Genetics of Benign Ethnic Neutropenia

Recent research has found the genetic cause of BEN. An association with a single nucleotide polymorphism (SNP) located on the long arm of chromosome 1 has been found. This SNP is located in the promoter region of the Duffy antigen receptor for chemokines (DARC), which encodes the Duffy (Fy) a and b antigens. There is, in fact, a high prevalence of Fy^a and Fy^b negative phenotypes in Africans and other mentioned populations. Interestingly, it has been shown that people with the Fy null phenotype are more resistant to malaria caused by Plasmodium vivax. Other gene variants have been associated with BEN, mostly those encoding chemokine receptors.

Why these gene variants cause neutropenia is not entirely known. However, it is most likely because these genes encode chemokine receptors. Although we associate Fy antigens with red blood cells, the majority of Fy antigen is found on the surface of endothelial cells (noted by arrows on endothelial cells in the transmission electron micrograph to the right). Some studies on this condition have shown that bone marrow cellularity is essentially normal, but the problem is in the release of neutrophils into circulation. Some have also proposed that the lack of certain chemokine stimuli affects mainly the release specifically from the bone marrow reserve. Yet, others have shown a decrease in the reserve itself. So, the exact mechanism is not fully understood but most likely relates to the Duffy null phenotypes.