Distinct Transcript Isoforms of the Atypical Chemokine Receptor 1 (ACKR1) / Duffy Antigen Receptor for Chemokines (DARC) Gene Are Expressed in Lymphoblasts and Altered Isoform Levels Are Associated with Genetic Ancestry and the Duffy-Null Allele
Distinct Transcript Isoforms of the Atypical Chemokine Receptor 1 (ACKR1) / Duffy Antigen Receptor for Chemokines (DARC) Gene Are Expressed in Lymphoblasts and Altered Isoform Levels Are Associated with Genetic Ancestry and the Duffy-Null Allele
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DOI：
10.1371/journal.pone.0140098
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发表时间：
2015-10-16
期刊：
影响因子：
3.7
通讯作者：
Monteil, Michele
中科院分区：
文献类型：
--
作者：
Davis, Melissa B.;Walens, Andrea;Monteil, Michele
非典型趋化因子受体1（ACKR 1）基因，更好地称为Duffy抗原趋化因子受体（DARC或Duffy），负责Duffy血型，并在调节促炎趋化因子的循环稳态水平中起主要作用。之前的研究表明，一种常见的变体，即非洲血统群体特有的达菲空（Fy-）等位基因，完全消除了该基因在红细胞上的表达;然而，这些个体保留了内皮表达。其他等位基因与免疫反应和炎症相关的无数临床结果相关。除了等位基因变体之外，还有两种不同的DARC转录异构体，它们由不同的启动子表达，并且关于这些蛋白质异构体的不同转录调控或不同功能知之甚少。我们的目的是确定非洲特异性Fy等位基因是否改变DARC亚型的表达模式，从而可能导致基因产物（通常称为抗原）的独特特征。我们的工作是第一个建立有DARC的淋巴母细胞的表达。我们的数据表明，非洲血统的人在这些细胞中表达的DARC亚型具有不同的相对水平。我们得出结论，这两种亚型的表达与交替等位基因的组合产生多个达菲抗原的祖先群体，这取决于整个基因的单倍型。重要的是，我们假设DARC亚型表达模式将转化为祖先特异性炎症反应，这些炎症反应与促炎趋化因子水平的轴和与这些趋化因子的不同亚型特异性相互作用相关。最终，这项工作将增加对种族和地理祖先群体之间炎症相关疾病不同临床结果的生物学机制的了解。
The Atypical ChemoKine Receptor 1 (ACKR1) gene, better known as Duffy Antigen Receptor for Chemokines (DARC or Duffy), is responsible for the Duffy Blood Group and plays a major role in regulating the circulating homeostatic levels of pro-inflammatory chemokines. Previous studies have shown that one common variant, the Duffy Null (Fy-) allele that is specific to African Ancestry groups, completely removes expression of the gene on erythrocytes; however, these individuals retain endothelial expression. Additional alleles are associated with a myriad of clinical outcomes related to immune responses and inflammation. In addition to allele variants, there are two distinct transcript isoforms of DARC which are expressed from separate promoters, and very little is known about the distinct transcriptional regulation or the distinct functionality of these protein isoforms. Our objective was to determine if the African specific Fy-allele alters the expression pattern of DARC isoforms and therefore could potentially result in a unique signature of the gene products, commonly referred to as antigens. Our work is the first to establish that there is expression of DARC on lymphoblasts. Our data indicates that people of African ancestry have distinct relative levels of DARC isoforms expressed in these cells. We conclude that the expression of both isoforms in combination with alternate alleles yields multiple Duffy antigens in ancestry groups, depending upon the haplotypes across the gene. Importantly, we hypothesize that DARC isoform expression patterns will translate into ancestry-specific inflammatory responses that are correlated with the axis of pro-inflammatory chemokine levels and distinct isoform-specific interactions with these chemokines. Ultimately, this work will increase knowledge of biological mechanisms underlying disparate clinical outcomes of inflammatory-related diseases among ethnic and geographic ancestry groups.