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

TitleAnalyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.
Publication TypeJournal Article
Year of Publication2018
AuthorsCharles, 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
JournalPLoS One
Volume13
Issue3
Paginatione0194400
Date Published2018
ISSN1932-6203
KeywordsAfrican Americans, Chromosomes, Human, Pair 1, Cytokines, Duffy Blood-Group System, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Humans, Male, Neutropenia, Polymorphism, Single Nucleotide, Receptors, Cell Surface
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.

DOI10.1371/journal.pone.0194400
Alternate JournalPLoS ONE
PubMed ID29596498
PubMed Central IDPMC5875757