title: 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.
abstract: 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.
authors.affiliation: Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, United States of America; Department of Molecular Biology and Biochemistry, Georgia Regents University-University of Georgia Medical Partnership, Athens, GA, United States of America.
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Davis
authors.affiliation: Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, United States of America.
authors.forename: Andrea
authors.initials: A
authors.lastname: Walens
authors.affiliation: Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, United States of America.
authors.forename: Rupali
authors.initials: R
authors.lastname: Hire
authors.affiliation: Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, United States of America.
authors.forename: Kauthar
authors.initials: K
authors.lastname: Mumin
authors.affiliation: Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, United States of America.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Brown
authors.affiliation: Department of Genetics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, United States of America.
authors.forename: DeJuana
authors.initials: D
authors.lastname: Ford
authors.affiliation: Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States of America.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Howerth
authors.affiliation: Department of Molecular Biology and Biochemistry, Georgia Regents University-University of Georgia Medical Partnership, Athens, GA, United States of America.
authors.forename: Michele
authors.initials: M
authors.lastname: Monteil
mesh_terms: D000483:Alleles; D044383:Black People; D002460:Cell Line; D004375:Duffy Blood-Group System / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000208:ethnology / Q000235:genetics / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology
chemical_list: C473745:ACKR1 protein, human; D004375:Duffy Blood-Group System; D020033:Protein Isoforms; D011956:Receptors, Cell Surface