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

• Published in: Blood Vol. 115; no. 26; pp. 5289 - 5299
• 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, 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: Washington, DC Elsevier Inc 01-07-2010; Americain Society of Hematology; American Society of Hematology
• Series: Plenary Paper
• Subjects: Adult; Biological and medical sciences; 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; Hematologic and hematopoietic diseases; Humans; Inflammation Mediators - blood; Male; Medical sciences; Middle Aged; Plenary Paper; Polymorphism, Single Nucleotide; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Antigen; Chemokine; Blood group; Genetic variability; Hematology; Genotype; Duffy system; Inflammation; Chemokine receptor; Monocyte chemoattractant protein 1; Polymorphism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2009-05-221382

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.