Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene

Abstract

Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

“…To investigate whether there was a genetic basis for this, we determined whether there was any relationship between the aforementioned findings and the recent observation demonstrating that DARC Ϫ46C/C is a strong genetic basis for benign ethnic leukopenia, attributable to neutropenia, in HIV-negative subjects. 21,22 In our study population, DARC Ϫ46C/C was present nearly exclusively in AAs (69.1%) compared with EA (0.2%). 10 Among the hematologic parameters available for assessment, DARC T-46C genotype (T/T, T/C, and C/C), but not race, was a strong determinant of the variability in the WBC counts during disease (Table 2) and at entry into the cohort (P Ͻ .001).…”

“…Recent studies revealed 2 phenotypes associated with the DARC Ϫ46C/C genotype that had relevance to both leukopenia and HIV pathogenesis. First, admixture mapping and other genetic studies in large nonimmunosuppressed cohorts of EAs and AAs demonstrate that, over and above its strong link with African ancestry, DARC Ϫ46C/C is the main genetic basis for ethnic leukopenia 21 and neutropenia 22 ; other observational studies substantiate this relationship between DARC Ϫ46C/C genotype and leukopenia or neutropenia. 23,24 Second, in our study population of HIV ϩ AAs, those with the DARC Ϫ46C/C genotype had a slower rate of HIV disease progression than those with DARC ϪT/T or C/T.…”

“…DARC is expressed mainly on the surface of red blood cells (RBCs) and endothelial cells, where it binds multiple chemokines that have relevance to both HIV pathogenesis (eg, RANTES and MCP-1) and neutrophil biology (eg, GRO␣). 18,19 The Ϫ46T3C polymorphism is specific to persons of African ancestry, 10,[20][21][22] and homozygosity for the Ϫ46C allele (Ϫ46C/C genotype) abrogates DARC expression on erythrocytes. [18][19][20] Because DARC on RBC serves as a receptor for the malarial protozoa Plasmodium vivax, 19,20 Duffynull status (DARC Ϫ46C/C genotype) on RBC is associated with a selective advantage against this form of malaria.…”

Impact of genetic polymorphisms determining leukocyte/neutrophil count on chemotherapy toxicity

“…The African, or "null," form of this variant abolishes expression of the "Duffy Antigen Receptor for Chemokines" on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration [Reich et al, 2009].…”

Erythrocyte Duffy antigen receptor for chemokines (DARC): diagnostic and therapeutic implications in atherosclerotic cardiovascular disease

“…Most West Africans and 68% of African Americans do not express Duffy antigens on their erythrocytes [2,3] . Interestingly recent data suggest that reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor gene [4] .…”