Duffy antigen system
Encyclopedia
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
.
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 glycosylated
membrane protein
and a non-specific receptor
for several chemokine
s. The protein is also the receptor for the human malarial parasites Plasmodium vivax
and Plasmodium knowlesi
. Polymorphisms
in this gene are the basis of the Duffy blood group system.
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
.
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.
/chemokine
receptor
gene
(gp-Fy; CD234) is located on the long arm of chromosome 1 (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
s. It encodes a 336 amino acid acidic glycoprotein
. The gene
carries the antigen
ic 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 antigen
s. 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). This mutation occurs in the Fy-b allelle and has been designated Fy-bEs (erythroid silent). Two isotypes have been identified. The Fy-x allelle is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate transitions
: Cytosine
265Threonine
(Arginine
89Cysteine
) and Guanine
298Adenosine (Alanine
100Threonine
). A third mutation (a transversion) in this gene has also been described - G145T (Alanine
49Serine
) - 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).
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
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 (chimpanzee), Macaca mulatta (rhesus monkey), Pongo pygmaeus (orangutan), Rattus norvegicus (brown rat), Mus musculus (mouse), Monodelphis domestica (opposum), Bos taurus (cow) and Canis familiaris (dog).
Three exons are present in humans and chimpanzees while 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
.
The ancestral form of extant DARC alleles in humans appears to be the FY*B allele.
s than on mature erythrocytes. While the Duffy antigen is expressed on erythrocytes it is also found on some epithelial cells, Purkinje cells of the cerebellum
, endothelial cells of thyroid
capillaries, the post-capillary venule
s of some organs including the spleen, liver and kidney and the large pulmonary venules.
In some people who lack the Duffy antigen on their erythrocytes it may still be expressed in some cells. 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:
and the angiogenic CXC chemokines:
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 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 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.
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. 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 and in modulating the inflammatory response.
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.
DARC has been shown to internalise chemokines but does not scavenge them. 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.
Fy(a-b-): 68% in African American
s and 88-100% in African blacks (including more than 90% of West Africa
n blacks). This phenotype
is exceedingly rare in whites. 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.
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 fequencies 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. Since then many surveys have been carried out to elucidate the prevalence of Duffy antigen alleles in different populations including:
parasitic protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein.
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.
. This condition is also found in Arab
Jordan
ians, 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. Although the mechanism is as yet unknown, it is known that neutrophils are retained in the bone marrow through interaction of CXCL12 with its receptor CXCR4
. A number of rare diseases are known in which disruption or desensitization of CXCR4 results in failure to release mature neutrophils from bone marrow
.
on tumor cells and the cytokine receptor DARC on adjacent vascular cells suppresses tumor metastasis
. 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.
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
(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 negroids 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
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.
for invasion by the human malaria
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 it has been reported that P. vivax infection in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection. 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.
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. Malaria has also been found in Angola
and Equatorial Guinea
in Duffy negative individuals. P. vivax malaria in a Duffy antigen negative individual in Mauritania
has also been reported. Similar infections have been reported in Brazil
and Kenya
. 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.
n males of black African descent. It was found that none of the increased risk could be attributed to the DARC gene.
ISBT number: 008
Gene symbol: FY
Gene name: Duffy blood group
Number of Duffy antigens: 6
Antibody type: Almost entirely IgG. IgM does occur but is rare. These antibodies do not typically bind complement.
Transfusion reactions: Typically mild but may be serious. Although these usually occur immediately they may occur after a delay (up to 24 hours). These reactions are usually caused by Fya or Fyb. Fy3 may cause a reaction but only rarely.
Hemolytic disease of the newborn: This is typically mild but rarely may be serious. Almost always due to Fya: rarely Fyb or Fy3.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the DARC gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
The Duffy antigen is located on the surface of red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s, and is named after the patient in which it was discovered. The protein encoded by this gene is a glycosylated
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
membrane protein
Membrane protein
A membrane protein is a protein molecule that is attached to, or associated with the membrane of a cell or an organelle. More than half of all proteins interact with membranes.-Function:...
and a non-specific receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for several chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s. The protein is also the receptor for the human malarial parasites Plasmodium vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
and Plasmodium knowlesi
Plasmodium knowlesi
Plasmodium knowlesi is a primate malaria parasite commonly found in Southeast Asia. It causes malaria in long-tailed macaques , but it may also infect humans, either naturally or artificially....
. Polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
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 infection with 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, thalassemiaThalassemia
Thalassemia is an inherited autosomal recessive blood disease that originated in the Mediterranean region. In thalassemia the genetic defect, which could be either mutation or deletion, results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin...
and glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase
Glucose-6-phosphate dehydrogenase is a cytosolic enzyme in the pentose phosphate pathway , a metabolic pathway that supplies reducing energy to cells by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate...
.
In 1950, the Duffy antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
was discovered in a multiply-transfused hemophiliac whose serum contained the first example of anti-Fya antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
.
In 1951, the antibody to a second antigen, Fyb, was discovered in serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
. 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 antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
/chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(gp-Fy; CD234) is located on the long arm of chromosome 1 (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
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
spanning over 1500 bases and is in two exon
Exon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s. It encodes a 336 amino acid acidic glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
. The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
carries the antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
ic determinants of the Duffy blood group system which consist of four codominant allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s—FY*A and FY*B—coding for the Fy-a and Fy-b antigens respectively, FY*X and FY*Fy, five phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
s (Fy-a, Fy-b, Fy-o, Fy-x and Fy-y) and five antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s. 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
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
at position 42: glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
in Fy-a and aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
in Fy-b (guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
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
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
is a point mutation
Point mutation
A point mutation, or single base substitution, is a type of mutation that causes the replacement of a single base nucleotide with another nucleotide of the genetic material, DNA or RNA. Often the term point mutation also includes insertions or deletions of a single base pair...
in the erythroid specific promoter (a T -> C mutation at position -33 in the GATA box). This mutation occurs in the Fy-b allelle and has been designated Fy-bEs (erythroid silent). Two isotypes have been identified. The Fy-x allelle is characterized by a weak anti-Fy-b reaction and appears to be the result of two separate transitions
Transition (genetics)
In genetics, a transition is a point mutation that changes a purine nucleotide to another purine or a pyrimidine nucleotide to another pyrimidine . Approximately two out of three single nucleotide polymorphisms are transitions....
: Cytosine
Cytosine
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
265Threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
(Arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
89Cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
) and Guanine
Guanine
Guanine is one of the four main nucleobases found in the nucleic acids DNA and RNA, the others being adenine, cytosine, and thymine . In DNA, guanine is paired with cytosine. With the formula C5H5N5O, guanine is a derivative of purine, consisting of a fused pyrimidine-imidazole ring system with...
298Adenosine (Alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
100Threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
). A third mutation (a transversion) in this gene has also been described - G145T (Alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
49Serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
) - that has been associated with the Fy-x phenotype.
Most Duffy negative blacks carry a silent Fy-b allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
with a single T to C substitution at nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
-46, impairing the promoter activity in erythroid cells by disrupting a binding site for the GATA1
GATA1
Erythroid transcription factor also known as GATA-binding factor 1 or GATA-1 is a protein that in humans is encoded by the GATA1 gene....
erythroid transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
. The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
is still transcribed in non erythroid cells in the presence of this mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
.
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
Cytosine is one of the four main bases found in DNA and RNA, along with adenine, guanine, and thymine . It is a pyrimidine derivative, with a heterocyclic aromatic ring and two substituents attached . The nucleoside of cytosine is cytidine...
-> thymidine
Thymidine
Thymidine is a chemical compound, more precisely a pyrimidine deoxynucleoside. Deoxythymidine is the DNA nucleoside T, which pairs with deoxyadenosine in double-stranded DNA...
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
Papua New Guinea , officially the Independent State of Papua New Guinea, is a country in Oceania, occupying the eastern half of the island of New Guinea and numerous offshore islands...
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 (chimpanzee), Macaca mulatta (rhesus monkey), Pongo pygmaeus (orangutan), Rattus norvegicus (brown rat), Mus musculus (mouse), Monodelphis domestica (opposum), Bos taurus (cow) and Canis familiaris (dog).
Three exons are present in humans and chimpanzees while 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
Hepatocystis
Hepatocystis is a genus of parasitic protozoa transmitted by midges of the Culicoides genus. Hosts include Old World primates, bats, hippopotamus and squirrels. This genus is not found in the New World...
.
The ancestral form of extant DARC alleles in humans appears to be the FY*B allele.
Molecular biology
The Duffy antigen is expressed in greater quantities on reticulocyteReticulocyte
Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the human body.Reticulocytes develop and mature in the red bone marrow and then circulate for about a day in the blood stream before developing into mature red blood cells. Like mature red blood cells,...
s than on mature erythrocytes. While the Duffy antigen is expressed on erythrocytes it is also found on some epithelial cells, Purkinje cells of the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, endothelial cells of thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
capillaries, the post-capillary venule
Venule
A venule is a very small blood vessel in the microcirculation that allows deoxygenated blood to return from the capillary beds to the larger blood vessels called veins. Venules range from 8 to 100μm in diameter and are formed when capillaries unite .Venules are blood vessels that drain blood...
s of some organs including the spleen, liver and kidney and the large pulmonary venules.
In some people who lack the Duffy antigen on their erythrocytes it may still be expressed in some cells. It has two potential N-linked glycosylation sites at asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...
(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) - CCL2CCL2For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.Chemokine ligand 2 also known as monocyte chemotactic protein-1 or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC...
- regulated upon activation normal T expressed and secreted (RANTES) - CCL5
- melanoma growth stimulatory activity (MSGA-α), KC, neutrophil-activating protein 3 (NAP-3) - CXCL1CXCL1Chemokine ligand 1 is a small cytokine belonging to the CXC chemokine family that was previously called GRO1 oncogene, GROα, KC, Neutrophil-activating protein 3 and melanoma growth stimulating activity, alpha...
/CXCL2CXCL2Chemokine ligand 2 is a small cytokine belonging to the CXC chemokine family that is also called macrophage inflammatory protein 2-alpha , Growth-regulated protein beta and Gro oncogene-2 . CXCL2 is 90% identical in amino acid sequence as a related chemokine, CXCL1...
and the angiogenic CXC chemokines:
- growth related gene alpha (GRO-α) - CXCL1CXCL1Chemokine ligand 1 is a small cytokine belonging to the CXC chemokine family that was previously called GRO1 oncogene, GROα, KC, Neutrophil-activating protein 3 and melanoma growth stimulating activity, alpha...
- ENA-78 - CXCL5CXCL5C-X-C motif chemokine 5 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-derived neutrophil-activating peptide 78...
- neutrophil activating peptide-2 (NAP-2) - CXCL7CXCL7Chemokine ligand 7 is a human gene.The encoded protein, Chemokine 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) - CXCL8Interleukin 8Interleukin-8 is a chemokine produced by macrophages and other cell types such as epithelial cells. It is also synthesized by endothelial cells, which store IL-8 in their storage vesicles, the Weibel-Palade bodies...
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 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
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
receptors. Based on these alignments the Duffy antigen is considered to be most similar to the interleukin-8B receptor
Interleukin 8 receptor, beta
Interleukin 8 receptor, beta is a chemokine receptor. IL8RB is also known as CXCR2, and CXCR2 is now the IUPHAR Committee on Receptor Nomenclature and Drug classification-recommended name.-Function:...
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.
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. This hypothesis has also been questioned after knock out
Gene knockout
A gene knockout is a genetic technique in which one of an organism's genes is made inoperative . Also known as knockout organisms or simply knockouts, they are used in learning about a gene that has been sequenced, but which has an unknown or incompletely known function...
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 and in modulating the inflammatory response.
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
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
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 leds to apical retention of intact chemokines and more leukocyte migration.
Binding melanoma growth-stimulating activity inhibits the binding of P. knowlesi
Plasmodium knowlesi
Plasmodium knowlesi is a primate malaria parasite commonly found in Southeast Asia. It causes malaria in long-tailed macaques , but it may also infect humans, either naturally or artificially....
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 phenotypePhenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
Fy(a-b-): 68% in African American
African American
African Americans are citizens or residents of the United States who have at least partial ancestry from any of the native populations of Sub-Saharan Africa and are the direct descendants of enslaved Africans within the boundaries of the present United States...
s and 88-100% in African blacks (including more than 90% of West Africa
West Africa
West Africa or Western Africa is the westernmost region of the African continent. Geopolitically, the UN definition of Western Africa includes the following 16 countries and an area of approximately 5 million square km:-Flags of West Africa:...
n blacks). This phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
is exceedingly rare in whites. Because the Duffy antigen is uncommon in those of Black African
Black people
The term black people is used in systems of racial classification for humans of a dark skinned phenotype, relative to other racial groups.Different societies apply different criteria regarding who is classified as "black", and often social variables such as class, socio-economic status also plays a...
descent, the presence of this antigen has been used to detect genetic admixture
Admixture
Admixture can refer to:* Genetic admixture, the result of interbreeding between two or more previously isolated populations within a species.* Racial admixture, admixture between humans, also referred to as Miscegenation* Hybrid...
. 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 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 fequencies 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. 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 CaucasianCaucasian raceThe term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...
genotype, but has since been described in BrazilBrazilBrazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
ians. 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.
- This antigen along with other blood group antigens was used to identify the Basque peopleBasque peopleThe Basques as an ethnic group, primarily inhabit an area traditionally known as the Basque Country , a region that is located around the western end of the Pyrenees on the coast of the Bay of Biscay and straddles parts of north-central Spain and south-western France.The Basques are known in the...
as a genetically separate group. Its use in forensic science is under consideration.
- The AndamanAndaman IslandsThe Andaman Islands are a group of Indian Ocean archipelagic islands in the Bay of Bengal between India to the west, and Burma , to the north and east...
and NicobarNicobarNicobar can refer to:* Nicobar Islands**Car Nicobar**Great Nicobar Island**Little Nicobar* Nicobar district-Animals:*Nicobar Shrew*Nicobar Treeshrew*Nicobar long-tailed macaque*Nicobar Flying Fox* Nicobar Pigeon* Nicobar Megapode...
Islands, now part of India, were originally inhabited by 14 aboriginal tribes. Several of these have gone extinct. One surviving tribe—the JarawasJarawa (Andaman Islands)The Jarawa are one of the adivasi indigenous peoples of the Andaman Islands. Their present numbers are estimated at between 250-350 individuals. Since they have largely shunned interactions with outsiders, many particulars of their society, culture and traditions are poorly understood...
—live in three jungle areas of South Andaman and one jungle area in Middle Andaman. The area is endemic for malariaMalariaMalaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
. The causative species is Plasmodium falciparumPlasmodium falciparumPlasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
: there is no evidence for the presence of Plasmodium vivaxPlasmodium vivaxPlasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
. 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 YemenYemenThe Republic of Yemen , commonly known as Yemen , is a country located in the Middle East, occupying the southwestern to southern end of the Arabian Peninsula. It is bordered by Saudi Arabia to the north, the Red Sea to the west, and Oman to the east....
ite Jews the frequency of the Fy allele is 0.5879 The frequency of this allelle varies from 0.1083 to 0.2191 among Jews from the Middle East, North Africa and Southern EuropeSouthern EuropeThe term Southern Europe, at its most general definition, is used to mean "all countries in the south of Europe". However, the concept, at different times, has had different meanings, providing additional political, linguistic and cultural context to the definition in addition to the typical...
. 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 ChineseChinese peopleThe term Chinese people may refer to any of the following:*People with Han Chinese ethnicity ....
ethnic populations—the Han and the She peopleShe peopleThe She people are a Chinese ethnic group. They form one of the 56 ethnic groups officially recognized by the People's Republic of China....
—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 allelle in most Asian populations is ~95%.
- In Grande ComoreGrande ComoreGrande Comore is an island in the Indian Ocean 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 as of 2006 is about 316,600. The island's capital is Moroni, which is also the national capital...
(also known as Ngazidja) the frequency of the Fy(a- b-) phenotype is 0.86.
- In a survey of 115 unrelated TunisTunisTunis is the capital of both the Tunisian Republic and the Tunis Governorate. It is Tunisia's largest city, with a population of 728,453 as of 2004; the greater metropolitan area holds some 2,412,500 inhabitants....
ians using both serological and DNA based methods gave the following results: FY*X frequency 0.0174; FY*1 = 0.291 (expressed 0.260, silent 0.031); FY*2 = 0.709 (expressed 0.427; silent 0.282). FY*2 silent is the most common allele in West African blacks and the high prevalence in this sample was interpreted as historical admixture.
- The incidence of Fy(a+b-) in northern India among blood donors is 43.85%.
- In NouakchottNouakchott-Government:The town was first divided into districts in 1973. First it was divided into four. From 1986, the city has been split into nine districts.* Arafat* Dar Naim* El Mina* Ksar* Riad* Sebkha* Tevragh-Zeina* Teyarett* Toujounine...
, MauritaniaMauritaniaMauritania is a country in the Maghreb and West Africa. It is bordered by the Atlantic Ocean in the west, by Western Sahara in the north, by Algeria in the northeast, by Mali in the east and southeast, and by Senegal in the southwest...
overall 27% of the population are Duffy-positive. 54% of MoorMoorsThe description Moors has referred to several historic and modern populations of the Maghreb region who are predominately of Berber and Arab descent. They came to conquer and rule the Iberian Peninsula for nearly 800 years. At that time they were Muslim, although earlier the people had followed...
s are Duffy antigen positive, while only 2% of black ethnic groups (mainly Poular, Soninke and WolofWolof peopleThe Wolof are an ethnic group found in Senegal, The Gambia, and Mauritania.In Senegal, the Wolof form an ethnic plurality with about 43.3% of the population are Wolofs...
) 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.
Clinical significance
Historically the role of this antigen other than its importance as a receptor for plasmodiumPlasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
parasitic protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein.
Asthma
AsthmaAsthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
is more common and tends to be more severe in those of African descent. There appears to be a correlation with both total IgE
IGE
IGE was one of the largest services company buying and selling virtual currencies and accounts for MMORPG. During its peak time, it had offices in Los Angeles, China , and headquarters & customer service centre in Hong Kong. IGE was one of the main monopoly in virtual economy services, also known...
levels and asthma and mutations in the Duffy antigen.
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 neutropeniaNeutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
. This condition is also found in Arab
Arab
Arab people, also known as Arabs , are a panethnicity primarily living in the Arab world, which is located in Western Asia and North Africa. They are identified as such on one or more of genealogical, linguistic, or cultural grounds, with tribal affiliations, and intra-tribal relationships playing...
Jordan
Jordan
Jordan , officially the Hashemite Kingdom of Jordan , Al-Mamlaka al-Urduniyya al-Hashemiyya) is a kingdom on the East Bank of the River Jordan. The country borders Saudi Arabia to the east and south-east, Iraq to the north-east, Syria to the north and the West Bank and Israel to the west, sharing...
ians, Black Bedouin, Falashah Jews, Yemenite Jews
Yemenite Jews
Yemenite Jews are those Jews who live, or whose recent ancestors lived, in Yemen . Between June 1949 and September 1950, the overwhelming majority of Yemen's Jewish population was transported to Israel in Operation Magic Carpet...
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. Although the mechanism is as yet unknown, it is known that neutrophils are retained in the bone marrow through interaction of CXCL12 with its receptor CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
. A number of rare diseases are known in which disruption or desensitization of CXCR4 results in failure to release mature neutrophils from bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
.
Cancer
Interactions between the metastasis suppressor KAI1CD82 (gene)
CD82 is a human protein encoded by the gene.-Interactions:CD82 has been shown to interact with CD19, CD63 and CD234-External links:...
on tumor cells and the cytokine receptor DARC on adjacent vascular cells suppresses tumor metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
. 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 lipopolysaccaride (bacterial endotoxin) is reduced in Duffy antigen negative Africans compared with Duffy positive Caucasians. This erence is likely to involve additional genes.HIV infection
A connection has been found between HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
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
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
(a low total white cell count) is associated with relatively poor survival in HIV infection and this association is more marked in caucasians
White people
White people is a term which usually refers to human beings characterized, at least in part, by the light pigmentation of their skin...
than in negroids 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
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
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.
Lung transplantation
The Duffy antigen has been implicated in lung transplantation rejection.Malaria
On erythrocytes the Duffy antigen acts as a receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
for invasion by the human malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
l parasites P. vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
and P. knowlesi
Plasmodium knowlesi
Plasmodium knowlesi is a primate malaria parasite commonly found in Southeast Asia. It causes malaria in long-tailed macaques , but it may also infect humans, either naturally or artificially....
. 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 it has been reported that P. vivax infection in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection. This antigen may also play a role in erythrocyte invasion in the rodent malarial parasite P. yoelii
Plasmodium yoelii
Plasmodium yoelii is a parasite of the genus Plasmodium subgenus Vinckeia.Like all Plasmodium species P. yoelii has both vertebrate and insect hosts. The vertebrate hosts for this parasite are mammals.- Notes :...
. The epitope
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 part of an antibody that recognizes the epitope is called a paratope...
Fy6 is required for P. vivax
Plasmodium vivax
Plasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of the four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the...
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
The Republic of Madagascar is an island country located in the Indian Ocean off the southeastern coast of Africa...
. Although 72% of the population are Duffy antigen negative, 8.8% of the Duffy antigen negative individuals were asymptomatic carrier
Asymptomatic carrier
An asymptomatic carrier is a person or other organism that has contracted an infectious disease, but who displays no symptoms. Although unaffected by the disease themselves, carriers can transmit it to others...
s of P. vivax. Malaria has also been found in Angola
Angola
Angola, officially the Republic of Angola , is a country in south-central Africa bordered by Namibia on the south, the Democratic Republic of the Congo on the north, and Zambia on the east; its west coast is on the Atlantic Ocean with Luanda as its capital city...
and Equatorial Guinea
Equatorial Guinea
Equatorial Guinea, officially the Republic of Equatorial Guinea where the capital Malabo is situated.Annobón is the southernmost island of Equatorial Guinea and is situated just south of the equator. Bioko island is the northernmost point of Equatorial Guinea. Between the two islands and to the...
in Duffy negative individuals. P. vivax malaria in a Duffy antigen negative individual in Mauritania
Mauritania
Mauritania is a country in the Maghreb and West Africa. It is bordered by the Atlantic Ocean in the west, by Western Sahara in the north, by Algeria in the northeast, by Mali in the east and southeast, and by Senegal in the southwest...
has also been reported. Similar infections have been reported in Brazil
Brazil
Brazil , officially the Federative Republic of Brazil , is the largest country in South America. It is the world's fifth largest country, both by geographical area and by population with over 192 million people...
and Kenya
Kenya
Kenya , officially known as the Republic of Kenya, is a country in East Africa that lies on the equator, with the Indian Ocean to its south-east...
. 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.
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.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 JamaicaJamaica
Jamaica is an island nation of the Greater Antilles, in length, up to in width and 10,990 square kilometres in area. It is situated in the Caribbean Sea, about south of Cuba, and west of Hispaniola, the island harbouring the nation-states Haiti and the Dominican Republic...
n males of black African descent. 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.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. 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 erythocytes.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: FYISBT number: 008
Gene symbol: FY
Gene name: Duffy blood group
Number of Duffy antigens: 6
Antibody type: Almost entirely IgG. IgM does occur but is rare. These antibodies do not typically bind complement.
Transfusion reactions: Typically mild but may be serious. Although these usually occur immediately they may occur after a delay (up to 24 hours). These reactions are usually caused by Fya or Fyb. Fy3 may cause a reaction but only rarely.
Hemolytic disease of the newborn: This is typically mild but rarely may be serious. Almost always due to Fya: rarely Fyb or Fy3.
External links
- Duffy at BGMUTBGMUTThe BGMUT 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 . Since 2006, it has been a part of the dbRBC resource of NCBI at the NIH...
Blood Group Antigen Gene Mutation Database at NCBINational Center for Biotechnology InformationThe National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper...
, NIH - Duffy gene
- Population data