International Journal of Inflammation / 2019 / Article / Tab 2

Review Article

Epigenetics and Inflammatory Markers: A Systematic Review of the Current Evidence

Table 2

Gene-specific DNA methylation and inflammatory markers.

AuthorStudy designOutcomeTissue typePopulation
Sex/Age/Sample size/ Country
Methylation sites/ methodAdjustmentMain findingsClinical condition associated with the main findings

Piperi et al., 2010 [20]CSIL-6, IL-8, VEGF, COX-2Tumour specimensM and W/25-76/n=23/GreeceMGMT, RARβ, RASSF1A, CDH13/MS-PCRIL-6: positive correlation with the four genes; IL-8 and COX-2: no correlation for any gene; VEGF: positive correlation with MGMT and RARβ, no correlation with RASSF1A and CDH13.IPA: Cancer, neurological diseases, ophthalmic diseases.

Uddin et al., 2010 [27]CSIL-6, CRPPBMCM and W/ 45.3±16.7/ n=100/ USAIL-6/Illumina HumanMethylation27K DNA Analysis BeadChipAmong patients with lifetime depression, there was a significant inverse correlation between methylation of IL-6 and serum levels of IL-6 and CRP (Pearson r=-0.54, p=0.001 and Pearson r=-0.48, p=0.006, respectively.IL-6: Rheumatic diseases, inflammatory bowel disease, Kaposi sarcoma.

Fu et al., 2011 [28]CSIL-10 (mRNA)PBMCM and W/39 ± 10.8/ n=40/ ChinaIL-10 promoter, 5 CpG sites/ Pyro Q-CpG systemHypomethylation of -145C was correlated with higher IL-10 mRNA expression (r=-0.746, p=0.001). The authors did not report the results for the other CpG sites.IL-10: Susceptibility to HIV type 1, rheumatic conditions, cutaneous leishmaniasis.

Zhang et al., 2012 [14]CSCRPPBM and W/18-78/ n=165/USAIL-6 promoter, 6 sites/ bisulfite treatmentAge, sex, race, dietary folate intake, prudent diet pattern, western dietWith a spearman correlation coefficient of 0.11 (p=0.18), no association was found.Not applicable

García-Cardona et al., 2014 [29]CSLeptinPBM and W/ 10-16/ n=106/ MexicoLEP promoter/ MS-PCRNo significant correlation was observed between the circulating levels of leptin and the methylation frequencies of the two selected CpG sites of LEP promoter (at − 51 and − 31 nt).Not applicable

Lai et al., 2014 [24]CSIL-6, TNF-α and CRPPBM and W/ 36-80/ n=46/ChinaSOCS-1 gene, 11 CpG sites/ Bisulfite methodA positive trend between the levels of SOCS-1 methylation and CRP levels was observed (R2=0.1127, p=0.0278). Patients with serum IL-6 above median showed a significantly higher SOCS-1 methylation than the patients with serum IL-6 below median (p<0.001). Similar results were observed for TNF-α (p<0.001).SOCS-1: Cancer, hepatic system diseases, ophthalmological diseases.

Smith et al., 2014 [12]CS and prospectivesTNFR2, IL-6PBMCW/56.4 ± 9.4/ n=61/USAUSP2, TMEM49, SMAD3, DTNB, 8 CpG sites/ HumanMethylation 450 Bead CheapAt baseline, lower methylation at each of the 8 CpG sites was significantly correlated with increased sTNFR2 and IL-6.IPA: Gastrointestinal diseases, hepatic system diseases, cancer (like gynaecological cancer), dermatological diseases.

Wang et al., 2014 [22]CSFibrinogen and CRPPBM and W/16.2 ±1.2/ n=703/ USALY86 gene, 6 CpG sites / HumanMethylation 27 BeadChip and ThumanMethylation 450 BeadChip from IlluminaAge, sex, race, BMI and batchThey performed a principal component analysis to combine the six CpG sites into one score. The score of these CpG sites was significantly associated with fibrinogen (partial r=0.145, p<0.001) and CRP (partial r=0.114, p=0.005).LY86: Pelvic inflammation, pulmonary interstitial emphysema.

Wei et al., 2016 [21]CSCRPWBCM and W/ /n=673/ChinaIL-6 promoter/EZ DNA Methylation KitAge and sexPlasma CRP levels were significantly associated with IL-6 promoter methylation (p=0.025). One interquartile range increase in plasma CRP was associated with a decrease in IL-6 methylation by 0.78% (95% CI: -1.47% to -0.1%).IL-6: Rheumatic diseases, inflammatory bowel disease, Kaposi sarcoma.

Arpón et al., 2017 [25]CSTNF-α, VCAM-1, sICAM-1, CRP, leptinPBM and W/63.8±2.74/ n=36/ SpainEEF2, COL18A1, IL4I1, LEPR, PLAGL1, IFRD1, MAPKAPK2 and PPARGC1B/ llumina Infinium HumanMethylation 450K BeadChipResults showed correlations between LEPR methylation and concentration of LEP (r=-0.24, p=0.047). Also, between EEF2 methylation and concentration of TNF-α (r=0.24, p= 0.0408) and CRP (r=0.24, p=0.0457).IPA: Inflammatory response, cardiovascular disease, reproductive system diseases.

Min A Jhun. et al., 2017 [23]CSCRP, IL-6, IL-18, fibrinogenPBLM and W/66 7.5/n=822/ USACg0363183 in F2RL3/ Illumina Infinium HumanMethylation 27 BeadChips and the Illumina BeadXpress reader.Age, sex, four principal component, five cell proportions, plate and random intercepts for family.DNA methylation level of Cg03636183 in F2RL3 was significantly associated with log (IL-18) levels (-0.11, 95% CI (-0.19, -0.04)).Unknown.

Miller et al., 2017 [26]CSCRPWBCM and W/32.08±8.36/ n=286/ USAAIM2,cg10636246/
llumina Infinium HumanMethylation 450K
Log CRP levels were negatively correlated with cg10636246
(r=-0.264, p<0.001).
AIM2: Skin disease, melanoma.

We used Ingenuity Pathway Analysis (IPA) for studies that found significant association between multiple inflammatory markers and/or methylation in multiple genes [12, 20, 25]. For the other studies, the connection between findings and disease was assessed through literature review and gene cards (https://www.genecards.org/).
CS: cross-sectional; IL: interleukin; VEGF: vascular endothelial growth factor; Cox-2: cyclooxygenase; M: men; W: women; MS-PCR: methylation-specific PCR; IPA: ingenuity pathway analysis; PBMC: peripheral blood mononuclear cells; HIV: human immunodeficiency virus; PB: peripheral blood; TNF- α: tumour necrosis factor-alpha; sTNFR2: soluble tumour necrosis factor receptor 2; BMI: body mass index; WBC: white blood cells; VCAM-1: vascular cell adhesion molecule 1; sICAM-1: soluble intercellular adhesion molecule 1; PBL: peripheral blood leucocytes.