Duffy Antigen System
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Duffy antigen/chemokine receptor (DARC), also known as Fy glycoprotein (FY) or CD234 (Cluster of Differentiation 234), is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''ACKR1''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. The Duffy antigen is located on the surface of
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s, and is named after the patient in whom it was discovered. The protein encoded by this gene is a
glycosylated Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not alw ...
membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane ...
and a non-specific
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for several
chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In additio ...
s. The protein is also the receptor for the human malarial parasites ''
Plasmodium vivax ''Plasmodium vivax'' is a protozoal parasite and a human pathogen. This parasite is the most frequent and widely distributed cause of recurring malaria. Although it is less virulent than ''Plasmodium falciparum'', the deadliest of the five huma ...
'', ''
Plasmodium knowlesi ''Plasmodium knowlesi'' is a parasite that causes malaria in humans and other primates. It is found throughout Southeast Asia, and is the most common cause of human malaria in Malaysia. Like other ''Plasmodium'' species, ''P. knowlesi'' has a li ...
'' and simian malarial parasite ''
Plasmodium cynomolgi ''Plasmodium cynomolgi'' is an apicomplexan parasite that infects mosquitoes and Asian Old World monkeys. In recent years, a number of natural infections of humans have also been documented. This species has been used as a model for human ''Plas ...
''. Polymorphisms in this gene are the basis of the Duffy blood group system.


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 Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
,
thalassemia Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
and
glucose-6-phosphate dehydrogenase Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) () is a cytosolic enzyme that catalyzes the chemical reaction : D-glucose 6-phosphate + NADP+ + H2O 6-phospho-D-glucono-1,5-lactone + NADPH + H+ This enzyme participates in the pentose phosph ...
. In 1950, the Duffy
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. ...
was discovered in a multiply-transfused
hemophiliac Haemophilia, or hemophilia (), is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, ...
whose serum contained the first example of anti-Fya
antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...
. In 1951, the antibody to a second antigen, Fyb, was discovered in serum. Using these two antibodies, three common
phenotypes In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
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. The Fy4 antigen, originally described on Fy (a–b–) RBCs, is now thought to be a distinct, unrelated antigen and is no longer included in the FY system.


Genetics and genomics

The Duffy antigen/chemokine
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
gene (gp-Fy; CD234) is located on the long arm of
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ar ...
(1.q22-1.q23) and was cloned in 1993. 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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s. The gene encodes a 336 amino acid acidic
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
. It carries the antigenic determinants of the Duffy blood group system which consist of four codominant
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
s—FY*A and FY*B—coding for the Fy-a and Fy-b antigens respectively, FY*X and FY*Fy, five
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
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-bweak or Fy-bWk. This gene has been redesignated '' ACKR1''. Fy-a and Fy-b differ by in a single
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
at position 42:
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
in Fy-a and
aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
in Fy-b (
guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
in Fy-a and
adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
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 A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequences ...
in the erythroid specific promoter (a T -> C mutation at position -33 in the GATA box). 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:
Cytosine Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...
265
Threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
(
Arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
89
Cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
) and
Guanine Guanine () ( symbol G or Gua) is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine (uracil in RNA). In DNA, guanine is paired with cytosine. The guanine nucleoside is called ...
298
Adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
(
Alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side c ...
100
Threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO ...
). A third mutation (a
transversion Transversion, in molecular biology, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by ioni ...
) in this gene has also been described - G145T (
Alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side c ...
49
Serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
) - that has been associated with the Fy-x phenotype. Most Duffy negative blacks carry a silent Fy-b
allele An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chro ...
with a single T to C substitution at
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules wi ...
-33, impairing the promoter activity in erythroid cells by disrupting a binding site for the
GATA1 GATA-binding factor 1 or GATA-1 (also termed Erythroid transcription factor) is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by ...
erythroid
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
. The gene is still transcribed in non erythroid cells in the presence of this
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
. 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 Cytosine () ( symbol C or Cyt) is one of the four nucleobases found in DNA and RNA, along with adenine, guanine, and thymine (uracil in RNA). It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached (an am ...
->
thymidine Thymidine (symbol dT or dThd), also known as deoxythymidine, deoxyribosylthymine, or thymine deoxyriboside, is a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine (A) in double-stranded DNA. I ...
at position 265). The silent allele has evolved at least twice in the black population of Africa and evidence for selection for this allele has been found. The selection pressure involved here appears to be more complex than many text books might suggest. An independent evolution of this phenotype occurred in
Papua New Guinea Papua New Guinea (abbreviated PNG; , ; tpi, Papua Niugini; ho, Papua Niu Gini), officially the Independent State of Papua New Guinea ( tpi, Independen Stet bilong Papua Niugini; ho, Independen Stet bilong Papua Niu Gini), is a country i ...
has also been documented. A comparative study of this gene in seven mammalian species revealed significant differences between species. The species examined included ''
Pan troglodytes The chimpanzee (''Pan troglodytes''), also known as simply the chimp, is a species of Hominidae, great ape native to the forest and savannah of tropical Africa. It has four confirmed subspecies and a fifth proposed subspecies. When its close r ...
'' (chimpanzee), ''
Macaca mulatta The rhesus macaque (''Macaca mulatta''), colloquially rhesus monkey, is a species of Old World monkey. There are between six and nine recognised subspecies that are split between two groups, the Chinese-derived and the Indian-derived. Generally b ...
'' (rhesus monkey), ''
Pongo pygmaeus The Bornean orangutan (''Pongo pygmaeus'') is a species of orangutan endemic to the island of Borneo. Together with the Sumatran orangutan (''Pongo abelii'') and Tapanuli orangutan (''Pongo tapanuliensis''), it belongs to the only genus of grea ...
'' (orangutan), ''
Rattus norvegicus ''Rattus'' is a genus of muroid rodents, all typically called rats. However, the term rat can also be applied to rodent species outside of this genus. Species and description The best-known ''Rattus'' species are the black rat (''R. rattus'') ...
'' (brown rat), ''
Mus musculus Mus or MUS may refer to: Abbreviations * MUS, the NATO country code for Mauritius * MUS, the IATA airport code for Minami Torishima Airport * MUS, abbreviation for the Centre for Modern Urban Studies on Campus The Hague, Leiden University, Neth ...
'' (mouse), ''
Monodelphis domestica The gray short-tailed opossum (''Monodelphis domestica'') is a small South American member of the family Didelphidae. Unlike most other marsupials, the gray short-tailed opossum does not have a true pouch. The scientific name ''Monodelphis'' is ...
'' (opossum), ''
Bos taurus Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referred to as cows and adult ma ...
'' (cow) and ''
Canis familiaris The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is Domestication of the dog, derived from the extinct Pleistocene wolf, and the modern wolf is the dog's n ...
'' (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), 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 The yellow baboon (''Papio cynocephalus'') is a baboon in the family of Old World monkeys. The species epithet means "dog-head" in Greek, due to the dog-like shape of the muzzle and head. Yellow baboons have slim bodies with long arms and legs, a ...
'') mutations in this gene have been associated with protection from infection with species of the genus ''
Hepatocystis ''Hepatocystis'' is a genus of parasites transmitted by midges of the genus ''Culicoides''. Hosts include Old World primates, bats, hippopotamus and squirrels. This genus is not found in the New World. The genus was erected by Levaditi and Schoe ...
''. The ancestral form of extant DARC alleles in humans appears to be the FY*B allele. The gene appears to be under strong purifying selection. 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. 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 Reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis (red blood cell formation), reticulocytes develop and mature in the bone marrow and then circulatory system, circulate for about a day in the blood stream before ...
s than on mature erythrocytes. While the Duffy antigen is expressed on bone marrow
erythroblasts A nucleated red blood cell (NRBC), also known by several other names, is a red blood cell that contains a cell nucleus. Almost all vertebrate organisms have hemoglobin-containing cells in their blood, and with the exception of mammals, all of t ...
and circulating
erythrocytes Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
it is also found on
Purkinje cells Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Structure The ...
of the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
, endothelial cells of
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
, the post-capillary
venule A venule is a very small blood vessel in the microcirculation that allows blood to return from the capillary beds to drain into the larger blood vessels, the veins. Venules range from 7μm to 1mm in diameter. Veins contain approximately 70% of t ...
s of some organs including the spleen, liver and kidney and the large pulmonary venules. Duffy antigen has then a very unique cell expression profile in cerebellar neurons, venular endothelial cells and erythroid cells. In some people who lack the Duffy antigen on their erythrocytes it is still expressed in the other cell types. It has two potential N-linked glycosylation sites at
asparagine Asparagine (symbol Asn or N) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
(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 chemotactic protein-1 (MCP-1) -
CCL2 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL ...
* regulated upon activation normal T expressed and secreted (RANTES) -
CCL5 Chemokine (C-C motif) ligand 5 (also CCL5) is a protein which in humans is encoded by the ''CCL5'' gene. The gene has been discovered in 1990 by ''in situ'' hybridisation and it is localised on 17q11.2-q12 chromosome. It is also known as RANTE ...
* melanoma growth stimulatory activity (MSGA-α), KC, neutrophil-activating protein 3 (NAP-3) -
CXCL1 The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infecti ...
/ CXCL2 and the angiogenic CXC chemokines: * Growth related gene alpha (GRO-α) -
CXCL1 The chemokine (C-X-C motif) ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infecti ...
* Platelet factor 4 -
CXCL4 Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is also known as chemokine (C-X-C motif) ligand 4 (CXCL4) . This chemokine is released from alpha-granules of activated platelets during platelet aggregation ...
* ENA-78 -
CXCL5 C-X-C motif chemokine 5 (CXCL5 or ENA78) is a protein that in humans is encoded by the ''CXCL5'' gene. Function The protein encoded by this gene, CXCL5 is a small cytokine belonging to the CXC chemokine family that is also known as epithelial- ...
* Neutrophil activating peptide-2 (NAP-2) -
CXCL7 Chemokine (C-X-C motif) ligand 7 (CXCL7) is a human gene. The encoded protein, Chemokine (C-X-C motif) ligand is a small cytokine belonging to the CXC chemokine family. It is an isoform of Beta-Thromboglobulin or ''Pro-Platelet basic protein'' ( ...
* Interleukin-8 (IL-8) -
CXCL8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage ...
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 The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
. 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 G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s shows that DARC lacks the highly conserved DRY motif in the second intracellular loop of the
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
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. 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 The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
, neuronal cells and
epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...
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. This hypothesis has also been questioned after
knock out A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
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 Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
migration from the blood into the tissues and in modulating the inflammatory response. The protein is also known to interact with the protein KAI1 ( CD82) a surface glycoprotein of
leukocyte White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
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. DARC has been shown to internalise chemokines but does not scavenge them. It mediates chemokine transcytosis, which leads 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 people of African descent had the
erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
phenotype Fy(a-b-): 68% in
African American African Americans (also referred to as Black Americans and Afro-Americans) are an ethnic group consisting of Americans with partial or total ancestry from sub-Saharan Africa. The term "African American" generally denotes descendants of ens ...
s and 88-100% in African people (including more than 90% of
West Africa West Africa or Western Africa is the westernmost region of Africa. The United Nations defines Western Africa as the 16 countries of Benin, Burkina Faso, Cape Verde, The Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali, Maurit ...
n people). This phenotype is exceedingly rare in Whites. Because the Duffy antigen is uncommon in those of
Black African Black is a Racialization, racialized classification of people, usually a Politics, political and Human skin color, skin color-based category for specific populations with a mid to dark brown complexion. Not all people considered "black" have ...
descent, the presence of this antigen has been used to detect
genetic admixture Genetic admixture occurs when previously diverged or isolated genetic lineages mix.⅝ Admixture results in the introduction of new genetic lineages into a population. Examples Climatic cycles facilitate genetic admixture in cold periods and gene ...
. 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. Overall the frequencies of Fya and Fyb antigens in Whites 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% Whites, 99.9% Asians and 32% Blacks. Phenotype frequencies are: * Fy(a+b+): 49% Whites, 1% Blacks, 9% Chinese * Fy(a-b+): 34% Whites, 22% Blacks, <1% Chinese * Fy(a+b-): 17% Whites, 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. 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 The genetic code is the set of rules used by living cells to translate information encoded within genetic material ( DNA or RNA sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the ribosome, which links ...
position—base number 298) within the FY*B allele was thought to be purely a
White White is the lightest color and is achromatic (having no hue). It is the color of objects such as snow, chalk, and milk, and is the opposite of black. White objects fully reflect and scatter all the visible wavelengths of light. White on ...
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-White 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. * This antigen along with other blood group antigens was used to identify the
Basque people The Basques ( or ; eu, euskaldunak ; es, vascos ; french: basques ) are a Southwestern European ethnic group, characterised by the Basque language, a common culture and shared genetic ancestry to the ancient Vascones and Aquitanians. Ba ...
as a genetically separate group. Its use in forensic science is under consideration. * The
Andaman Andaman may refer to: * Andaman Islands * Andaman Sea * ''Andaman'' (1998 film), a Kannada-language film * ''Andaman'' (2016 film), a Tamil-language film * ''Andaman'' (2021 film), a Hindi-language film See also * Andaman and Nicobar Islands ...
and Nicobar Islands, 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 South Andaman Island is the southernmost island of the Great Andaman and is home to the majority of the population of the Andaman Islands. It belongs to the South Andaman administrative district, part of the Indian union territory of Andaman an ...
and one jungle area in
Middle Andaman Middle Andaman Island is an island of the Andaman Islands. It belongs to the North and Middle Andaman administrative district, part of the Indian union territory of Andaman and Nicobar Islands. Geography The island belongs to the Great Andam ...
. The area is endemic for
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
. The causative species is ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans, and the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mosqu ...
'': 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. * In the
Yemen Yemen (; ar, ٱلْيَمَن, al-Yaman), officially the Republic of Yemen,, ) is a country in Western Asia. It is situated on the southern end of the Arabian Peninsula, and borders Saudi Arabia to the Saudi Arabia–Yemen border, north and ...
ite
Jew Jews ( he, יְהוּדִים, , ) or Jewish people are an ethnoreligious group and nation originating from the Israelites Israelite origins and kingdom: "The first act in the long drama of Jewish history is the age of the Israelites""Th ...
s the frequency of the Fy allele is 0.5879 The frequency of this allele varies from 0.1083 to 0.2191 among Jews from the Middle East, North Africa and
Southern Europe Southern Europe is the southern regions of Europe, region of Europe. It is also known as Mediterranean Europe, as its geography is essentially marked by the Mediterranean Sea. Definitions of Southern Europe include some or all of these countrie ...
. 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. * In the
Chinese Chinese can refer to: * Something related to China * Chinese people, people of Chinese nationality, citizenship, and/or ethnicity **''Zhonghua minzu'', the supra-ethnic concept of the Chinese nation ** List of ethnic groups in China, people of ...
ethnic populations—the
Han Han may refer to: Ethnic groups * Han Chinese, or Han People (): the name for the largest ethnic group in China, which also constitutes the world's largest ethnic group. ** Han Taiwanese (): the name for the ethnic group of the Taiwanese p ...
and the
She people The She people (; Shehua: ; Cantonese: , Fuzhou: ) are an ethnic group in China. They form one of the 56 ethnic groups officially recognized by the People's Republic of China. The She are the largest ethnic minority in Fujian, Zhejiang, and Jia ...
—the frequencies of Fya and Fyb alleles were 0.94 and 0.06 and 0.98 and 0.02 respectively. * The frequency of the Fya allele in most Asian populations is ~95%. * In
Grande Comore Grande Comore () is an island in Comoros off the coast of Africa. It is the largest island in the Comoros nation. Most of its population is of the Comorian ethnic group. Its population is about 316,600. The island's capital is Moroni, Comoros, ...
(also known as
Ngazidja Grande Comore () is an island in Comoros off the coast of Africa. It is the largest island in the Comoros nation. Most of its population is of the Comorian ethnic group. Its population is about 316,600. The island's capital is Moroni, which is ...
) the frequency of the Fy(a- b-) phenotype is 0.86. * The incidence of Fy(a+b-) in northern India among blood donors is 43.85%. * In the
Maghreb The Maghreb (; ar, الْمَغْرِب, al-Maghrib, lit=the west), also known as the Arab Maghreb ( ar, المغرب العربي) and Northwest Africa, is the western part of North Africa and the Arab world. The region includes Algeria, ...
,
Horn of Africa The Horn of Africa (HoA), also known as the Somali Peninsula, is a large peninsula and geopolitical region in East Africa.Robert Stock, ''Africa South of the Sahara, Second Edition: A Geographical Interpretation'', (The Guilford Press; 2004), ...
and the
Nile Valley The Nile, , Bohairic , lg, Kiira , Nobiin: Áman Dawū is a major north-flowing river in northeastern Africa. It flows into the Mediterranean Sea. The Nile is the longest river in Africa and has historically been considered the longest rive ...
, the
Afroasiatic The Afroasiatic languages (or Afro-Asiatic), also known as Hamito-Semitic, or Semito-Hamitic, and sometimes also as Afrasian, Erythraean or Lisramic, are a language family of about 300 languages that are spoken predominantly in the geographic su ...
(Hamitic-Semitic) speaking populations are largely Duffy-positive. Between 70%-98% of Hamito-Semitic groups in Ethiopia were found to be Duffy-positive. Serological and DNA based analysis of 115 unrelated
Tunis ''Tounsi'' french: Tunisois , population_note = , population_urban = , population_metro = 2658816 , population_density_km2 = , timezone1 = CET , utc_offset1 ...
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. * In
Nouakchott , image_skyline = Nouakchott.jpg , image_caption = City view of Nouakchott , pushpin_map = Mauritania#Arab world#Africa , pushpin_relief = 1 , mapsize = , map_caption ...
,
Mauritania Mauritania (; ar, موريتانيا, ', french: Mauritanie; Berber: ''Agawej'' or ''Cengit''; Pulaar: ''Moritani''; Wolof: ''Gànnaar''; Soninke:), officially the Islamic Republic of Mauritania ( ar, الجمهورية الإسلامية ...
overall 27% of the population are Duffy-positive. 54% of
Moor Moor or Moors may refer to: Nature and ecology * Moorland, a habitat characterized by low-growing vegetation and acidic soils. Ethnic and religious groups * Moors, Muslim inhabitants of the Maghreb, Iberian Peninsula, Sicily, and Malta during ...
s are Duffy antigen positive, while only 2% of black ethnic groups (mainly Poular, Soninke and
Wolof Wolof or Wollof may refer to: * Wolof people, an ethnic group found in Senegal, Gambia, and Mauritania * Wolof language, a language spoken in Senegal, Gambia, and Mauritania * The Wolof or Jolof Empire, a medieval West African successor of the Mal ...
) are Duffy positive. * A map of the Duffy antigen distribution has been produced. The most prevalent allele globally is FY*A. Across sub-Saharan Africa the predominant allele is the silent FY*BES variant. * In
Iran Iran, officially the Islamic Republic of Iran, and also called Persia, is a country located in Western Asia. It is bordered by Iraq and Turkey to the west, by Azerbaijan and Armenia to the northwest, by the Caspian Sea and Turkmeni ...
the Fy (a-b-) phenotype was found in 3.4%. 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) The distribution within India has been studied in some detail.


Clinical significance

Historically the role of this antigen other than its importance as a receptor for
Plasmodium ''Plasmodium'' is a genus of unicellular eukaryotes that are obligate parasites of vertebrates and insects. The life cycles of ''Plasmodium'' species involve development in a blood-feeding insect host which then injects parasites into a vert ...
protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein.


Malaria

On erythrocytes, the Duffy antigen acts as a
receptor Receptor may refer to: * Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
for invasion by the human
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
l 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 although ''P. vivax'' infection has been reported in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection. This antigen may also play a role in
erythrocyte Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
invasion in the rodent malarial parasite '' P. yoelii''. The
epitope An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The epitope is the specific piece of the antigen to which an antibody binds. The p ...
Fy6 is required for ''P. vivax'' invasion. The protection to ''P. vivax'' malaria conferred by the absence of the Duffy antigen appears to be very limited at best in
Madagascar Madagascar (; mg, Madagasikara, ), officially the Republic of Madagascar ( mg, Repoblikan'i Madagasikara, links=no, ; french: République de Madagascar), is an island country in the Indian Ocean, approximately off the coast of East Africa ...
. Although 72% of the population are Duffy antigen negative, 8.8% of the Duffy antigen negative individuals were
asymptomatic carrier An asymptomatic carrier is a person or other organism that has become infected with a pathogen, but shows no signs or symptoms. Although unaffected by the pathogen, carriers can transmit it to others or develop symptoms in later stages of the d ...
s of ''P. vivax''. Malaria has also been found in
Angola , national_anthem = " Angola Avante"() , image_map = , map_caption = , capital = Luanda , religion = , religion_year = 2020 , religion_ref = , coordina ...
and
Equatorial Guinea Equatorial Guinea ( es, Guinea Ecuatorial; french: Guinée équatoriale; pt, Guiné Equatorial), officially the Republic of Equatorial Guinea ( es, link=no, República de Guinea Ecuatorial, french: link=no, République de Guinée équatoria ...
in Duffy negative individuals. ''P. vivax'' malaria in a Duffy antigen negative individual in
Mauritania Mauritania (; ar, موريتانيا, ', french: Mauritanie; Berber: ''Agawej'' or ''Cengit''; Pulaar: ''Moritani''; Wolof: ''Gànnaar''; Soninke:), officially the Islamic Republic of Mauritania ( ar, الجمهورية الإسلامية ...
has also been reported. Similar infections have been reported in Brazil and
Kenya ) , national_anthem = "Ee Mungu Nguvu Yetu"() , image_map = , map_caption = , image_map2 = , capital = Nairobi , coordinates = , largest_city = Nairobi , ...
. Additional cases of infection in Duffy antigen negative individuals have been reported from the Congo and Uganda. A study in
Brazil Brazil ( pt, Brasil; ), officially the Federative Republic of Brazil (Portuguese: ), is the largest country in both South America and Latin America. At and with over 217 million people, Brazil is the world's fifth-largest country by area ...
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. 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. 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. 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. 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 Platelet factor 4 (PF4) is a small cytokine belonging to the CXC chemokine family that is also known as chemokine (C-X-C motif) ligand 4 (CXCL4) . This chemokine is released from alpha-granules of activated platelets during platelet aggregation ...
) appears to be critical for the platelet induced killing of '' P. falciparum. The Duffy antigen binding protein in ''P. vivax'' is composed of three subdomains and is thought to function as a dimer. The critical DARC binding residues are concentrated at the dimer interface and along a relatively flat surface spanning portions of two subdomains. A study in Brazil confirmed the protective effect of FY*A/FY*O against malaria. In contrast the genotype FY*B/FY*O was associated with a greater risk.


Asthma

Asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
is more common and tends to be more severe in those of African descent. There appears to be a correlation with both total
IgE Immunoglobulin E (IgE) is a type of antibody (or immunoglobulin (Ig) " isotype") that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains (ε chain) and two light chains, with the ε c ...
levels and asthma and mutations in the Duffy antigen.


Hematopoiesis

Duffy antigen plays a fundamental role on
hematopoiesis Haematopoiesis (, from Greek , 'blood' and 'to make'; also hematopoiesis in American English; sometimes also h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. ...
. Indeed, nucleated red blood cells present in the bone marrow have high expression of DARC, which facilitates their direct contact with
hematopoietic stem cells Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...
. 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. Therefore, alternative physiological patterns of hematopoiesis and bone marrow cell outputs depend on the expression of DARC in the erythroid lineage.


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 Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
. This condition is also found in
Arab The Arabs (singular: Arab; singular ar, عَرَبِيٌّ, DIN 31635: , , plural ar, عَرَب, DIN 31635: , Arabic pronunciation: ), also known as the Arab people, are an ethnic group mainly inhabiting the Arab world in Western Asia, ...
Jordan Jordan ( ar, الأردن; tr. ' ), officially the Hashemite Kingdom of Jordan,; tr. ' is a country in Western Asia. It is situated at the crossroads of Asia, Africa, and Europe, within the Levant region, on the East Bank of the Jordan Rive ...
ians, Black Bedouin,
Beta Israel The Beta Israel ( he, בֵּיתֶא יִשְׂרָאֵל, ''Bēteʾ Yīsrāʾēl''; gez, ቤተ እስራኤል, , modern ''Bēte 'Isrā'ēl'', EAE: "Betä Ǝsraʾel", "House of Israel" or "Community of Israel"), also known as Ethiopian Jews ...
,
Yemenite Jews Yemenite Jews or Yemeni Jews or Teimanim (from ''Yehudei Teman''; ar, اليهود اليمنيون) are those Jews who live, or once lived, in Yemen, and their descendants maintaining their customs. Between June 1949 and September 1950, the ...
and
West Indian A West Indian is a native or inhabitant of the West Indies (the Antilles and the Lucayan Archipelago). For more than 100 years the words ''West Indian'' specifically described natives of the West Indies, but by 1661 Europeans had begun to use it ...
s. This condition is associated with a reduced capacity to mobilize bone marrow
neutrophil Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying in ...
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. 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.


Cancer

Interactions between the metastasis suppressor
KAI1 CD82 (Cluster of Differentiation 82), or ''KAI1'', is a human protein encoded by the gene. This metastasis suppressor gene product is a membrane glycoprotein that is a member of the tetraspanin/transmembrane 4 superfamily. Expression of this g ...
on tumor cells and the cytokine receptor DARC on adjacent vascular cells suppresses tumor
metastasis Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
. 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.


Endotoxin response

The procoagulant response to lipopolysaccharide (bacterial endotoxin) is reduced in Duffy antigen negative Africans compared with Duffy positive Whites. This difference is likely to involve additional genes.


HIV infection

A connection has been found between
HIV The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
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. HIV-1 appears to be able to attach to erythrocytes via DARC. The association between the Duffy antigen and HIV infection appears to be complex.
Leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
(a low total white cell count) is associated with relatively poor survival in HIV infection and this association is more marked in
whites White is a racialized classification of people and a skin color specifier, generally used for people of European origin, although the definition can vary depending on context, nationality, and point of view. Description of populations as " ...
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. 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 Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
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%. Risk of seroconversion appeared to be correlated with Duffy-null-associated low neutrophil counts.


Inflammation

An association with the levels
monocyte chemoattractant protein-1 ''For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.'' The chemokine (C-C motif) ligand 2 (CCL2) is also referred to as monocyte chemoattractant protein 1 (MCP1) and small inducible cytokine A2. CCL ...
has been reported. 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. 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.


Lung transplantation

The Duffy antigen has been implicated in lung transplantation rejection.


Multiple myeloma

An increased incidence of Duffy antigen has been reported in patients with multiple myeloma compared with healthy controls.


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.


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 European or Asian descendant (60% greater incidence and double the mortality compared to Whites). However, the contribution of DARC to this increased risk has been tested in
Jamaica Jamaica (; ) is an island country situated in the Caribbean Sea. Spanning in area, it is the third-largest island of the Greater Antilles and the Caribbean (after Cuba and Hispaniola). Jamaica lies about south of Cuba, and west of His ...
n males of black African descent. It was found that none of the increased risk could be attributed to the DARC gene. The reason for this increased risk is as yet unknown.


Psychiatry

The use of the antipsychotic agent
clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...
is associated with
neutropenia Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
. An increased risk of this side effect has been reported in Duffy null patients.


Renal transplantion

Antibodies and a cellular response to the Duffy antigen have been associated with renal transplant rejection.


Sickle cell anaemia

Duffy antigen-negative individuals with
sickle cell anaemia Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blo ...
tend to sustain more severe organ damage than do those with the Duffy antigen. Duffy-positive patients exhibit higher counts of white blood cells, polynuclear neutrophils, higher plasma levels of IL-8 and RANTES than Duffy-negative patients.


Southeast Asian ovalocytosis

There is a ~10% increase in Fy expression in
Southeast Asian ovalocytosis Southeast Asian ovalocytosis is a blood disorder that is similar to, but distinct from hereditary elliptocytosis. It is common in some communities in Malaysia and Papua New Guinea, as it confers some resistance to cerebral Falciparum Malaria. Pat ...
erythrocytes.


Transfusion medicine

A Duffy negative blood recipient may have a transfusion reaction if the donor is Duffy positive. 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., 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).


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, but only rarely. Anti-Fy5 may also cause delayed hemolytic transfusion reactions.


Hemolytic disease of the fetus and newborn

Hemolytic disease of the fetus and newborn Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules (one of the five ...
is typically mild but rarely may be serious. Almost always due to anti-Fya and rarely anti-Fyb or Fy3.


References


Further reading

* * * * * * * * * *


External links

*
Duffy
at
BGMUT The BGMUT (Blood Group antigen gene MUTation) Database documents allelic variations in the genes encoding for human blood group systems. It was set up in 1999 through an initiative of the Human Genome Variation Society ( HGVS). Since 2006, it has ...
Blood Group Antigen Gene Mutation Database at
NCBI The National Center for Biotechnology Information (NCBI) is part of the United States National Library of Medicine (NLM), a branch of the National Institutes of Health (NIH). It is approved and funded by the government of the United States. The ...
,
NIH The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

Duffy gene

Population data
* {{DEFAULTSORT:Duffy Antigen System Clusters of differentiation Immune system Blood antigen systems HIV/AIDS Transfusion medicine