Management of ACKR1 Homozygous Genetic Status
Patients with homozygous ACKR1 (rs2814778-CC genotype) who present with neutropenia do not require treatment, as this represents a benign physiological variant rather than a pathological condition requiring intervention. 1
Understanding ACKR1-Associated Neutropenia
The ACKR1 gene encodes the Duffy antigen receptor for chemokines. The homozygous variant (rs2814778-CC, also called Duffy-negative phenotype) is present in approximately 70% of individuals of African ancestry but is essentially absent in European ancestry populations. 2, 3
Key Physiological Characteristics
Neutrophil redistribution, not deficiency: The neutropenia results from altered neutrophil trafficking patterns where neutrophils preferentially redistribute from peripheral blood to tissues (including spleen), rather than representing an absolute decrease in total body neutrophils. 3, 4
No increased infection risk: Despite lower peripheral neutrophil counts (typically mild to moderate neutropenia), individuals with ACKR1-associated neutropenia do not experience increased susceptibility to infections, distinguishing this from pathological neutropenia. 5, 4
Normal variant status: Recent medical initiatives have established that this should be considered a normal variant with adjusted reference ranges rather than a clinical disorder. 4
Clinical Management Approach
Transfusion Medicine Considerations
For patients with sickle cell disease who are homozygous for ACKR1 (GATA mutation), do not provide Fyb-negative red blood cells, as these patients are not at risk for developing anti-Fyb antibodies. 1
This is a critical transfusion medicine consideration because:
- Patients with the GATA mutation in ACKR1 lack Fy antigen expression on red blood cells 1
- They cannot develop alloimmunization to Fyb antigen 1
- Unnecessary restriction to Fyb-negative blood would limit the donor pool without clinical benefit 1
Laboratory Interpretation
Establish appropriate reference ranges: Use ancestry-adjusted neutrophil count reference ranges when evaluating complete blood counts in patients with known or suspected ACKR1 homozygosity. 4
Avoid unnecessary workup: Do not pursue extensive hematologic evaluation for isolated neutropenia in patients with ACKR1-CC genotype, as this represents their physiological baseline. 5, 4
Consider genotyping: In patients of African ancestry presenting with chronic neutropenia without infectious complications, consider ACKR1 genotyping to establish the diagnosis and avoid unnecessary interventions. 2, 5
Important Clinical Caveats
Associated Conditions to Monitor
While ACKR1-associated neutropenia itself is benign, emerging research suggests potential associations that warrant awareness:
Possible increased proinflammatory signaling: Some evidence suggests ACKR1 deficiency may lead to altered inflammatory responses, with theoretical implications for immune senescence and autoimmunity, though clinical significance remains unclear. 4
Lupus considerations: In patients with systemic lupus erythematosus, ACKR1-CC genotype accounts for higher rates of leucopenia in African ancestry patients (67.7% vs 42.1% in CT/TT genotype), but does not explain differences in thrombocytopenia or anemia rates. 2
What NOT to Do
Do not treat with G-CSF or other growth factors: The neutropenia is not pathological and does not require pharmacologic intervention. 5, 4
Do not delay necessary procedures: Surgical or chemotherapy decisions should not be altered based solely on neutrophil counts in ACKR1-associated neutropenia, as infection risk is not elevated. 4
Do not restrict Fyb-negative blood products: This is unnecessary and potentially harmful by limiting transfusion options. 1