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 Duffy antigen acts as a
receptor for invasion by the human
malarial parasites
P. vivax and
P. knowlesi. This was first shown in 1980. Duffy negative individuals whose erythrocytes do not express the receptor are believed to be resistant to merozoite invasion although
P. vivax infection has been reported in Duffy negative children in Kenya, suggesting a role in resistance to disease, not infection. 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. and Uganda. A study in
Brazil of the protection against
P. vivax offered by the lack of the Duffy antigen found no differential resistance to malaria vivax between Duffy antigen positive and negative individuals. 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) 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 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.
Hematopoiesis Duffy 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 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. but the lower amount of circulating neutrophils associated with this genotype does not seem to confer an increased risk of infection. Clinical use of the term "benign ethnic neutropenic" to describe this phenomenon remains widespread, but the term is problematic as the Duffy-null genotype is common in individuals with African and certain Middle Eastern ancestries, and the term implies that individuals with European ancestry have the normal reference neutrophil count. The distinctive neutrophils that are formed in the absence of DARC on erythroid lineage (see above - role of DARC on hematopoiesis) readily leave the blood stream, which explains the apparent lower numbers of neutrophils in the blood of Duffy-null individuals. The lower number of circulating neutrophils can cause individuals with the Duffy-null genotype to fall below what typically would be considered safe to continue these treatments, despite new data showing that neutrophil functioning is preserved in these 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 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 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. 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.
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 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
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.
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 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 erythrocytes.
Transfusion medicine , including Duffy. 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. == Clinical diagnostic==