What is Duffy-null associated neutrophil count (DANC)?

Duffy-null Associated Neutrophil Count (DANC)

Duffy-null associated neutrophil count (DANC) refers to a lower baseline neutrophil count that is commonly found in individuals with the Duffy-null genotype, particularly those of African or Middle Eastern ancestry, without increased risk of infection or other adverse health outcomes. 1

Definition and Mechanism

The Duffy-null genotype is a mutation in the ACKR1/DARC gene that results in the absence of the Duffy antigen receptor for chemokines on red blood cells. This genetic variant:

• Is present in approximately two-thirds (67%) of Black patients in the United States 1
• Is highly prevalent (69%) in South African populations 2
• Is extremely common in specific ethnic groups: 96.6% in Yemeni, 91% in African American, and 52.9% in non-Yemeni Middle Eastern patients 3
• Has been positively selected in African populations because it provides protection against Plasmodium vivax malaria 4

Clinical Significance

Reference Range

Individuals with Duffy-null status typically have a lower absolute neutrophil count (ANC), with studies suggesting a reference range of 1,210–5,390 cells per microliter 1, compared to the conventional reference range of >1,500 cells/μL used for individuals of European descent.

Impact on Clinical Decision-Making

The lower neutrophil counts in Duffy-null individuals have important clinical implications:

• Medication Dosing: Patients may receive inappropriate dose reductions of medications like lenalidomide or pomalidomide due to perceived neutropenia 1
• Treatment Access: 21% of individuals with the Duffy-null genotype have neutrophil counts below thresholds often used as cut-offs for access to certain treatments, compared to only 1% of those with other genotypes 5
• Unnecessary Testing: Duffy-null associated neutropenia is the most common reason for leukopenia/neutropenia referrals (77.7%) at some tertiary children's hospitals 3

Infection Risk

Despite lower neutrophil counts, individuals with the Duffy-null genotype:

• Are not at higher risk of infections or other adverse events 1
• Show no increased risk of bacterial or viral infections 5
• Do not demonstrate impaired neutrophil effector functions 2

Neutrophil Function in Duffy-null Individuals

Research has demonstrated that key neutrophil functions remain intact or even enhanced in individuals with the Duffy-null trait:

• Enhanced proteolytic activity within the phagosome following Fc receptor-mediated phagocytosis 2
• Normal reactive oxygen species (ROS) production 2
• Slightly reduced neutrophil extracellular trap (NET) formation in HIV-1 infected subjects, but overall neutrophil effector functions are not deleterious 2

Clinical Recommendations

When evaluating neutropenia in patients of African or Middle Eastern ancestry:

1. Consider Duffy-null status before reducing doses of medications or restricting treatment access 1
2. Recognize that neutrophil counts <1,500 cells/μL are common and harmless in these populations 6
3. Consider genotyping confirmation when appropriate to avoid unnecessary interventions 1
4. Understand that neutrophil thresholds for treatment access could potentially be lowered in individuals with the Duffy-null genotype without increasing infection risk 5

Important Considerations

• The term "benign ethnic neutropenia" has been used to describe this condition, but this terminology has been criticized for implying that common phenotypes in non-White populations are abnormal 6
• Unnecessary referrals and investigations for neutropenia in patients with Duffy-null associated neutropenia without recurrent/frequent/serious infections can be reduced with greater availability of Duffy typing 3
• Clinical trials, such as the SWOG S2209 trial, are attempting to address disparities in treatment related to Duffy-null associated neutropenia 1