Cigarette and Cannabis Smoking Effects on GPR15+ Helper T Cell Levels in Peripheral Blood: Relationships with Epigenetic Biomarkers

Abstract

Background: Smoking causes widespread epigenetic changes that have been linked with an increased risk of smoking-associated diseases and elevated mortality. Of particular interest are changes in the level of T cells expressing G-protein-coupled receptor 15 (GPR15), a chemokine receptor linked with multiple autoimmune diseases, including inflammatory bowel disease, multiple sclerosis and psoriasis. Accordingly, a better understanding of the mechanisms by which smoking influences variation in the GPR15+ helper T cell subpopulation is of potential interest. Methods: In the current study, we used flow cytometry and digital PCR assays to measure the GPR15+CD3+CD4+ populations in peripheral blood from a cohort of n = 62 primarily African American young adults (aged 27–35 years) with a high rate of tobacco and cannabis use. Results: We demonstrated that self-reported tobacco and cannabis smoking predict GPR15+CD3+CD4+ helper T cell levels using linear regression models. Further, we demonstrated that methylation of two candidate CpGs, cg19859270, located in GPR15, and cg05575921, located in the gene Aryl Hydrocarbon Receptor Repressor (AHRR), were both significant predictors of GPR15+CD3+CD4+ cell levels, mediating the relationship between smoking habits and increases in GPR15+CD3+CD4+ cells. As hypothesized, the interaction between cg05575921 and cg19859270 was also significant, indicating that low cg05575921 methylation was more strongly predictive of GPR15+CD3+CD4+ cell levels for those who also had lower cg19859270 methylation. Conclusions: Smoking leads changes in two CpGs, cg05575921 and cg19859270, that mediate 38.5% of the relationship between tobacco and cannabis smoking and increased GPR15+ Th levels in this sample. The impact of cg19859270 in amplifying the association between cg05575921 and increased GPR15+ Th levels is of potential theoretical interest given the possibility that it reflects a permissive interaction between different parts of the adaptive immune system.

The Effect of Tobacco Smoking Differs across Indices of DNA Methylation-Based Aging in an African American Sample: DNA Methylation-Based Indices of Smoking Capture These Effects

“…Because these individual differences may account for, or confound, associations with morbidity and mortality risk, and because they may have somewhat different impact on different aging indices, it may be useful to control for cell-type variation when comparing effects across different indices. Conversely, it should be noted that some of the association between smoking and health outcomes could be the result of effects of smoking on cell-type variation [41,42]. However, prior research with African Americans has not found that correcting for cell-type variation decreases the association of lifestyle factors such as smoking with accelerated aging indices of morbidity or mortality [30].…”

Dysregulated epigenetic modifications in psoriasis

“…148 Cigarette and cannabis smoking have been shown to lead to hypermethylation of two CpGs located in GPR15 and AHRR genes in helper T cells, leading to increased number of GPR15 + CD3 + CD4 + cells in peripheral blood, a well-known marker for autoimmune diseases, including psoriasis. 149…”

The Role of GPR15 Function in Blood and Vasculature

“…In blood, the most prominent upregulation of GPR15 in PBMCs was found to be associated with chronic cigarette smoking [ 3 , 18 , 38 , 39 , 40 ]. This upregulation slowly reverses over many years after cessation to the range of never smokers.…”

“…Surprisingly, the strongest association to GPR15 methylation in blood cells was related to smoking, particularly to chronic cigarette tobacco smoking as reviewed in [ 49 ]. In addition to cigarette smoking, cannabis smoking similarly mediates hypomethylation at cg19859270 in cells of the adaptive immune system accompanied by an excess in GPR15+ Th cells [ 39 ]. Whether combustion products from electronic cigarette smoking would exert a similar effect has not been studied to date.…”