Smoking-Induced Expression of the GPR15 Gene Indicates Its Potential Role in Chronic Inflammatory Pathologies

Kõks, Gea; Uudelepp, Mari-Liis; Limbach, Maia; Peterson, Pärt; Reimann, Ene; Kõks, Sulev

doi:10.1016/j.ajpath.2015.07.006

Cited by 52 publications

(47 citation statements)

References 47 publications

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“…In particular, loci cg07826859 (MYO1G) and cg19859270 (GPR15) have been reported to play a role in the formation of chronic inflammation via regulating the activity of T cells. 32,33 Locus cg25189904 is located on the south shore of a CpG island spanning the promoter of GNG12 that has been suggested to be an important factor in the overall inflammatory signaling cascade. 34 Moreover, another 3 loci are mapped to genes linked to the risks of various age-related cancers.…”

Section: Discussionmentioning

confidence: 99%

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

et al. 2017

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Tobacco smoking is a preventable environmental factor that contributes to a wide spectrum of age-related health outcomes; however, its association with the development of frailty is not yet well established. We examined the associations of self-reported smoking indicators, serum cotinine levels and smoking-related DNA methylation biomarkers with a quantitative frailty index (FI) in 2 independent subsets of older adults (age 50-75) recruited in Saarland, Germany in 2000 -2002 (discovery set: n D 978, validation set: n D 531). We obtained DNA methylation profiles in whole blood samples by Illumina HumanMethylation450 BeadChip and calculated the FI according to the method of Mitnitski and Rockwood. Mixed linear regression models were implemented to assess the associations between smoking indicators and the FI. After controlling for potential covariates, current smoking, cumulative smoking exposure (pack-years), and time after smoking cessation (years) were significantly associated with the FI (P-value < 0.05). In the discovery panel, 17 out of 151 previously identified smoking-related CpG sites were associated with the FI after correction for multiple testing (FDR < 0.05). Nine of them survived in the validation phase and were designated as frailty-associated loci. A smoking index (SI) based on the 9 loci manifested a monotonic association with the FI. In conclusion, this study suggested that epigenetic alterations could play a role in smoking-associated development of frailty. The identified CpG sites have the potential to be prognostic biomarkers of frailty and frailty-related health outcomes. Our findings and the underlying mechanisms should be followed up in further, preferably longitudinal studies.

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Section: Discussionmentioning

confidence: 99%

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

et al. 2017

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“…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. 45 These authors found that the methylation was reversible after smoking cessation.…”

Section: Gpr15 and Smokingmentioning

confidence: 99%

“…46 While GPR15 hypomethylation correlates very well with the increased RNA expression, with AHRR only methylation changes have been described and no difference in gene expression has been found. 42 Therefore, GPR15 is almost the only gene related to smoking and having a clear correlation of methylation and expression.…”

Section: Gpr15 and Smokingmentioning

confidence: 99%

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

Kõks

2017

Exp Biol Med (Maywood)

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The review describes an orphan receptor GPR15 that has recently been found to be influenced by smoking. This makes GPR15 very sensitive and adequate biomarker for smoking and smoking studies. Also, activation of GPR15 by smoking could help to explain its effects on health. AbstractSmoking is one of the most significant modifiable environmental risk factors for many diseases. Smoking causes excessive mortality worldwide. Despite decades of long research, there has not been a clear understanding regarding the molecular mechanism that makes smoking harmful to health. Some recent studies have found that smoking influences most significantly the expression and methylation of GPR15. GPR15 is an orphan receptor that is involved in the regulation of the innate immunity and the T-cell trafficking in the intestinal epithelium. Further studies have confirmed that GPR15 is very strongly involved in smoking and smoking-induced molecular changes. Therefore, the altered expression and epigenetic regulation of GPR15 could have a significant role in the health impact of smoking.

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“… smoke-mediated redistribution of the interleukin (IL)-33 receptor, ST2, a member of the IL-1 pro-inflammatory cytokine family, resulting in increased expression on alveolar macrophages and natural killer cells, thereby potentiating the inflammatory potential of these cells [62]  increased expression of the G-protein-coupled receptor 15 gene (GPR15) in the blood of smokers resulting from hypomethylation of DNA [63]. This is an orphan receptor involved in the homing of effector, pro-inflammatory Th1 and Th17 cells to the colon [64].…”

Section: Pro-inflammatory Effects Of Smokingmentioning

confidence: 99%

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

Anderson

Meyer

Ally

et al. 2016

NICTOB

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Smoking is now well recognised not only as a risk factor for rheumatoid arthritis (RA), but also as a determinant of disease activity, severity, response to therapy, and possibly mortality. Recent studies have provided significant insights into the molecular and cellular mechanisms which underpin the pathogenesis of smokingrelated RA. These involve release of the enzymes, peptidylarginine deiminases (PADs) 2 and 4 from smoke-activated, resident and infiltrating pulmonary phagocytes. PADs, in turn, mediate the conversion of various endogenous proteins to putative citrullinated autoantigens. In genetically susceptible individuals, these autoantigens trigger the production of anti-citrullinated peptide/protein pathogenic autoantibodies (ACPA), an event which precedes the development of RA. This review is focused primarily on smoking-mediated harmful chronic inflammatory responses, both local and systemic, which promote the formation of ACPA, as well as the possible involvement of other types of outdoor and indoor pollution in the pathogenesis of RA. This is preceded by a brief overview of the evidence implicating smoking as a risk factor for development of ACPA-positive RA.Keywords: Anti-citrullinated peptide/protein antibodies; airway microbiota; atmospheric pollution; heavy metals; peptidylarginine deiminases; smoking cessation strategies. ImplicationsChronic inflammatory mechanisms operative in the lungs of smokers lead to the production of anti-citrullinated protein antibodies which, in turn, drive the development of rheumatoid arthritis. These mechanistic insights not only reinforce the association between smoking and risk for rheumatoid arthritis, but also the necessity to increase the level of awareness in those at highest risk.

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Smoking-Induced Expression of the GPR15 Gene Indicates Its Potential Role in Chronic Inflammatory Pathologies

Cited by 52 publications

References 47 publications

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

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

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

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