TY - JOUR
T1 - Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
AU - Schnabel, Renate B.
AU - Baumert, Jens
AU - Barbalic, Maja
AU - Dupuis, Josée
AU - Ellinor, Patrick T.
AU - Durda, Peter
AU - Dehghan, Abbas
AU - Bis, Joshua C.
AU - Illig, Thomas
AU - Morrison, Alanna C.
AU - Jenny, Nancy S.
AU - Keaney, John F.
AU - Gieger, Christian
AU - Tilley, Cathy
AU - Yamamoto, Jennifer F.
AU - Khuseyinova, Natalie
AU - Heiss, Gerardo
AU - Doyle, Margaret
AU - Blankenberg, Stefan
AU - Herder, Christian
AU - Walston, Jeremy D.
AU - Zhu, Yanyan
AU - Vasan, Ramachandran S.
AU - Klopp, Norman
AU - Boerwinkle, Eric
AU - Larson, Martin G.
AU - Psaty, Bruce M.
AU - Peters, Annette
AU - Ballantyne, Christie M.
AU - Witteman, Jacqueline C.M.
AU - Hoogeveen, Ron C.
AU - Benjamin, Emelia J.
AU - Koenig, Wolfgang
AU - Tracy, Russell P.
PY - 2010/7/1
Y1 - 2010/7/1
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2009-05-221382
DO - 10.1182/blood-2009-05-221382
M3 - Article
C2 - 20040767
AN - SCOPUS:77955897953
SN - 0006-4971
VL - 115
SP - 5289
EP - 5299
JO - Blood
JF - Blood
IS - 26
ER -