Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators
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DOI：
10.1182/blood-2009-05-221382
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发表时间：
2010-07-01
期刊：
影响因子：
20.3
通讯作者：
Tracy, Russell P.
中科院分区：
文献类型：
--
作者：
Schnabel, Renate B.;Baumert, Jens;Tracy, Russell P.
为了确定单核细胞趋化蛋白-1 （MCP-1）循环浓度的遗传基础，我们在3个独立队列（n = 9598）中对MCP-1进行了全基因组关联分析。血清MCP-1与DARC的非同同义词多态性rs12075 （Asp42Gly）相关性最强，DARC是趋化因子Duffy抗原受体的基因，是已知的促炎细胞因子的血管库（次要等位基因频率，45.6%;P < 1.0 * 10(-323)）。这种关联得到了包含DARC基因的一个位点的家族遗传连锁的支持（全基因组P = 8.0 * 10(-13)）。Asp42Gly约占血清MCP-1浓度变异的20%，并且还与血清白细胞介素-8和RANTES浓度相关。在探索这种多态性与EDTA血浆MCP-1浓度之间缺乏相关性（P = 0.82）的同时，我们确定凝血和外源性硫酸肝素（未分离肝素）都能从Darc释放大量的MCP-1。定量免疫流式细胞术未能发现有意义的asp42gly相关的Darc表达差异，这表明功能变化是导致细胞因子结合差异的原因。我们得出结论，Asp42Gly是红细胞darc介导的细胞因子结合的主要调节因子，从而调节几种促炎细胞因子的循环浓度。我们还首次确定了两种可能具有临床意义的蓄水池趋化因子释放机制。（血液杂志，2010;115(26):5289-5299）
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)