Historically the role of this antigen other than its importance as a receptor for Plasmodium protozoa has not been appreciated. Recent work has identified a number of additional roles for this protein. Malaria On erythrocytes, the<unk>  antigen acts as a receptor for invasion by the human malarial parasites P. vivax and P. knowlesi. This was first shown in 1980.<unk>  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<unk>  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<unk>  antigen appears to be very limited at best in Madagascar. Although 72% of the population are<unk>  antigen negative, 8.8% of the<unk>  antigen negative individuals were asymptomatic carriers of P. vivax. Malaria has also been found in Angola and Equatorial Guinea in<unk>  negative individuals. P. vivax malaria in a<unk>  antigen negative individual in Mauritania has also been reported. Similar infections have been reported in Brazil and Kenya. Additional cases of infection in<unk>  antigen negative individuals have been reported from the Congo and Uganda. A study in Brazil of the protection against P. vivax offered by the lack of the<unk>  antigen found no differential resistance to malaria vivax between<unk>  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<unk>  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) appears to be critical for the platelet induced killing of P. falciparum. The<unk>  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 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<unk>  antigen. Hematopoiesis<unk>  antigen plays a fundamental role on hematopoiesis. Indeed, nucleated red blood cells present in the bone marrow have high expression of DARC, which facilitates their direct contact with hematopoietic stem cells. The absence of erythroid DARC alters hematopoiesis including stem and progenitor cells, which ultimately gives rise to phenotypically distinct neutrophils. As a result, mature neutrophils of<unk> -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. This condition is also found in Arab Jordanians, Black Bedouin, Beta Israel, 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<unk>  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<unk> -negative individuals. Cancer Interactions between the metastasis suppressor KAI1 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. Endotoxin response The procoagulant response to lipopolysaccaride (bacterial endotoxin) is reduced in<unk>  antigen negative Africans compared with<unk>  positive Whites. This difference is likely to involve additional genes. HIV infection A connection has been found between HIV susceptibility and the expression of the<unk>  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<unk>  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 whites 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<unk>  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<unk>  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<unk> -null-associated low neutrophil counts. Inflammation An association with the levels monocyte chemoattractant protein-1 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<unk>  antigen has been implicated in lung transplantation rejection. Multiple myeloma An increased incidence of<unk>  antigen has been reported in patients with multiple myeloma compared with healthy controls. Pneumonia The<unk>  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<unk>  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 Jamaican 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 is associated with neutropenia. An increased risk of this side effect has been reported in<unk>  null patients. Renal transplantion Antibodies and a cellular response to the<unk>  antigen have been associated with renal transplant rejection. Sickle cell anaemia<unk>  antigen-negative individuals with sickle cell anaemia tend to suffer from more severe organ damage than do those with the<unk>  antigen.<unk> -positive patients exhibit higher counts of white blood cells, polynuclear neutrophils, higher plasma levels of IL-8 and RANTES than<unk> -negative patients. Southeast Asian ovalocytosis There is a ~10% increase in Fy expression in Southeast Asian ovalocytosis erythrocytes. Transfusion medicine Interpretation of antibody panel to detect patient antibodies towards the most relevant human blood group systems, including<unk> . A<unk>  negative blood recipient may have a transfusion reaction if the donor is<unk>  positive. Since most<unk> -negative people are of African descent, blood donations from people of black African origin are important to transfusion banks.
Duffy antigen system
Kidd antigen system
Ii antigen system
MNS antigen system
Lewis antigen system
Yt antigen system
Lymphocyte function-associated antigen 1
Lutheran antigen system