reactions are usually caused by anti-Fy<sup>a</sup> or anti-Fy<sup>b</sup>. anti-Fy3 may cause acute or delayed [[hemolytic transfusion reactions]] (HTRs), but only rarely.<br/> Anti-Fy5 may also cause delayed hemolytic transfusion reactions.<ref name="Roback JD 2008"/> | |||
===Hemolytic disease of the fetus and newborn (HDFN)=== | |||
[[Hemolytic disease of the fetus and newborn]] is typically mild but rarely may be serious. Almost always due to anti-Fy<sup>a</sup> and rarely anti-Fyb or Fy3. | |||
== References == | == References == | ||
{{ | {{reflist|2}} | ||
==Further reading== | |||
{{refbegin | 2}} | |||
*{{cite journal | vauthors = Pogo AO, Chaudhuri A | title = Duffy and receptors for P. vivax and chemotactic peptides | journal = Transfusion clinique et biologique : journal de la Société française de transfusion sanguine | volume = 2 | issue = 4 | pages = 269–76 | year = 1996 | pmid = 8542025 | doi = 10.1016/s1246-7820(05)80093-x }} | |||
*{{cite journal | vauthors = Pruenster M, Rot A | title = Throwing light on DARC | journal = Biochem. Soc. Trans. | volume = 34 | issue = Pt 6 | pages = 1005–8 | year = 2007 | pmid = 17073738 | doi = 10.1042/BST0341005 }} | |||
*{{cite journal | vauthors = Raeymaekers P, Van Broeckhoven C, Backhovens H, Wehnert A, Muylle L, De Jonghe P, Gheuens J, Vandenberghe A | title = 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 | journal = Hum. Genet. | volume = 78 | issue = 1 | pages = 76–8 | year = 1988 | pmid = 2892777 | doi = 10.1007/BF00291239 }} | |||
*{{cite journal | vauthors = Lu ZH, Wang ZX, Horuk R, Hesselgesser J, Lou YC, Hadley TJ, Peiper SC | title = The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain | journal = J. Biol. Chem. | volume = 270 | issue = 44 | pages = 26239–45 | year = 1995 | pmid = 7592830 | doi = 10.1074/jbc.270.44.26239 }} | |||
*{{cite journal | vauthors = Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, Miller LH | title = A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor | journal = Science | volume = 261 | issue = 5125 | pages = 1182–4 | year = 1993 | pmid = 7689250 | doi = 10.1126/science.7689250 | bibcode = 1993Sci...261.1182H }} | |||
*{{cite journal | vauthors = Tournamille C, Le Van Kim C, Gane P, Cartron JP, Colin Y | title = Molecular basis and PCR-DNA typing of the Fya/fyb blood group polymorphism | journal = Hum. Genet. | volume = 95 | issue = 4 | pages = 407–10 | year = 1995 | pmid = 7705836 | doi = 10.1007/BF00208965 }} | |||
*{{cite journal | vauthors = Iwamoto S, Omi T, Kajii E, Ikemoto S | title = Genomic organization of the glycoprotein D gene: Duffy blood group Fya/Fyb alloantigen system is associated with a polymorphism at the 44-amino acid residue | journal = Blood | volume = 85 | issue = 3 | pages = 622–6 | year = 1995 | pmid = 7833467 | doi = }} | |||
*{{cite journal | vauthors = Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC | title = Expression of chemokine receptors by subsets of neurons in the central nervous system | journal = Journal of Immunology | volume = 158 | issue = 6 | pages = 2882–90 | year = 1997 | pmid = 9058825 | doi = }} | |||
*{{cite journal | vauthors = Tournamille C, Le Van Kim C, Gane P, Blanchard D, Proudfoot AE, Cartron JP, Colin Y | title = Close association of the first and fourth extracellular domains of the Duffy antigen/receptor for chemokines by a disulfide bond is required for ligand binding | journal = J. Biol. Chem. | volume = 272 | issue = 26 | pages = 16274–80 | year = 1997 | pmid = 9195930 | doi = 10.1074/jbc.272.26.16274 }} | |||
*{{cite journal | vauthors = Tournamille C, Le Van Kim C, Gane P, Le Pennec PY, Roubinet F, Babinet J, Cartron JP, Colin Y | title = Arg89Cys substitution results in very low membrane expression of the Duffy antigen/receptor for chemokines in Fy(x) individuals | journal = Blood | volume = 92 | issue = 6 | pages = 2147–56 | year = 1998 | pmid = 9731074 | doi = }} | |||
*{{cite journal | vauthors = Parasol N, Reid M, Rios M, Castilho L, Harari I, Kosower NS | title = A novel mutation in the coding sequence of the FY*B allele of the Duffy chemokine receptor gene is associated with an altered erythrocyte phenotype | journal = Blood | volume = 92 | issue = 7 | pages = 2237–43 | year = 1998 | pmid = 9746760 | doi = }} | |||
*{{cite journal | vauthors = Olsson ML, Smythe JS, Hansson C, Poole J, Mallinson G, Jones J, Avent ND, Daniels G | title = The Fy(x) phenotype is associated with a missense mutation in the Fy(b) allele predicting Arg89Cys in the Duffy glycoprotein | journal = Br. J. Haematol. | volume = 103 | issue = 4 | pages = 1184–91 | year = 1999 | pmid = 9886340 | doi = 10.1046/j.1365-2141.1998.01083.x }} | |||
*{{cite journal | vauthors = Lachgar A, Jaureguiberry G, Le Buenac H, Bizzini B, Zagury JF, Rappaport J, Zagury D | title = Binding of HIV-1 to RBCs involves the Duffy antigen receptors for chemokines (DARC) | journal = Biomed. Pharmacother. | volume = 52 | issue = 10 | pages = 436–9 | year = 1999 | pmid = 9921412 | doi = 10.1016/S0753-3322(99)80021-3 }} | |||
*{{cite journal | vauthors = Zimmerman PA, Woolley I, Masinde GL, Miller SM, McNamara DT, Hazlett F, Mgone CS, Alpers MP, Genton B, Boatin BA, Kazura JW | title = Emergence of FY*Anull in a Plasmodium vivax-endemic region of Papua New Guinea | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 24 | pages = 13973–7 | year = 2000 | pmid = 10570183 | pmc = 24175 | doi = 10.1073/pnas.96.24.13973 | bibcode = 1999PNAS...9613973Z }} | |||
*{{cite journal | vauthors = Woolley IJ, Kalayjian R, Valdez H, Hamza N, Jacobs G, Lederman MM, Zimmerman PA | title = HIV nephropathy and the Duffy antigen/receptor for Chemokines in African Americans | journal = J. Nephrol. | volume = 14 | issue = 5 | pages = 384–7 | year = 2002 | pmid = 11730271 | doi = }} | |||
*{{cite journal | vauthors = Hamblin MT, Thompson EE, Di Rienzo A | title = Complex Signatures of Natural Selection at the Duffy Blood Group Locus | journal = American Journal of Human Genetics | volume = 70 | issue = 2 | pages = 369–83 | year = 2002 | pmid = 11753822 | pmc = 419988 | doi = 10.1086/338628 }} | |||
*{{cite journal | vauthors = Patterson AM, Siddall H, Chamberlain G, Gardner L, Middleton J | title = Expression of the duffy antigen/receptor for chemokines (DARC) by the inflamed synovial endothelium | journal = J. Pathol. | volume = 197 | issue = 1 | pages = 108–16 | year = 2002 | pmid = 12081195 | doi = 10.1002/path.1100 }} | |||
{{refend}} | |||
== External links == | == External links == | ||
* {{MeshName|DARC+protein,+human}} | |||
* [ | * [https://www.ncbi.nlm.nih.gov/projects/mhc/xslcgi.fcgi?cmd=bgmut/systems_info&system=duffy Duffy] at [[BGMUT]] Blood Group Antigen Gene Mutation Database at [[National Center for Biotechnology Information|NCBI]], [[NIH]] | ||
* [http://www.dsi.univ-paris5.fr/genatlas/fiche1.php?symbol=FY Duffy gene] | * [http://www.dsi.univ-paris5.fr/genatlas/fiche1.php?symbol=FY Duffy gene] | ||
* [http://www.genes.uchicago.edu/fri/Hamblin2002.pdf Population data] | * [http://www.genes.uchicago.edu/fri/Hamblin2002.pdf Population data] | ||
{{Clusters of differentiation}} | |||
{{transfusion medicine}} | {{transfusion medicine}} | ||
{{DEFAULTSORT:Duffy Antigen System}} | |||
[[Category:Clusters of differentiation]] | |||
[[Category:Immune system]] | [[Category:Immune system]] | ||
[[Category:Blood antigen systems]] | [[Category:Blood antigen systems]] | ||
[[Category: | [[Category:HIV/AIDS]] | ||
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Duffy antigen/chemokine receptor (DARC), also known as Fy glycoprotein (FY) or CD234 (Cluster of Differentiation 234), is a protein that in humans is encoded by the DARC gene.[1][2][3]
The Duffy antigen is located on the surface of red blood cells, and is named after the patient in which it was discovered. The protein encoded by this gene is a glycosylated membrane protein and a non-specific receptor for several chemokines. The protein is also the receptor for the human malarial parasites Plasmodium vivax, Plasmodium knowlesi and simian malarial parasite Plasmodium cynomolgi.[4] Polymorphisms in this gene are the basis of the Duffy blood group system.[5]
History
It was noted in the 1920s that black Africans had some intrinsic resistance to malaria, but the basis for this remained unknown. The Duffy antigen gene was the fourth gene associated with the resistance after the genes responsible for sickle cell anaemia, thalassemia and glucose-6-phosphate dehydrogenase.
In 1950, the Duffy antigen was discovered in a multiply-transfused hemophiliac whose serum contained the first example of anti-Fya antibody.[6] In 1951, the antibody to a second antigen, Fyb, was discovered in serum. Using these two antibodies, three common phenotypes were defined: Fy(a+b+), Fy(a+b-), and Fy(a-b+).
Several other types were later discovered bringing the current total up to 6: Fya, Fyb, Fy3, Fy4, Fy5 and Fy6. Only Fya, Fyb and Fy3 are considered clinically important. Reactions to Fy5 have also rarely been reported.
Genetics and genomics
The Duffy antigen/chemokine receptor gene (gp-Fy; CD234) is located on the long arm of chromosome 1 (1.q22-1.q23) and was cloned in 1993.[2] The gene was first localised to chromosome 1 in 1968, and was the first blood system antigen to be localised. It is a single copy gene spanning over 1500 bases and is in two exons. The gene encodes a 336 amino acid acidic glycoprotein. It carries the antigenic determinants of the Duffy blood group system which consist of four codominant alleles—FY*A and FY*B—coding for the Fy-a and Fy-b antigens respectively, FY*X and FY*Fy, five phenotypes (Fy-a, Fy-b, Fy-o, Fy-x and Fy-y) and five antigens. Fy-x is a form of Fy-b where the Fy-b gene is poorly expressed. Fy-x is also known as Fy-bweak or Fy-bWk.
Fy-a and Fy-b differ by in a single amino acid at position 42: glycine in Fy-a and aspartic acid in Fy-b (guanine in Fy-a and adenosine in Fy-b at position 125). A second mutation causing a Duffy negative phenotype is known: the responsible mutation is G -> A at position 298. The genetic basis for the Fy(a-b-) phenotype is a point mutation in the erythroid specific promoter (a T -> C mutation at position -33 in the GATA box).[7] This mutation occurs in the Fy-b allele and has been designated Fy-bEs (erythroid silent). Two isotypes have been identified. The Fy-x allele is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate transitions: Cytosine265Threonine (Arginine89Cysteine) and Guanine298Adenosine (Alanine100Threonine). A third mutation (a transversion) in this gene has also been described - G145T (Alanine49Serine) - that has been associated with the Fy-x phenotype.
Most Duffy negative blacks carry a silent Fy-b allele with a single T to C substitution at nucleotide -46, impairing the promoter activity in erythroid cells by disrupting a binding site for the GATA1 erythroid transcription factor. The gene is still transcribed in non erythroid cells in the presence of this mutation.
The Duffy negative phenotype occurs at low frequency among whites (~3.5%) and is due to a third mutation that results in an unstable protein (Arg89Cys: cytosine -> thymidine at position 265).[8]
The silent allele has evolved at least twice in the black population of Africa and evidence for selection for this allele has been found.[9] The selection pressure involved here appears to be more complex than many text books might suggest.[10] An independent evolution of this phenotype occurred in Papua New Guinea has also been documented.[11]
A comparative study of this gene in seven mammalian species revealed significant differences between species.[12] The species examined included Pan troglodytes (chimpanzee), Macaca mulatta (rhesus monkey), Pongo pygmaeus (orangutan), Rattus norvegicus (brown rat), Mus musculus (mouse), Monodelphis domestica (opossum), Bos taurus (cow) and Canis familiaris (dog).
Three exons are present in humans and chimpanzees, whereas only two exons occur in the other species. This additional exon is located at the 5' end and is entirely non coding. Both intron and exon size vary considerably between the species examined. Between the chimpanzee and the human, 24 differences in the nucleotide sequence were noted. Of these 18 occurred in non coding regions. Of the remaining 6, 3 were synonymous and 3 non synonymous mutations. The significance of these mutations if any is not known.
The mouse ortholog has been cloned and exhibits 63% homology to the human gene at the amino acid level. The mouse gene is located on chromosome 1 between the genetic markers Xmv41 and D1Mit166. The mouse gene has two exons (100 and 1064 nucleotides in length respectively), separated by a 461 base pair intron. In the mouse DARC is expressed during embryonic development between days 9.5 and 12.
In yellow baboons (Papio cynocephalus) mutations in this gene have been associated with protection from infection with species of the genus Hepatocystis.[13]
The ancestral form of extant DARC alleles in humans appears to be the FY*B allele.[14]
The gene appears to be under strong purifying selection.[15] The cause of this selective pressure has not yet been identified.
Molecular biology
Biochemical analysis of the Duffy antigen has shown that it has a high content of α-helical secondary structure - typical of chemokine receptors.[16] Its N-glycans are mostly of the triantennary complex type terminated with α2-3- and α2-6-linked sialic acid residues with bisecting GlcNAc and α1-6-linked fucose at the core.
The Duffy antigen is expressed in greater quantities on reticulocytes than on mature erythrocytes.[17] While the Duffy antigen is expressed on erythrocytes it is also found on some epithelial cells, Purkinje cells of the cerebellum,[18] endothelial cells of thyroid capillaries, the post-capillary venules of some organs including the spleen, liver and kidney[19] and the large pulmonary venules. In some people who lack the Duffy antigen on their erythrocytes it may still be expressed in some cells.[20] It has two potential N-linked glycosylation sites at asparagine (Asn) 16 and Asn27.
The Duffy antigen has been found to act as a multispecific receptor for chemokines of both the C-C and C-X-C families, including:
- monocyte chemotatic protein-1 (MCP-1) - CCL2[21]
- regulated upon activation normal T expressed and secreted (RANTES) - CCL5[22]
- melanoma growth stimulatory activity (MSGA-α), KC, neutrophil-activating protein 3 (NAP-3) - CXCL1/CXCL2[23]
and the angiogenic CXC chemokines:
- Growth related gene alpha (GRO-α) - CXCL1
- Platelet factor 4 - CXCL4[24]
- ENA-78 - CXCL5
- Neutrophil activating peptide-2 (NAP-2) - CXCL7
- Interleukin-8 (IL-8) - CXCL8
Consequently, the Fy protein is also known as DARC (Duffy Antigen Receptor for Chemokines). The chemokine binding site on the receptor appears to be localised to the amino terminus.[25] The antigen is predicted to have 7 transmembrane domains, an exocellular N-terminal domain and an endocellular C-terminal domain. Alignment with other seven transmembrane G-protein-coupled receptors shows that DARC lacks the highly conserved DRY motif in the second intracellular loop of the protein that is known to be associated with G-protein signaling. Consistent with this finding ligand binding by DARC does not induce G-protein coupled signal transduction nor a Ca2+ flux unlike other chemokine receptors. Based on these alignments the Duffy antigen is considered to be most similar to the interleukin-8B receptors.
Scatchard analysis of competition binding studies has shown high affinity binding to the Duffy antigen with dissociation constants (KD) binding values of 24 ± 4.9, 20 ± 4.7, 41.9 ± 12.8, and 33.9 ± 7 nanoMoles for MGSA, interleukin-8, RANTES and monocyte chemotactic peptide-1 respectively.[26]
In DARC-transfected cells, DARC is internalized following ligand binding and this led to the hypothesis that expression of DARC on the surface of erythrocytes, endothelial, neuronal cells and epithelial cells may act as a sponge and provide a mechanism by which inflammatory chemokines may be removed from circulation as well as their concentration modified in the local environment.[27] This hypothesis has also been questioned after knock out mice were created. These animals appeared healthy and had normal responses to infection. While the function of the Duffy antigen remains presently (2006) unknown, evidence is accumulating that suggests a role in neutrophil migration from the blood into the tissues[28] and in modulating the inflammatory response.[29][30][31][32][33][34][35][36][37][38]
The protein is also known to interact with the protein KAI1 (CD82) a surface glycoprotein of leukocytes and may have a role in the control of cancer.
The Duffy antigen has been shown to exist as a constitutive homo-oligomer and that it hetero-oligomerizes with the CC chemokine receptor CCR5 (CD195). The formation of this heterodimer impairs chemotaxis and calcium flux through CCR5, whereas internalization of CCR5 in response to ligand binding remains unchanged.[39]
DARC has been shown to internalise chemokines but does not scavenge them.[40] It mediates chemokine transcytosis, which leds to apical retention of intact chemokines and more leukocyte migration.
Binding melanoma growth-stimulating activity inhibits the binding of P. knowlesi to DARC.
Population genetics
Differences in the racial distribution of the Duffy antigens were discovered in 1954, when it was found that the overwhelming majority of blacks had the erythrocyte phenotype Fy(a-b-): 68% in African Americans and 88-100% in African blacks (including more than 90% of West African blacks).[41] This phenotype is exceedingly rare in Caucasians. Because the Duffy antigen is uncommon in those of Black African descent, the presence of this antigen has been used to detect genetic admixture. In a sample of unrelated African Americans (n = 235), Afro-Caribbeans (n = 90) and Colombians (n = 93), the frequency of the -46T (Duffy positive) allele was 21.7%, 12.2% and 74.7% respectively.[42]
Overall the frequencies of Fya and Fyb antigens in Caucasians are 66% and 83% respectively, in Asians 99% and 18.5% respectively and in blacks 10% and 23% respectively. The frequency of Fy3 is 100% Caucasians, 99.9% Asians and 32% Blacks. Phenotype frequencies are:
- Fy(a+b+): 49% Caucasians, 1% Blacks, 9% Chinese
- Fy(a-b+): 34% Caucasians, 22% Blacks, <1% Chinese
- Fy(a+b-): 17% Caucasians, 9% Blacks, 91% Chinese
While a possible role in the protection of humans from malaria had been previously suggested, this was only confirmed clinically in 1976.[43] Since then many surveys have been carried out to elucidate the prevalence of Duffy antigen alleles in different populations including:
- The mutation Ala100Thr (G -> A in the first codon position—base number 298) within the FY*B allele was thought to be purely a Caucasian genotype, but has since been described in Brazilians. However, the study's authors point out that the Brazilian population has arisen from intermarriage between Portuguese, Black Africans, and Indians, which accounts for the presence of this mutation in a few members of Brazil's non-Caucasian groups. Two of the three Afro-Brazilian test subjects that were found to have the mutation (out of a total of 25 Afro-Brazilians tested) were also related to one another, as one was a mother and the other her daughter.[44]
- This antigen along with other blood group antigens was used to identify the Basque people as a genetically separate group.[45] Its use in forensic science is under consideration.[46]
- The Andaman and Nicobar Islands, now part of India, were originally inhabited by 14 aboriginal tribes. Several of these have gone extinct. One surviving tribe—the Jarawas—live in three jungle areas of South Andaman and one jungle area in Middle Andaman. The area is endemic for malaria. The causative species is Plasmodium falciparum: there is no evidence for the presence of Plasmodium vivax. Blood grouping revealed an absence of both Fy(a) and Fy(b) antigens in two areas and a low prevalence in two others.[47]
- In the Yemenite Jews the frequency of the Fy allele is 0.5879[48] The frequency of this allele varies from 0.1083 to 0.2191 among Jews from the Middle East, North Africa and Southern Europe. The incidence of Fya among Ashkenazi Jews is 0.44 and among the non-Ashkenazi Jews it is 0.33. The incidence of Fyb is higher in both groups with frequencies of 0.53 and 0.64 respectively.[49]
- In the Chinese ethnic populations—the Han and the She people—the frequencies of Fya and Fyb alleles were 0.94 and 0.06 and 0.98 and 0.02 respectively.[50]
- The frequency of the Fya allele in most Asian populations is ~95%.
- In Grande Comore (also known as Ngazidja) the frequency of the Fy(a- b-) phenotype is 0.86.[51]
- The incidence of Fy(a+b-) in northern India among blood donors is 43.85%.[52]
- In the Maghreb, Horn of Africa and the Nile Valley, the Afroasiatic (Hamitic-Semitic) speaking populations are largely Duffy-positive.[53] Between 70%-98% of Hamito-Semitic groups in Ethiopia were found to be Duffy-positive.[54] Serological and DNA based analysis of 115 unrelated Tunisians also found an FY*X frequency of 0.0174; FY*1 = 0.291 (expressed 0.260, silent 0.031); FY*2 = 0.709 (expressed 0.427; silent 0.282). Since the FY*2 silent is the most common allele in West Africa, its minor occurrence in the sample probably represents recent diffusion from the latter region.[55]
- In Nouakchott, Mauritania overall 27% of the population are Duffy-positive. 54% of Moors are Duffy antigen positive, while only 2% of black ethnic groups (mainly Poular, Soninke and Wolof) are Duffy positive.[56]
- A map of the Duffy antigen distribution has been produced.[57] The most prevalent allele globally is FY*A. Across sub-Saharan Africa the predominant allele is the silent FY*BES variant.
- In Iran the Fy (a-b-) phenotype was found in 3.4%.[58]
There appears to have been a selective sweep in Africa which reduced the incidence of this antigen there. This sweep appears to have occurred between 6,500 and 97,200 years ago (95% confidence interval)[9]
The distribution within India has been studied in some detail.[59]
Clinical significance
Historically the role of this antigen other than its importance as a receptor for Plasmodium protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein.
Asthma
Asthma is more common and tends to be more severe in those of African descent. There appears to be a correlation with both total IgE levels and asthma and mutations in the Duffy antigen.[60]
Hematopoiesis
Duffy antigen plays a fundamental role on hematopoiesis.[61] Indeed, nucleated red blood cells present in the bone marrow have high expression of DARC, which facilitates their direct contact with hematopoietic stem cells. The absence of erythroid DARC alters hematopoiesis including stem and progenitor cells, which ultimately gives rise to phenotypically distinct neutrophils. As a result, mature neutrophils of Duffy-negative individuals carry more molecular “weapons” against infectious pathogens.[62] Therefore, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of DARC in the erythroid lineage.[61]
Benign ethnic neutropenia
A significant proportion (25–50%) of otherwise healthy African Americans are known to have a persistently lower white blood cell count than the normal range defined for individuals of European ancestry—a condition known as benign ethnic neutropenia. This condition is also found in Arab Jordanians, Black Bedouin, Falashah Jews, Yemenite Jews and West Indians. This condition is associated with a reduced capacity to mobilize bone marrow neutrophil reserves in response to corticosteroids, despite normal cellularity and maturation of all cell lines in bone marrow aspirates. Strongly suggestive evidence has been found that links condition to a mutation in the Duffy gene.[63] The distinctive neutrophils that are formed in the absence of DARC on erythroid lineage (see above - role of DARC on hematopoieisis) readily leave the blood stream, which explains the apparent lower numbers of neutrophils in the blood of Duffy-negative individuals.[61][62]
Cancer
Interactions between the metastasis suppressor KAI1 on tumor cells and the cytokine receptor DARC on adjacent vascular cells suppresses tumor metastasis.[64] In human breast cancer samples low expression of the DARC protein is significantly associated with estrogen receptor status, both lymph node and distant metastasis and poor survival.[65]
Endotoxin response
The procoagulant response to lipopolysaccaride (bacterial endotoxin) is reduced in Duffy antigen negative Africans compared with Duffy positive Caucasians.[66] This erence is likely to involve additional genes.
HIV infection
A connection has been found between HIV susceptibility and the expression of the Duffy antigen. The absence of the DARC receptor appears to increase the susceptibility to infection by HIV. However once established, the absence of the DARC receptor appears to slow down the progression of the disease.[67]
HIV-1 appears to be able to attach to erythrocytes via DARC.[67]
The association between the Duffy antigen and HIV infection appears to be complex. Leukopenia (a low total white cell count) is associated with relatively poor survival in HIV infection and this association is more marked in caucasians than in people of Black African descent, despite the (on average) lower white cell counts found in black Africans. This difference appears to correlate with a particular genotype (-46C/C) associated with the absence of the Duffy antigen.[68] This genotype has only been found in black Africans and their descendants. The strength of this association increases inversely with the total white cell count. The basis for this association is probably related to the role of the Duffy antigen in cytokine binding but this has yet to be verified.
A study of 142 black South African high-risk female sex workers over 2 years revealed a seroconversion rate of 19.0%.[69] Risk of seroconversion appeared to be correlated with Duffy-null-associated low neutrophil counts.
Inflammation
An association with the levels monocyte chemoattractant protein-1 has been reported.[70]
In the Sardinian population, an association of several variants in the DARC gene (coding and non-coding) correlates with increased serum levels of monocyte chemoattractant protein (MCP -1). A new variant in this population, consisting of the amino acid substitution of arginine for a cysteine at position 89 of the protein diminishes the ability to bind chemokines.[71]
DARC has also been linked to rheumatoid arthritis (RA), possibly displaying chemokines such as CXCL5 on the surface of endothelial cells within the synovium, increasing the recruitment of neutrophils in the disease state.[72]
Lung transplantation
The Duffy antigen has been implicated in lung transplantation rejection.[73]
Malaria
On erythrocytes, the Duffy antigen acts as a receptor for invasion by the human malarial parasites P. vivax and P. knowlesi. This was first shown in 1980. Duffy negative individuals whose erythrocytes do not express the receptor are believed to be resistant to merozoite invasion[74] although P. vivax infection has been reported in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection.[74] This antigen may also play a role in erythrocyte invasion in the rodent malarial parasite P. yoelii. The epitope Fy6 is required for P. vivax invasion.[17]
The protection to P. vivax malaria conferred by the absence of the Duffy antigen appears to be very limited at best in Madagascar. Although 72% of the population are Duffy antigen negative, 8.8% of the Duffy antigen negative individuals were asymptomatic carriers of P. vivax.[75] Malaria has also been found in Angola and Equatorial Guinea in Duffy negative individuals.[76] P. vivax malaria in a Duffy antigen negative individual in Mauritania has also been reported.[77] Similar infections have been reported in Brazil[78][79] and Kenya.[74] Additional cases of infection in Duffy antigen negative individuals have been reported from the Congo[80] and Uganda.[81] A study in Brazil of the protection against P. vivax offered by the lack of the Duffy antigen found no differential resistance to malaria vivax between Duffy antigen positive and negative individuals.[82]
Nancy Ma's night monkey (A. nancymaae) is used as an animal model of P. vivax infection. This species' erythrocytes possess the Duffy antigen and this antigen is used as the receptor for P. vivax on the erythrocytes in this species.[83]
Examination of this gene in 497 patients in the Amazonas State, Brazil, made by the doctor Sérgio Albuquerque, suggests that the genotypes FY*A/FY*B-33 and FY*B/FY*B-33 (where -33 refers to the null mutation at position -33 in the GATA box) may have an advantage over the genotypes FY*A/FY*B and FY*A/FY*A, FY*A/FY*B, FY*A/FY*X and FY*B/FY*X.[84] FY*A/FY*B and FY*A/FY*A genotypes showed to be associated with increased rates of P. vivax infection and FY*B/FY*X and FY*A/FY*X were shown to be associated with the low levels of parasitism.
A difference between the susceptibility to Plasmodium vivax malaria has been reported.[85] Erythrocytes expressing Fya had 41-50% lower binding of P. vivax compared with Fyb cells. Individuals with the Fy(a+b-) phenotype have a 30-80% reduced risk of clinical vivax but not falciparum malaria.
The binding of platelet factor 4 (CXCL4) appears to be critical for the platelet induced killing of P. falciparum.[86]
The Duffy antigen binding protein in P. vivax is composed of three subdomains and is thought to function as a dimer.[87] The critical DARC binding residues are concentrated at the dimer interface and along a relatively flat surface spanning portions of two subdomains.
Multiple myeloma
An increased incidence of Duffy antigen has been reported in patients with multiple myeloma compared with healthy controls.[88]
Pneumonia
The Duffy antigen is present in the normal pulmonary vascular bed. Its expression is increased in the vascular beds and alveolar septa of the lung parenchyma during suppurative pneumonia.[89]
Pregnancy
Duffy antigen has been implicated in haemolytic disease of the newborn.
Prostate cancer
Experimental work has suggested that DARC expression inhibits prostate tumor growth. Men of black African descent are at greater risk of prostate cancer than are men of either Causcasian or Asian descendant (60% greater incidence and double the mortality compared to Caucasians). The reasons for this increased risk are not known. The contribution of DARC to this increased risk has been tested in Jamaican males of black African descent.[90] It was found that none of the increased risk could be attributed to the DARC gene.
Renal transplantion
Antibodies and a cellular response to the Duffy antigen have been associated with renal transplant rejection.[91]
Sickle cell anaemia
Duffy antigen-negative individuals with sickle cell anaemia tend to suffer from more severe organ damage than do those with the Duffy antigen.[92] Duffy-positive patients exhibit higher counts of white blood cells, polynuclear neutrophils, higher plasma levels of IL-8 and RANTES than Duffy-negative patients.[93]
Southeast Asian ovalocytosis
There is a ~10% increase in Fy expression in Southeast Asian ovalocytosis erythocytes.[94]
Transfusion medicine
A Duffy negative blood recipient may have a transfusion reaction if the donor is Duffy positive.[42] Since most Duffy-negative people are of African descent, blood donations from people of black African origin are important to transfusion banks.
Transfusion data
International Society for Blood Transfusion (ISBT) symbol: FY
ISBT number: 008
Gene symbol: FY
Gene name: Duffy blood group
Number of Duffy antigens: 6
Antibody type
Almost entirely IgG. IgG1 usually predominates. IgM does occur but is rare.
Antibody behavior
Anti-Fya is a common antibody while anti-Fyb is approximately 20 times less common.,[95][96] They are reactive at body temperature and are therefore clinically significant, although they do not typically bind complement. Antibodies are acquired through exposure (pregnancy or history of blood transfusion) and subsequent alloimmunization. They display dosage (react more strongly to homozygous cells versus heterozygous cells).[95]
Transfusion reactions
Typically mild but may be serious, even fatal. Although these usually occur immediately they may occur after a delay (up to 24 hours). These reactions are usually caused by anti-Fya or anti-Fyb. anti-Fy3 may cause acute or delayed hemolytic transfusion reactions (HTRs), but only rarely.
Anti-Fy5 may also cause delayed hemolytic transfusion reactions.[95]
Hemolytic disease of the fetus and newborn (HDFN)
Hemolytic disease of the fetus and newborn is typically mild but rarely may be serious. Almost always due to anti-Fya and rarely anti-Fyb or Fy3.
References
- ↑ "Entrez Gene: DARC Duffy blood group, chemokine receptor".
- ↑ 2.0 2.1 Chaudhuri A, Polyakova J, Zbrzezna V, Williams K, Gulati S, Pogo AO (November 1993). "Cloning of glycoprotein D cDNA, which encodes the major subunit of the Duffy blood group system and the receptor for the Plasmodium vivax malaria parasite". Proc. Natl. Acad. Sci. U.S.A. 90 (22): 10793–7. Bibcode:1993PNAS...9010793C. doi:10.1073/pnas.90.22.10793. PMC 47864. PMID 8248172.
- ↑ Tournamille C, Colin Y, Cartron JP, Le Van Kim C (June 1995). "Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals". Nat. Genet. 10 (2): 224–8. doi:10.1038/ng0695-224. PMID 7663520.
- ↑ Kosaisavee V, Suwanarusk R, Chua ACY, Kyle DE, Malleret B, Zhang R, Imwong M, Imerbsin R, Ubalee R, Sámano-Sánchez H, Yeung BKS, Ong J, Lombardini E, Nosten F, Tan KSW, Bifani P, Snounou G, Rénia L, Russell B (2017). "Strict Tropism for CD71+/ CD234+ Human Reticulocytes Limits Plasmodium cynomolgi's Zoonotic Potential". Blood. doi:10.1182/blood-2017-02-764787. PMID 28698207.
- ↑ "Entrez Gene: Duffy antigen".
- ↑ Cutbush M, Mollison PL, Parkin DM (4 February 1950). "A New Human Blood Group" (PDF). Nature. 165 (188–189): 188–189. Bibcode:1950Natur.165..188C. doi:10.1038/165188b0.
- ↑ Tournamille C, Colin Y, Cartron JP, Le Van KC (Jun 1995). "Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals". Nat Genet. 10 (2): 224–8. doi:10.1038/ng0695-224. PMID 7663520.
- ↑ Yazdanbakhsh K, Rios M, Storry JR, Kosower N, Parasol N, Chaudhuri A, Reid ME (March 2000). "Molecular mechanisms that lead to reduced expression of duffy antigens". Transfusion. 40 (3): 310–20. doi:10.1046/j.1537-2995.2000.40030310.x. PMID 10738032.
- ↑ 9.0 9.1 Hamblin MT, Di Rienzo A (May 2000). "Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus". American Journal of Human Genetics. 66 (5): 1669–79. doi:10.1086/302879. PMC 1378024. PMID 10762551.
- ↑ Hamblin MT, Thompson EE, Di Rienzo A (February 2002). "Complex Signatures of Natural Selection at the Duffy Blood Group Locus". American Journal of Human Genetics. 70 (2): 369–83. doi:10.1086/338628. PMC 419988. PMID 11753822.
- ↑ Zimmerman PA, Woolley I, Masinde GL, Miller SM, McNamara DT, Hazlett F, Mgone CS, Alpers MP, Genton B, Boatin BA, Kazura JW (November 1999). "Emergence of FY*Anull in a Plasmodium vivax-endemic region of Papua New Guinea". Proc. Natl. Acad. Sci. U.S.A. 96 (24): 13973–7. Bibcode:1999PNAS...9613973Z. doi:10.1073/pnas.96.24.13973. PMC 24175. PMID 10570183.
- ↑ Awasthi G, Dashb AP, Dasa A (September 2009). "Evolutionary insights into duffy gene in mammalian taxa with comparative genetic analysis". J Vector Borne Dis. 46 (3): 230–6. PMID 19724088.
- ↑ Tung J, Primus A, Bouley AJ, Severson TF, Alberts SC, Wray GA (July 2009). "Evolution of a malaria resistance gene in wild primates". Nature. 460 (7253): 388–91. Bibcode:2009Natur.460..388T. doi:10.1038/nature08149. PMID 19553936.
- ↑ Schmid P, Ravenell KR, Sheldon SL, Flegel WA (2011) DARC alleles and Duffy phenotypes in African Americans. Transfusion doi:10.1111/j.1537-2995.2011.03431.x.
- ↑ Oliveira TY, Harris EE, Meyer D, Jue CK, Silva WA (2012). "Molecular evolution of a malaria resistance gene (DARC) in primates". Immunogenetics. 64 (7): 497–505. doi:10.1007/s00251-012-0608-2. PMID 22395823.
- ↑ Grodecka M, Bertrand O, Karolak E, Lisowski M, Waśniowska K (2012). "One-step immunopurification and lectinochemical characterization of the Duffy atypical chemokine receptor from human erythrocytes". Glycoconj. J. 29 (2–3): 93–105. doi:10.1007/s10719-011-9367-9. PMC 3311851. PMID 22246380.
- ↑ 17.0 17.1 Woolley IJ, Hotmire KA, Sramkoski RM, Zimmerman PA, Kazura JW (August 2000). "Differential expression of the duffy antigen receptor for chemokines according to RBC age and FY genotype". Transfusion. 40 (8): 949–53. doi:10.1046/j.1537-2995.2000.40080949.x. PMID 10960522.
- ↑ Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC (1997). "Expression of chemokine receptors by subsets of neurons in the central nervous system". Journal of Immunology. 158 (6): 2882–90. PMID 9058825.
- ↑ Hadley TJ, Lu ZH, Wasniowska K, Martin AW, Peiper SC, Hesselgesser J, Horuk R (1994). "Postcapillary venule endothelial cells in kidney express a multispecific chemokine receptor that is structurally and functionally identical to the erythroid isoform, which is the Duffy blood group antigen". J. Clin. Invest. 94 (3): 985–91. doi:10.1172/JCI117465. PMC 295143. PMID 8083383.
- ↑ Peiper SC, Wang ZX, Neote K, Martin AW, Showell HJ, Conklyn MJ, Ogborne K, Hadley TJ, Lu ZH, Hesselgesser J, Horuk R (April 1995). "The Duffy antigen/receptor for chemokines (DARC) is expressed in endothelial cells of Duffy negative individuals who lack the erythrocyte receptor". J. Exp. Med. 181 (4): 1311–7. doi:10.1084/jem.181.4.1311. PMC 2191961. PMID 7699323.
- ↑ Chaudhuri A, Zbrzezna V, Polyakova J, Pogo AO, Hesselgesser J, Horuk R (1994). "Expression of the Duffy antigen in K562 cells. Evidence that it is the human erythrocyte chemokine receptor". J. Biol. Chem. 269 (11): 7835–8. PMID 8132497.
- ↑ Horuk R, Wang ZX, Peiper SC, Hesselgesser J (1994). "Identification and characterization of a promiscuous chemokine-binding protein in a human erythroleukemic cell line". J. Biol. Chem. 269 (26): 17730–3. PMID 7517400.
- ↑ Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, Miller LH (August 1993). "A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor". Science. 261 (5125): 1182–4. Bibcode:1993Sci...261.1182H. doi:10.1126/science.7689250. PMID 7689250.
- ↑ McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ (2012). "Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum". Science. 338 (6112): 1348–51. Bibcode:2012Sci...338.1348M. doi:10.1126/science.1228892. PMID 23224555.
- ↑ Lu ZH, Wang ZX, Horuk R, Hesselgesser J, Lou YC, Hadley TJ, Peiper SC (1995). "The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain". J. Biol. Chem. 270 (44): 26239–45. doi:10.1074/jbc.270.44.26239. PMID 7592830.
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Further reading
- Pogo AO, Chaudhuri A (1996). "Duffy and receptors for P. vivax and chemotactic peptides". Transfusion clinique et biologique : journal de la Société française de transfusion sanguine. 2 (4): 269–76. doi:10.1016/s1246-7820(05)80093-x. PMID 8542025.
- Pruenster M, Rot A (2007). "Throwing light on DARC". Biochem. Soc. Trans. 34 (Pt 6): 1005–8. doi:10.1042/BST0341005. PMID 17073738.
- Raeymaekers P, Van Broeckhoven C, Backhovens H, Wehnert A, Muylle L, De Jonghe P, Gheuens J, Vandenberghe A (1988). "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 (1): 76–8. doi:10.1007/BF00291239. PMID 2892777.
- Lu ZH, Wang ZX, Horuk R, Hesselgesser J, Lou YC, Hadley TJ, Peiper SC (1995). "The promiscuous chemokine binding profile of the Duffy antigen/receptor for chemokines is primarily localized to sequences in the amino-terminal domain". J. Biol. Chem. 270 (44): 26239–45. doi:10.1074/jbc.270.44.26239. PMID 7592830.
- Horuk R, Chitnis CE, Darbonne WC, Colby TJ, Rybicki A, Hadley TJ, Miller LH (1993). "A receptor for the malarial parasite Plasmodium vivax: the erythrocyte chemokine receptor". Science. 261 (5125): 1182–4. Bibcode:1993Sci...261.1182H. doi:10.1126/science.7689250. PMID 7689250.
- Tournamille C, Le Van Kim C, Gane P, Cartron JP, Colin Y (1995). "Molecular basis and PCR-DNA typing of the Fya/fyb blood group polymorphism". Hum. Genet. 95 (4): 407–10. doi:10.1007/BF00208965. PMID 7705836.
- Iwamoto S, Omi T, Kajii E, Ikemoto S (1995). "Genomic organization of the glycoprotein D gene: Duffy blood group Fya/Fyb alloantigen system is associated with a polymorphism at the 44-amino acid residue". Blood. 85 (3): 622–6. PMID 7833467.
- Horuk R, Martin AW, Wang Z, Schweitzer L, Gerassimides A, Guo H, Lu Z, Hesselgesser J, Perez HD, Kim J, Parker J, Hadley TJ, Peiper SC (1997). "Expression of chemokine receptors by subsets of neurons in the central nervous system". Journal of Immunology. 158 (6): 2882–90. PMID 9058825.
- Tournamille C, Le Van Kim C, Gane P, Blanchard D, Proudfoot AE, Cartron JP, Colin Y (1997). "Close association of the first and fourth extracellular domains of the Duffy antigen/receptor for chemokines by a disulfide bond is required for ligand binding". J. Biol. Chem. 272 (26): 16274–80. doi:10.1074/jbc.272.26.16274. PMID 9195930.
- Tournamille C, Le Van Kim C, Gane P, Le Pennec PY, Roubinet F, Babinet J, Cartron JP, Colin Y (1998). "Arg89Cys substitution results in very low membrane expression of the Duffy antigen/receptor for chemokines in Fy(x) individuals". Blood. 92 (6): 2147–56. PMID 9731074.
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External links
- DARC+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
- Duffy at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH
- Duffy gene
- Population data