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Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.

Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.
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Charles BA, Hsieh MM, Adeyemo AA, Shriner D, Ramos E, Chin K, Srivastava K, Zakai NA, Cushman M, McClure LA, Howard V, Flegel WA, Rotimi CN, Rodgers GP,


Charles BA, Hsieh MM, Adeyemo AA, Shriner D, Ramos E, Chin K, Srivastava K, Zakai NA, Cushman M, McClure LA, Howard V, Flegel WA, Rotimi CN, Rodgers GP, (click to view)

Charles BA, Hsieh MM, Adeyemo AA, Shriner D, Ramos E, Chin K, Srivastava K, Zakai NA, Cushman M, McClure LA, Howard V, Flegel WA, Rotimi CN, Rodgers GP,

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PloS one 2018 03 2913(3) e0194400 doi 10.1371/journal.pone.0194400

Abstract
BACKGROUND
Benign ethnic neutropenia (BEN) is a hematologic condition associated with people of African ancestry and specific Middle Eastern ethnic groups. Prior genetic association studies in large population showed that rs2814778 in Duffy Antigen Receptor for Chemokines (DARC) gene, specifically DARC null red cell phenotype, was associated with BEN. However, the mechanism of this red cell phenotype leading to low white cell count remained elusive.

METHODS
We conducted an extreme phenotype design genome-wide association study (GWAS), analyzed ~16 million single nucleotide polymorphisms (SNP) in 1,178 African-Americans individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and replicated from 819 African-American participants in the Atherosclerosis Risk in Communities (ARIC) study. Conditional analyses on rs2814778 were performed to identify additional association signals on chromosome 1q22. In a separate cohort of healthy individuals with and without BEN, whole genome gene expression from peripheral blood neutrophils were analyzed for DARC.

RESULTS
We confirmed that rs2814778 in DARC was associated with BEN (p = 4.09×10-53). Conditioning on rs2814778 abolished other significant chromosome 1 associations. Inflammatory cytokines (IL-2, 6, and 10) in participants in the Howard University Family Study (HUFS) and Multi-Ethnic Study in Atherosclerosis (MESA) showed similar levels in individuals homozygous for the rs2814778 allele compared to others, indicating cytokine sink hypothesis played a minor role in leukocyte homeostasis. Gene expression in neutrophils of individuals with and without BEN was also similar except for low DARC expression in BEN, suggesting normal function. BEN neutrophils had slightly activated profiles in leukocyte migration and hematopoietic stem cell mobilization pathways (expression fold change <2). CONCLUSIONS
These results in humans support the notion of DARC null erythroid progenitors preferentially differentiating to myeloid cells, leading to activated DARC null neutrophils egressing from circulation to the spleen, and causing relative neutropenia. Collectively, these human data sufficiently explained the mechanism DARC null red cell phenotype causing BEN and further provided a biologic basis that BEN is clinically benign.

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