Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
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Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators. / 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.
In: BLOOD, Vol. 115, No. 26, 01.07.2010, p. 5289-5299.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research
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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 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.
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 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.
KW - Adult
KW - Chemokine CCL2/blood
KW - Chromosomes, Human, Pair 1
KW - Cohort Studies
KW - Duffy Blood-Group System/genetics
KW - Erythrocytes/metabolism
KW - Female
KW - Genetic Loci
KW - Genome-Wide Association Study
KW - Humans
KW - Inflammation Mediators/blood
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Receptors, Cell Surface/genetics
U2 - 10.1182/blood-2009-05-221382
DO - 10.1182/blood-2009-05-221382
M3 - SCORING: Journal article
C2 - 20040767
VL - 115
SP - 5289
EP - 5299
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 26
ER -
