title: Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators.
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.
authors.affiliation: National Heart, Lung, and Blood Institute and Boston University Framingham Heart Study, 73 Mount Wayte Avenue ,Framingham, MA 01702-5827, USA.
authors.forename: Renate B
authors.initials: RB
authors.lastname: Schnabel
authors.forename: Jens
authors.initials: J
authors.lastname: Baumert
authors.forename: Maja
authors.initials: M
authors.lastname: Barbalic
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Peter
authors.initials: P
authors.lastname: Durda
authors.forename: Abbas
authors.initials: A
authors.lastname: Dehghan
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Bis
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Alanna C
authors.initials: AC
authors.lastname: Morrison
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Jenny
authors.forename: John F
authors.initials: JF
authors.lastname: Keaney
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Cathy
authors.initials: C
authors.lastname: Tilley
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Yamamoto
authors.forename: Natalie
authors.initials: N
authors.lastname: Khuseyinova
authors.forename: Gerardo
authors.initials: G
authors.lastname: Heiss
authors.forename: Margaret
authors.initials: M
authors.lastname: Doyle
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Christian
authors.initials: C
authors.lastname: Herder
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Walston
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.forename: Martin G
authors.initials: MG
authors.lastname: Larson
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.forename: Jacqueline C M
authors.initials: JC
authors.lastname: Witteman
authors.forename: Ron C
authors.initials: RC
authors.lastname: Hoogeveen
authors.forename: Emelia J
authors.initials: EJ
authors.lastname: Benjamin
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Koenig
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
mesh_terms: D000328:Adult; D018932:Chemokine CCL2 / Q000097:blood* / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D015331:Cohort Studies; D004375:Duffy Blood-Group System / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
chemical_list: C473745:ACKR1 protein, human; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004375:Duffy Blood-Group System; D018836:Inflammation Mediators; D011956:Receptors, Cell Surface