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) 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 immuno-flow 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.
|Keywords||C reactive protein, CCL2 protein, DARC protein, Duffy antigen receptor for chemokine, Duffy binding protein, RANTES, autacoid, cell surface receptor, edetic acid, gamma interferon inducible protein 10, heparan sulfate, human, intercellular adhesion molecule 1, interleukin 18, interleukin 6, interleukin 8, macrophage migration inhibition factor, monocyte chemotactic protein 1, myeloperoxidase, unclassified drug|
|Persistent URL||dx.doi.org/10.1182/blood-2009-05-221382, hdl.handle.net/1765/21125|
Schnabel, R.B., Baumert, J., Barbalic, M., Dupuis, J., Ellinor, P.T., Durda, P., … Tracy, R.P.. (2010). Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators. Blood, 115(26), 5289–5299. doi:10.1182/blood-2009-05-221382