What is the constitutional cause of leukopenia in African Americans?

From the Guidelines

Benign ethnic neutropenia (BEN) is the constitutional cause of low white blood cell counts (WBCs) in African Americans, characterized by a genetic variant in the Duffy Antigen Receptor for Chemokines (DARC) gene. This condition is a result of evolutionary adaptations to malaria in regions where the disease was endemic, as discussed in the context of genetic diversity and disease susceptibility in African populations 1. The key points to consider are:

• BEN affects approximately 25-50% of individuals of African descent, with persistently lower neutrophil counts compared to reference ranges established primarily in Caucasian populations.
• The Duffy-null phenotype (Fy-/Fy-) is the specific genetic variation associated with BEN, which is more frequent in African populations due to its protective effects against malaria.
• Despite having lower neutrophil counts, individuals with BEN do not experience increased susceptibility to infections, impaired neutrophil function, or adverse health outcomes, as highlighted by the importance of characterizing genetic variation among individuals of diverse ancestral backgrounds to gain a better understanding of differential susceptibility to disease 1.
• Clinicians should be aware of this normal variation to avoid unnecessary diagnostic testing, bone marrow evaluations, or withholding of necessary treatments like chemotherapy, and consider BEN as a normal physiological variant rather than a pathological condition requiring intervention when evaluating African American patients with low WBC counts. Some of the key evidence supporting this recommendation includes the 1000 Genomes Project, which provided a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, including African populations 1. Additionally, initiatives such as the Human Heredity and Health in Africa (H3Africa) initiative have promoted genomic research in diverse global populations, highlighting the importance of discovery of genetic variation across human populations to enable advances in precision medicine 1.

From the Research

Constitutional Cause of Low WBC in African Americans

• The term "benign ethnic neutropenia" describes a phenotype of having an absolute neutrophil count (ANC) <1500 cells/μL with no increased risk of infection, commonly seen in those of African ancestry 2.
• This condition is driven by the Duffy null [Fy(a-b-)] phenotype, which is protective against malaria and seen in 80% to 100% of those of sub-Saharan African ancestry and <1% of those of European descent 2.
• Studies have shown that healthy African Americans have reduced white blood cell counts (WBC) and absolute neutrophil counts (ANC) compared with European Americans, with significantly lower reference intervals for WBC and ANC in African Americans 3.
• The DARC null red cell phenotype, associated with benign ethnic neutropenia, leads to relative neutropenia due to the preferential differentiation of DARC null erythroid progenitors to myeloid cells, causing activated DARC null neutrophils to egress from circulation to the spleen 4.
• Benign ethnic neutropenia is clinically insignificant, but the average ANC values differ from what are typically seen in those of European descent, highlighting the importance of race-specific reference intervals for proper diagnosis and clinical research 5, 3.