# The Role of Epigenetics in Periodontal and Systemic Diseases and Smoking: A Systematic Review
## 4 Discussion  
### Patients with Systemic Diseases  
Rheumatoid arthritis (RA) and periodontitis share a common pathogenesis pathway [21]; therefore, the epigenetic regulation in RA has been assessed and compared to periodontitis. [PERSON] et al. (2016) evaluated the DNA methylation of 12 CpG motifs in the _TNF-\(\alpha\)_ gene promoter region from peripheral blood of the Japanese population with CP compared to RA and controls [35], taking into consideration that _TNF-\(\alpha\)_ is an inflammatory cytokine that is elevated in active and progressing periodontitis [46; 47; 48]. Results of this study revealed that both CP and RA groups had higher DNA methylation rates and frequencies than the control groups at \(-72\ bp\)[35], suggesting a pattern of hypermethylated CpG motifs in the _TNF-\(\alpha\)_ gene promoter in blood cells in Japanese adults with CP and RA. In an earlier study on periodontitis and RA, [PERSON] et al. (2012) assessed the DNA methylation status of 19 CpG motifs in the _IL-6_ gene promoter from the peripheral blood of patients with CP compared to RA and controls [36]. Notably, IL-6 is a multifunctional pro-inflammatory cytokine that is highly expressed in periodontitis [49]. [PERSON]'s group reported significantly lower DNA methylation levels at \(-74\ bp\) and _+19 bp_ in CP and RA patients when compared to controls. Moreover, the methylation levels at \(-74\ bp\) but not _+19 bp_ were also associated with the production of _IL-6_ by mononuclear cells, suggesting that hypomethyllation of a single CpG motif in the _IL-6_ promoter region might result in increased levels of _IL-6_ in the serum. This observation could indicate the role of DNA methylation status at this specific CpG motif in the pathogenesis of RA and periodontitis [36]. The relationship between diabetes mellitus and periodontitis is well-established by the fact that periodontitis is the sixth complication of diabetes mellitus [50] and diabetes being a major risk factor for periodontitis [51]; therefore, the epigenetic modifications were evaluated in periodontitis and diabetic patients. In this context, [PERSON] et al. (2016) evaluated DNA methylation of _CXCL12_ promoter in epithelial cells from CP, diabetes/CP patients and healthy controls. _CXCL12_ is a pro- and anti-inflammatory chemokine [34], and its role in the development and progression of both periodontitis and diabetes remains elusive as its effects range from protective to destructive [34]. Although [PERSON] et al. (2016) demonstrated an increased DNA methylation percentage in the _CXCL12_ promoter in healthy patients with periodontitis and in diabetic patients with periodontitis, compared to healthy controls, these results failed to show a statistically significant difference [34]. Nonetheless, it can be inferred that chronic inflammation contributes to the change of DNA methylation of _CXCL12_ promoter in buccal epithelial cells, which might play a role in the development and progression of periodontal disease. Since epidemiological data have demonstrated that CP patients tend to have a significantly higher incidence of squamous cell carcinoma [52; 53], [PERSON] et al. (2016) analyzed DNA methylation in CP and healthy controls compared to oral squamous cell carcinoma samples [37]. Their results demonstrated hypermethylated CpG sites of _SOCS1_ and _RMI2_ in samples from periodontitis and in samples from squamous cell carcinoma, and hypomethyllated sites consistent in both periodontitis and squamous cell carcinoma. These findings might suggest the emergence of the pre-neoplastic epigenome in CP. In a recent systematic review, periodontitis was associated with an increased longitudinal risk of cancer mortality [54]. Due to the possible association between chronic periodontitis and cancer on the molecular level [55; 56], epigenetic changes in periodontitis and breast cancer have been evaluated. [PERSON] et al.