Journal
BLOOD
Volume 115, Issue 26, Pages 5289-5299Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-05-221382
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Funding
- NCRR NIH HHS [UL1RR025005, 1S10RR163736-01A1] Funding Source: Medline
- NHGRI NIH HHS [U01HG004402] Funding Source: Medline
- NHLBI NIH HHS [K24 HL105780, R01HL59367, R01 HL104156, R01HL086694, R01 HL077449, N01-HC-55018, N01-HC-55021, 2K24HL04334, N01-HC-55019, HL093328, HL064753, N01-HC-55022, N01-HC-55020, N01-HC-55016, HL076784, N01-HC-55015, R01HL087641] Funding Source: Medline
- NIA NIH HHS [AG028321] Funding Source: Medline
- NIDA NIH HHS [R21 DA027021] Funding Source: Medline
- NIDDK NIH HHS [DK080739] Funding Source: Medline
- NINDS NIH HHS [6R01-NS 17950] Funding Source: Medline
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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. (Blood. 2010; 115(26):5289-5299)
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