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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.

Davis MB, Walens A, Hire R, Mumin K, Brown AM, Ford D, Howerth EW, Monteil M - PLoS ONE (2015)

Bottom Line: Additional alleles are associated with a myriad of clinical outcomes related to immune responses and inflammation.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.Ultimately, this work will increase knowledge of biological mechanisms underlying disparate clinical outcomes of inflammatory-related diseases among ethnic and geographic ancestry groups.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

Statistical comparisons of relative levels of DARC isoform transcripts and ratios among ancestry and Fy- genotype groups.Statistical analyses across ancestry groups are on the left and genotype groups are on the right. ANOVA graphs indicate the individual group means (dotted blue line) of DARC isoform expression (top) and ratios (bottom) for stated categories. No statistically significant difference in individual transcript isoforms was identified across groups; however, significant differences were measured among ratios of DARC1/DARC2 isoforms. The means connection lines (solid blue and red) indicate the statistically significant comparisons. The significant p-values for pairwise T-test analyses of means is shown in the colors corresponding with each pair. The only statistically significant comparison across ancestry groups were between Amish and Yoruba groups. Across genotypes, there was a significant difference in DARC isoform ratios between TT genotype and both CT and CC genotypes. Significant differences between the isoform ratios indicate the isoforms are differentially regulated and the control of regulation is altered in isoform promoters with the C allele (Fy-).
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pone.0140098.g004: Statistical comparisons of relative levels of DARC isoform transcripts and ratios among ancestry and Fy- genotype groups.Statistical analyses across ancestry groups are on the left and genotype groups are on the right. ANOVA graphs indicate the individual group means (dotted blue line) of DARC isoform expression (top) and ratios (bottom) for stated categories. No statistically significant difference in individual transcript isoforms was identified across groups; however, significant differences were measured among ratios of DARC1/DARC2 isoforms. The means connection lines (solid blue and red) indicate the statistically significant comparisons. The significant p-values for pairwise T-test analyses of means is shown in the colors corresponding with each pair. The only statistically significant comparison across ancestry groups were between Amish and Yoruba groups. Across genotypes, there was a significant difference in DARC isoform ratios between TT genotype and both CT and CC genotypes. Significant differences between the isoform ratios indicate the isoforms are differentially regulated and the control of regulation is altered in isoform promoters with the C allele (Fy-).

Mentions: To thoroughly interrogate the differential expression of DARC/ACKR1 isoforms, we conducted a series of statistical tests to determine associations with either ancestry or the Fy- genotype. First, to determine if the specific isoform levels are associated with ethnicity, we conducted an ANOVA for each isoform across ethnicities. While we detected a trend for relatively lower and more tightly regulated levels in the EA group for both isoforms (Fig 4); however, this finding isn’t statistically significant (p = 0.482) possibly due to our small sample size. Similarly, when an ANOVA was conducted for each isoform across Fy- genotype groups, we found trends of expression levels with higher levels of both isoforms in individuals with the Fy- alleles.


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.

Davis MB, Walens A, Hire R, Mumin K, Brown AM, Ford D, Howerth EW, Monteil M - PLoS ONE (2015)

Statistical comparisons of relative levels of DARC isoform transcripts and ratios among ancestry and Fy- genotype groups.Statistical analyses across ancestry groups are on the left and genotype groups are on the right. ANOVA graphs indicate the individual group means (dotted blue line) of DARC isoform expression (top) and ratios (bottom) for stated categories. No statistically significant difference in individual transcript isoforms was identified across groups; however, significant differences were measured among ratios of DARC1/DARC2 isoforms. The means connection lines (solid blue and red) indicate the statistically significant comparisons. The significant p-values for pairwise T-test analyses of means is shown in the colors corresponding with each pair. The only statistically significant comparison across ancestry groups were between Amish and Yoruba groups. Across genotypes, there was a significant difference in DARC isoform ratios between TT genotype and both CT and CC genotypes. Significant differences between the isoform ratios indicate the isoforms are differentially regulated and the control of regulation is altered in isoform promoters with the C allele (Fy-).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4608815&req=5

pone.0140098.g004: Statistical comparisons of relative levels of DARC isoform transcripts and ratios among ancestry and Fy- genotype groups.Statistical analyses across ancestry groups are on the left and genotype groups are on the right. ANOVA graphs indicate the individual group means (dotted blue line) of DARC isoform expression (top) and ratios (bottom) for stated categories. No statistically significant difference in individual transcript isoforms was identified across groups; however, significant differences were measured among ratios of DARC1/DARC2 isoforms. The means connection lines (solid blue and red) indicate the statistically significant comparisons. The significant p-values for pairwise T-test analyses of means is shown in the colors corresponding with each pair. The only statistically significant comparison across ancestry groups were between Amish and Yoruba groups. Across genotypes, there was a significant difference in DARC isoform ratios between TT genotype and both CT and CC genotypes. Significant differences between the isoform ratios indicate the isoforms are differentially regulated and the control of regulation is altered in isoform promoters with the C allele (Fy-).
Mentions: To thoroughly interrogate the differential expression of DARC/ACKR1 isoforms, we conducted a series of statistical tests to determine associations with either ancestry or the Fy- genotype. First, to determine if the specific isoform levels are associated with ethnicity, we conducted an ANOVA for each isoform across ethnicities. While we detected a trend for relatively lower and more tightly regulated levels in the EA group for both isoforms (Fig 4); however, this finding isn’t statistically significant (p = 0.482) possibly due to our small sample size. Similarly, when an ANOVA was conducted for each isoform across Fy- genotype groups, we found trends of expression levels with higher levels of both isoforms in individuals with the Fy- alleles.

Bottom Line: Additional alleles are associated with a myriad of clinical outcomes related to immune responses and inflammation.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.Ultimately, this work will increase knowledge of biological mechanisms underlying disparate clinical outcomes of inflammatory-related diseases among ethnic and geographic ancestry groups.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus