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

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.

Activation of GPR15 and its involvement in the biological effects of smoking

“…In their next study, the same authors found that methylation of GPR15 locus that was dependent on the ethnicity and hypomethylation were found only in African Americans. 41 However, several following studies have found the highly significant (with genome-wide significance) hypomethylation and increased expression of GPR15 in smokers. [42][43][44] Another study analyzed the RNA expression from the whole blood together with methylation profile and found highly significant upregulation of GPR15 expression in the blood that correlated with the hypomethylation of the GPR15 locus.…”

Using DNA methylation to validate an electronic medical record phenotype for smoking

“…Analyses for cg03636183 were stratified by ancestry (African or European), because methylation of cg03636183 has been shown to vary by population (Dogan et al . ; Zhang et al . ).…”

“…), among both sexes (Dogan et al . ), across a wide range of ages (Beach et al . ) and different tissues (Stueve et al .…”

Lung cancer early detection and health disparities: the intersection of epigenetics and ethnicity

“…The frequency of these allele variants among Native American groups is unknown (44). This rationale follows for other cases as well considering a differential SNP mutation in rs2230344, a loci within the promoter region of GPR15, was observed within the AA cohort in Dogan et al's analysis (70).…”

“…Dogan et al, on the other hand, discovered that GPR15, a chemokine receptor involved in human immunodeficiency virus (HIV) propagation, was significantly differentially methylated in AA smokers when compared with Caucasian smokers. The group also mentioned that this could point towards a causal pathway for the increased prevalence of HIV within the AA community as the loss of function in the GPR15 gene may leave patients in this demographic subset at increased risk for HIV susceptibility (70).…”