Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators

To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly)...

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Published in:Blood Vol. 115; no. 26; p. 5289
Main Authors: Schnabel, Renate B, Baumert, Jens, Barbalic, Maja, Dupuis, Josée, Ellinor, Patrick T, Durda, Peter, Dehghan, Abbas, Bis, Joshua C, Illig, Thomas, Morrison, Alanna C, Jenny, Nancy S, Keaney, Jr, John F, Gieger, Christian, Tilley, Cathy, Yamamoto, Jennifer F, Khuseyinova, Natalie, Heiss, Gerardo, Doyle, Margaret, Blankenberg, Stefan, Herder, Christian, Walston, Jeremy D, Zhu, Yanyan, Vasan, Ramachandran S, Klopp, Norman, Boerwinkle, Eric, Larson, Martin G, Psaty, Bruce M, Peters, Annette, Ballantyne, Christie M, Witteman, Jacqueline C M, Hoogeveen, Ron C, Benjamin, Emelia J, Koenig, Wolfgang, Tracy, Russell P
Format: Journal Article
Language:English
Published: United States 01.07.2010
Subjects:
Adult
Chemokine CCL2 - blood
Chemokine CCL2 - genetics
Chromosomes, Human, Pair 1
Cohort Studies
Duffy Blood-Group System - genetics
Duffy Blood-Group System - metabolism
Erythrocytes - metabolism
Female
Genetic Loci
Genome-Wide Association Study
Humans
Inflammation Mediators - blood
Male
Middle Aged
Polymorphism, Single Nucleotide
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
ISSN:1528-0020, 1528-0020
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Summary:To identify the genetic basis of circulating concentrations of monocyte chemoattractant protein-1 (MCP-1), we conducted genome-wide association analyses for MCP-1 in 3 independent cohorts (n = 9598). The strongest association was for serum MCP-1 with a nonsynonymous polymorphism, rs12075 (Asp42Gly) in DARC, the gene for Duffy antigen receptor for chemokines, a known vascular reservoir of proinflammatory cytokines (minor allele frequency, 45.6%; P < 1.0 * 10(-323)). This association was supported by family-based genetic linkage at a locus encompassing the DARC gene (genome-wide P = 8.0 * 10(-13)). Asp42Gly accounted for approximately 20% of the variability in serum MCP-1 concentrations and also was associated with serum concentrations of interleukin-8 and RANTES. While exploring a lack of association between this polymorphism and EDTA plasma MCP-1 concentrations (P = .82), we determined that both clotting and exogenous heparan sulfate (unfractionated heparin) released substantial amounts of MCP-1 from Darc. Quantitative immunoflow cytometry failed to identify meaningful Asp42Gly-associated differences in Darc expression, suggesting that a functional change is responsible for the differential cytokine binding. We conclude that Asp42Gly is a major regulator of erythrocyte Darc-mediated cytokine binding and thereby the circulating concentrations of several proinflammatory cytokines. We have also identified for the first time 2 mechanisms for the release of reservoir chemokines with possible clinical implications.
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ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2009-05-221382