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) 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.
Schnabel
Renate B
RB
National Heart, Lung, and Blood Institute and Boston University Framingham Heart Study, 73 Mount Wayte Avenue ,Framingham, MA 01702-5827, USA.
Baumert
Jens
J
Barbalic
Maja
M
Dupuis
Josée
J
Ellinor
Patrick T
PT
Durda
Peter
P
Dehghan
Abbas
A
Bis
Joshua C
JC
Illig
Thomas
T
Morrison
Alanna C
AC
Jenny
Nancy S
NS
Keaney
John F
JF
Gieger
Christian
C
Tilley
Cathy
C
Yamamoto
Jennifer F
JF
Khuseyinova
Natalie
N
Heiss
Gerardo
G
Doyle
Margaret
M
Blankenberg
Stefan
S
Herder
Christian
C
Walston
Jeremy D
JD
Zhu
Yanyan
Y
Vasan
Ramachandran S
RS
Klopp
Norman
N
Boerwinkle
Eric
E
Larson
Martin G
MG
Psaty
Bruce M
BM
Peters
Annette
A
Ballantyne
Christie M
CM
Witteman
Jacqueline C M
JC
Hoogeveen
Ron C
RC
Benjamin
Emelia J
EJ
Koenig
Wolfgang
W
Tracy
Russell P
RP
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
C473745:ACKR1 protein, human; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D004375:Duffy Blood-Group System; D018836:Inflammation Mediators; D011956:Receptors, Cell Surface