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PLoS One. 2018 Mar 29;13(3):e0194400. doi: 10.1371/journal.pone.0194400. eCollection 2018.

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

Author information

1
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
2
Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, United States of America.
3
National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, Maryland, United States of America.
4
Warren Grant Magnuson Clinical Center, NIH, Bethesda, Maryland, United States of America.
5
Departments of Pathology and Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, United States of America.
6
School of Public Health, University of Alabama, Birmingham, Alabama, United States of America.
7
Department of Epidemiology and Biostatistics, Drexel University, Philadelphia, Pennsylvania, United States of America.

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.

PMID:
29596498
PMCID:
PMC5875757
DOI:
10.1371/journal.pone.0194400
[Indexed for MEDLINE]
Free PMC Article

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