Duffy Associated Neutrophil Count

The incidental finding of a low white cell count in asymptomatic individuals of African ancestry is not uncommon. The condition has commonly referred to as benign ethnic neutropenia but this terminology suggested that ethnicity alone caused an abnormal neutrophil count. 

More recent research has shown that lower absolute neutrophil counts in Blacks is associated with the Duffy-null blood group phenotype and has proposed that this phenomenon be renamed Duffy Associated Neutrophil Count (DANC).

DANC results from a polymorphism in a gene called ACKR1 that encodes for the Duffy antigen receptor for chemokines (DARC, also called Duffy antigen), which is a membrane glycoprotein that acts as a chemokine receptor for proinflammatory cytokines. The names used for this gene/protein are highly varied, and include FY, DARC, ACKR1, Duffy antigen and Duffy blood group. 

The approved name for both gene and protein is atypical chemokine receptor 1 (ACKR1). ACKR1 is expressed on RBCs and endothelial cells (ECs) but not on WBCs:

• On RBCs, the receptor binds chemokines. Instead of signaling, ACKR1 acts as a sink, resulting in lower circulating levels of chemokines. 
• EC ACKR1 binds and transports chemokines to underlying tissues.

In DANC, there is a one nucleotide substitution within the promoter of ACKR1, which leads to the selective loss of ACKR1 expression in red blood cells but not in endothelial cells. The selective loss of ACKR1 from RBCs leads to increased egress of neutrophils from the circulation into the tissue, resulting in lower circulating neutrophil counts.

The ACKR1 gene polymorphism and Duffy null phenotype is rare in Caucasians but present in > 60-70% of African Americans. It is an adaptive trait that evolved to impair entry of Plasmodium vivax into RBCs. 

African Americans who are Duffy null have lower absolute neutrophil counts compared with African Americans who are not null for Duffy. On study determined that 23.8% of healthy people with the Duffy null phenotype have an ANC below 2,000 cells/uL and 10% have an ANC < 1500/ul, suggesting they were neutropenic.

DANC is a diagnosis of exclusion. Once a diagnosis of DANC is made, it is not necessary to monitor neutrophil count. 

A research letter published in JAMA on June 20, 2023, established a Duffy null phenotype-specific absolute neutrophil count reference range. The Duffy null nonparametric central 95% ANC was 1210-5390 cells/uL. This reference range was significantly lower than the standard reference range of 1920-7600 cells/uL. 

Brigham and Women’s Hospital has added a comment below the ANC reference range indicating that the expected ANC reference range is 1210/uL to 5390/uL for individuals with Duffy null status.

Failure to recognize neutropenia associated with the Duffy null phenotype has led to African Americans being unnecessarily excluded from clinical trials. A recent study in JAMA Open Network found that no cancer clinical trials done between 2021 and 2023 included a reference range for people with the Duffy Null phenotype. Instead, most of the studies included criteria that would exclude them for having absolute neutrophil counts below the lower limit of normal established for Caucasian populations.

The study highlighted how medical norms based on European ancestry populations might lead to harm and bias against other populations. This is another example of structural racism.  

References

William Aird MD, Twitter, October 31, 2022

Merz LE, et al. Development of Duffy Null-Specific Absolute Neutrophil Count Reference Ranges, JAMA2023;329:2088-2089.

Merz LE, et al. Absolute neutrophil count by Duffy Status among healthy Black and African American adults. Blood Adv. 2023;7(3)317-320.

Hibbs SP, Aiken L, Vora K, et al. Cancer Trial Eligibility and Therapy Modifications for Individuals With Duffy Null–Associated Neutrophil Count. JAMA Netw Open. 2024;7(9):e2432475. doi:10.1001/jamanetworkopen.2024.32475