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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Veröffentlicht in:	Blood Jg. 115; H. 26; S. 5289
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 01.07.2010
Schlagworte:	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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Abstract	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.
AbstractList	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. 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.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.
Author	Yamamoto, Jennifer F Vasan, Ramachandran S Heiss, Gerardo Ellinor, Patrick T Illig, Thomas Baumert, Jens Boerwinkle, Eric Zhu, Yanyan Dehghan, Abbas Walston, Jeremy D Tracy, Russell P Jenny, Nancy S Gieger, Christian Morrison, Alanna C Psaty, Bruce M Durda, Peter Tilley, Cathy Keaney, Jr, John F Khuseyinova, Natalie Schnabel, Renate B Hoogeveen, Ron C Koenig, Wolfgang Peters, Annette Benjamin, Emelia J Bis, Joshua C Ballantyne, Christie M Blankenberg, Stefan Larson, Martin G Doyle, Margaret Barbalic, Maja Dupuis, Josée Klopp, Norman Witteman, Jacqueline C M Herder, Christian
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SubjectTerms	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
Title	Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
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