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Ethnicity and Smoking-Associated DNA Methylation Changes at HIV Co-Receptor GPR15.

Dogan MV, Xiang J, Beach SR, Cutrona C, Gibbons FX, Simons RL, Brody GH, Stapleton JT, Philibert RA - Front Psychiatry (2015)

Bottom Line: Smoking is associated with poorer health outcomes for both African and European Americans.In order to better understand whether ethnic-specific genetic variation may underlie some of these differences, we compared the smoking-associated genome-wide methylation signatures of African Americans with those of European Americans, and followed up this analysis with a focused examination of the most ethnically divergent locus, cg19859270, at the GPR15 gene.Gene and protein expression analyses showed that demethylation at cg19859270 was associated with an increase in both mRNA and protein levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of Iowa , Iowa City, IA , USA ; Department of Psychiatry, University of Iowa , Iowa City, IA , USA.

ABSTRACT
Smoking is associated with poorer health outcomes for both African and European Americans. In order to better understand whether ethnic-specific genetic variation may underlie some of these differences, we compared the smoking-associated genome-wide methylation signatures of African Americans with those of European Americans, and followed up this analysis with a focused examination of the most ethnically divergent locus, cg19859270, at the GPR15 gene. We examined the association of methylation at this locus to the rs2230344 SNP and GPR15 gene and protein expression. Consistent with prior analyses, AHRR residue cg05575921 was the most differentially methylated residue in both African Americans and European Americans. However, the second most differentially methylated locus in African Americans, cg19859270, was only modestly differentially methylated in European Americans. Interrogation of the methylation status of this CpG residue found in GPR15, a chemokine receptor involved in HIV pathogenesis, showed a significant interaction of ethnicity with smoking as well as a marginal effect of genotype at rs2230344, a neighboring non-synonymous SNP, but only among African Americans. Gene and protein expression analyses showed that demethylation at cg19859270 was associated with an increase in both mRNA and protein levels. Since GPR15 is involved in the early stages of viral replication for some HIV-1 and HIV-2 isolates, and the prevalence of HIV is increased in African Americans and smokers, these data support a possible role for GPR15 in the ethnically dependent differential prevalence of HIV.

No MeSH data available.


Related in: MedlinePlus

Relative ratio of GPR15/Actin. The figure depicts the relative ratio of GPR15/Actin for each PBMC cell pellet. H1 through H4 represent the four samples with the highest cg19859270 methylation, whereas L1 through L4 represent four samples with the lowest cg19859270 methylation.
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Figure 2: Relative ratio of GPR15/Actin. The figure depicts the relative ratio of GPR15/Actin for each PBMC cell pellet. H1 through H4 represent the four samples with the highest cg19859270 methylation, whereas L1 through L4 represent four samples with the lowest cg19859270 methylation.

Mentions: Finally, we examined whether cg19859270 methylation was associated with GPR15 protein expression. We utilized lymphocyte pellets from the BD cohort to determine the extent to which protein expression was influenced by methylation at cg19859270. The relative level of GPR15 protein was measured in 10 individuals, five with the highest and five with the lowest methylation levels at cg19859270. Results from two failed samples were excluded from the analysis (one high and one low methylation). Protein levels normalized to actin housekeeping protein was inversely correlated with methylation (p-value <0.01). Figure 2 illustrates the results. As can be seen, all four of the less methylated cells show greater relative production of GPR15 protein than any of the cells with a high level of methylation, indicating a substantial association between protein production and gene methylation at cg19859270. Figure S1 in Supplementary Material depicts the protein expression in immunoblot gels.


Ethnicity and Smoking-Associated DNA Methylation Changes at HIV Co-Receptor GPR15.

Dogan MV, Xiang J, Beach SR, Cutrona C, Gibbons FX, Simons RL, Brody GH, Stapleton JT, Philibert RA - Front Psychiatry (2015)

Relative ratio of GPR15/Actin. The figure depicts the relative ratio of GPR15/Actin for each PBMC cell pellet. H1 through H4 represent the four samples with the highest cg19859270 methylation, whereas L1 through L4 represent four samples with the lowest cg19859270 methylation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585036&req=5

Figure 2: Relative ratio of GPR15/Actin. The figure depicts the relative ratio of GPR15/Actin for each PBMC cell pellet. H1 through H4 represent the four samples with the highest cg19859270 methylation, whereas L1 through L4 represent four samples with the lowest cg19859270 methylation.
Mentions: Finally, we examined whether cg19859270 methylation was associated with GPR15 protein expression. We utilized lymphocyte pellets from the BD cohort to determine the extent to which protein expression was influenced by methylation at cg19859270. The relative level of GPR15 protein was measured in 10 individuals, five with the highest and five with the lowest methylation levels at cg19859270. Results from two failed samples were excluded from the analysis (one high and one low methylation). Protein levels normalized to actin housekeeping protein was inversely correlated with methylation (p-value <0.01). Figure 2 illustrates the results. As can be seen, all four of the less methylated cells show greater relative production of GPR15 protein than any of the cells with a high level of methylation, indicating a substantial association between protein production and gene methylation at cg19859270. Figure S1 in Supplementary Material depicts the protein expression in immunoblot gels.

Bottom Line: Smoking is associated with poorer health outcomes for both African and European Americans.In order to better understand whether ethnic-specific genetic variation may underlie some of these differences, we compared the smoking-associated genome-wide methylation signatures of African Americans with those of European Americans, and followed up this analysis with a focused examination of the most ethnically divergent locus, cg19859270, at the GPR15 gene.Gene and protein expression analyses showed that demethylation at cg19859270 was associated with an increase in both mRNA and protein levels.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of Iowa , Iowa City, IA , USA ; Department of Psychiatry, University of Iowa , Iowa City, IA , USA.

ABSTRACT
Smoking is associated with poorer health outcomes for both African and European Americans. In order to better understand whether ethnic-specific genetic variation may underlie some of these differences, we compared the smoking-associated genome-wide methylation signatures of African Americans with those of European Americans, and followed up this analysis with a focused examination of the most ethnically divergent locus, cg19859270, at the GPR15 gene. We examined the association of methylation at this locus to the rs2230344 SNP and GPR15 gene and protein expression. Consistent with prior analyses, AHRR residue cg05575921 was the most differentially methylated residue in both African Americans and European Americans. However, the second most differentially methylated locus in African Americans, cg19859270, was only modestly differentially methylated in European Americans. Interrogation of the methylation status of this CpG residue found in GPR15, a chemokine receptor involved in HIV pathogenesis, showed a significant interaction of ethnicity with smoking as well as a marginal effect of genotype at rs2230344, a neighboring non-synonymous SNP, but only among African Americans. Gene and protein expression analyses showed that demethylation at cg19859270 was associated with an increase in both mRNA and protein levels. Since GPR15 is involved in the early stages of viral replication for some HIV-1 and HIV-2 isolates, and the prevalence of HIV is increased in African Americans and smokers, these data support a possible role for GPR15 in the ethnically dependent differential prevalence of HIV.

No MeSH data available.


Related in: MedlinePlus