1  4194 231 METABOLIC MEMORY IN DIABETIC FOOT SYNDROME (DFS): MICRO-RNAS, SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) FREQUENCY AND THEIR RELATIONSHIP WITH INDICES OF ENDOTHELIAL FUNCTION AND ADIPO-INFLAMMATORY DYSFUNCTION. BACKGROUND: DIABETIC FOOT IS A SIGNIFICANT CAUSE OF MORBIDITY IN DIABETIC PATIENTS, WITH A RATE THAT IS APPROXIMATELY TWICE THAT OF PATIENTS WITHOUT FOOT ULCERS. "METABOLIC MEMORY" REPRESENTS THE EPIGENETIC CHANGES INDUCED BY CHRONIC HYPERGLYCAEMIA, DESPITE THE CORRECTION OF THE GLUCOSE LEVELS THEMSELVES. THESE EPIGENETIC MODIFICATIONS APPEAR TO PERPETUATE THE DAMAGE CAUSED BY PERSISTENTLY ELEVATED GLUCOSE LEVELS EVEN IN THEIR ABSENCE, ACTING AT VARIOUS LEVELS, MOSTLY AFFECTING THE MOLECULAR PROCESSES OF DIABETIC ULCER HEALING. METHODS: THE AIM OF OUR CROSS-SECTIONAL STUDY WAS TO ANALYSE A COHORT OF PATIENTS WITH DIABETES WITH AND WITHOUT LOWER LIMB ULCERS. WE EXAMINED THE EFFECTS OF EPIGENETIC CHANGES ON MIRNA 126, 305, AND 217 EXPRESSION AND THE FREQUENCY OF THE SNPS OF GENES ENCODING INFLAMMATORY MOLECULES (E.G., IL-6 AND TNF-ALPHA) AND THEIR CORRELATIONS WITH SERUM LEVELS OF PROANGIOGENIC MOLECULES (E.G., ENOS, VEGF AND HIF-1ALPHA) AND SEVERAL ADIPOKINES AS WELL AS WITH ENDOTHELIAL DYSFUNCTION, ASSESSED NONINVASIVELY BY REACTIVE HYPERAEMIA PERIPHERAL ARTERY TONOMETRY. BETWEEN MARCH 2021 AND JUNE 2022, 110 PATIENTS WERE ENROLLED INTO THE STUDY: 50 DIABETIC PATIENTS WITH DIABETIC FOOT INJURIES, 40 DIABETIC PATIENTS WITHOUT ULCERATIVE COMPLICATIONS AND 20 NONDIABETIC PATIENTS AS THE CONTROL GROUP. RESULTS: DIABETIC SUBJECTS WITH LOWER LIMB ULCERATIVE LESIONS EXHIBITED HIGHER LEVELS OF INFLAMMATORY CYTOKINES, SUCH AS VEGF (191.40 +/- 200 PG/ML VS. 98.27 +/- 56.92 PG/ML VS. 71.01 +/- 52.96 PG/ML; P = 0.22), HIF-1ALPHA (40.18 +/- 10.80 NG/ML VS. 33.50 +/- 6.16 NG/ML VS. 33.85 +/- 6.84 NG/ML; P = 0.10), AND GREMLIN-1 (1.72 +/- 0.512 NG/ML VS. 1.31 +/- 0.21 NG/ML VS. 1.11 +/- 0.19 NG/ML; P < 0.0005), THAN THOSE WITHOUT LOWER LIMB ULCERS AND HEALTHY CONTROLS. FURTHERMORE, WE OBSERVED THAT MIR-217-5P AND MIR-503-5P WERE 2.19-FOLD (P < 0.05) AND 6.21-FOLD (P = 0.001) MORE HIGHLY EXPRESSED IN DIABETIC FOOT PATIENTS THAN IN HEALTHY CONTROLS, RESPECTIVELY. ADDITIONALLY, DIABETIC PATIENTS WITHOUT LOWER LIMB ULCERATIVE COMPLICATIONS SHOWED 2.41-FOLD (P = 0) AND 2.24-FOLD (P = 0.029) HIGHER EXPRESSION OF MIR-217-5P AND MIR-503-5P, RESPECTIVELY, THAN HEALTHY CONTROLS. FINALLY, DIABETIC PATIENTS WITH AND WITHOUT ULCERATIVE COMPLICATIONS OF THE LOWER LIMBS SHOWED HIGHER EXPRESSION OF THE VEGFC2578A CC POLYMORPHISM (P = 0.001) AND LOWER EXPRESSION OF THE VEGFC2578A AC POLYMORPHISM (P < 0.005) THAN THE HEALTHY CONTROL POPULATION. WE OBSERVED A SIGNIFICANT INCREASE IN GREMLIN-1 LEVELS IN PATIENTS WITH DIABETIC FOOT, SUGGESTING THAT THIS INFLAMMATORY ADIPOKINE MAY SERVE AS A PREDICTIVE MARKER FOR THE DIAGNOSIS OF DIABETIC FOOT. CONCLUSIONS: OUR RESULTS HIGHLIGHTED THAT PATIENTS WITH DIABETIC FOOT SHOWED PREDOMINANT EXPRESSION OF THE VEGF C2578A CC POLYMORPHISM AND REDUCED EXPRESSION OF THE AC ALLELE. ADDITIONALLY, WE FOUND AN OVEREXPRESSION OF MIR-217-5P AND MIR-503-5P IN DIABETIC PATIENTS WITH AND WITHOUT DIABETIC FOOT SYNDROME COMPARED WITH HEALTHY CONTROLS. THESE RESULTS ALIGN WITH THOSE REPORTED IN THE LITERATURE, IN WHICH THE OVEREXPRESSION OF MIR-217-5P AND MIR-503-5P IN THE CONTEXT OF DIABETIC FOOT IS REPORTED. THE IDENTIFICATION OF THESE EPIGENETIC MODIFICATIONS COULD THEREFORE BE HELPFUL IN THE EARLY DIAGNOSIS OF DIABETIC FOOT AND THE TREATMENT OF RISK FACTORS. HOWEVER, FURTHER STUDIES ARE NECESSARY TO CONFIRM THIS HYPOTHESIS.	2023	

2  2149  39 EPIGENETIC MARKERS TO PREDICT CONVERSION FROM GESTATIONAL DIABETES TO TYPE 2 DIABETES. CONTEXT: LIFESTYLE FACTORS MEDIATE EPIGENETIC CHANGES THAT CAN CAUSE CHRONIC DISEASES. ALTHOUGH ANIMAL AND LABORATORY STUDIES LINK EPIGENETIC CHANGES TO DIABETES, EPIGENETIC INFORMATION IN WOMEN WITH GESTATIONAL DIABETES (GDM) AND TYPE 2 DIABETES IS LACKING. OBJECTIVE: THIS STUDY SOUGHT TO MEASURE EPIGENETIC MARKERS ACROSS PREGNANCY AND EARLY POSTPARTUM AND IDENTIFY MARKERS THAT COULD BE USED AS PREDICTORS FOR CONVERSION FROM GDM TO TYPE 2 DIABETES. DESIGN: GLOBAL HISTONE H3 DIMETHYLATION WAS MEASURED IN WHITE BLOOD CELLS AT THREE TIME POINTS: 30 WK GESTATION, 8-10 WK POSTPARTUM, AND 20 WK POSTPARTUM, FROM FOUR GROUPS OF WOMEN WITH AND WITHOUT DIABETES. SETTING AND PARTICIPANTS: A TOTAL OF 39 PARTICIPANTS (SIX TO NINE IN EACH GROUP) WERE RECRUITED INCLUDING: NONDIABETIC WOMEN; WOMEN WITH GDM WHO DEVELOPED POSTPARTUM TYPE 2 DIABETES; WOMEN WITH GDM WITHOUT POSTPARTUM TYPE 2 DIABETES; AND WOMEN WITH TYPE 2 DIABETES. MAIN OUTCOME MEASURE: PERCENTAGES OF DIMETHYLATION OF H3 HISTONES RELATIVE TO TOTAL H3 HISTONE METHYLATION WERE COMPARED BETWEEN DIABETIC/NONDIABETIC GROUPS USING APPROPRIATE COMPARATIVE STATISTICS. RESULTS: H3K27 DIMETHYLATION WAS 50-60% LOWER AT 8-10 AND 20 WK POSTPARTUM IN WOMEN WITH GDM WHO DEVELOPED TYPE 2 DIABETES, COMPARED WITH NONDIABETIC WOMEN. H3K4 DIMETHYLATION WAS 75% LOWER AT 8-10 WK POSTPARTUM IN WOMEN WITH GDM WHO SUBSEQUENTLY DEVELOPED TYPE 2 DIABETES COMPARED WITH WOMEN WHO HAD GDM WHO DID NOT. CONCLUSIONS: THE PERCENTAGE OF DIMETHYLATION OF HISTONES H3K27 AND H3K4 VARIED WITH DIABETIC STATE AND HAS THE POTENTIAL AS A PREDICTIVE TOOL TO IDENTIFY WOMEN WHO WILL CONVERT FROM GDM TO TYPE 2 DIABETES.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3  5108  56 POLYMORPHISMS OF TNF-ALPHA (- 308), IL-1BETA (+ 3954) AND IL1-RA (VNTR) ARE ASSOCIATED TO SEVERE STAGE OF ENDOMETRIOSIS IN MEXICAN WOMEN: A CASE CONTROL STUDY. BACKGROUND: ENDOMETRIOSIS IS AN ESTROGEN-DEPENDENT AND CHRONIC INFLAMMATORY DISEASE AFFECTING UP TO 10% OF WOMEN. IT IS THE RESULT OF A COMBINED INTERACTION OF GENETIC, EPIGENETIC, ENVIRONMENTAL, LIFESTYLE, REPRODUCTIVE AND LOCAL INFLAMMATORY FACTORS. IN THIS STUDY, WE INVESTIGATED WHETHER SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) MAPPING TO TNF-ALPHA (TNF, RS1800629) AND IL-1BETA (IL1B, RS1143634) AND VARIABLE NUMBER TANDEM REPEAT POLYMORPHISM MAPPING TO IL1-RA (IL1RN INTRON 2, RS2234663) GENETIC LOCI ARE ASSOCIATED WITH RISK FOR ENDOMETRIOSIS IN A MEXICAN MESTIZO POPULATION. METHODS: THIS STUDY INCLUDED 183 WOMEN WITH CONFIRMED ENDOMETRIOSIS (ENDO) DIAGNOSED AFTER SURGICAL LAPAROSCOPY AND 186 WOMEN WITH SATISFIED PARITY AND WITHOUT ENDOMETRIOSIS AS CONTROLS (CTR). PCR/RFLP TECHNIQUE WAS USED FOR GENOTYPING SNPS (RS1800629 AND RS1143634); PCR FOR GENOTYPING RS2234663. RESULTS: WE FOUND NO STATISTICAL DIFFERENCES IN AGE BETWEEN GROUPS NOR AMONG STAGES OF ENDOMETRIOSIS AND THE CTR GROUP. WE OBSERVED NO DIFFERENCE IN GENOTYPE AND ALLELE FREQUENCIES, NOR CARRIAGE RATE BETWEEN GROUPS IN NONE OF THE THREE STUDIED POLYMORPHISMS. THE PREVALENCE OF TNF*2-ALLELE HETEROZYGOTES (P = 0.025; OR 3.8), TNF*2-ALLELE (P = 0.029; OR 3.4), IL1B*2-ALLELE HETEROZYGOTES (P = 0.044; OR 2.69) AND ITS CARRIAGE RATE (P = 0.041; OR 2.64) IN ENDOMETRIOSIS STAGE IV WAS HIGHER THAN THE CTR GROUP. SURPRISINGLY, THE CARRIAGE RATE OF IL1RN*2-ALLELE (ENDO: P = 0.0004; OR 0.4; STAGE I: P = 0.002, OR 0.38; STAGE II: P = 0.002, OR 0.35; STAGE III: P = 0.003, OR 0.33), AS WELL AS THE IL1RN*2-ALLELE FREQUENCIES (ENDO: P = 0.0008, OR 0.55; I: P = 0.037, OR 0.60; II: P = 0.002, OR 0.41; III: P = 0.003, OR 0.38) WERE LOWER THAN THE CTR GROUP. WOMEN WITH ENDOMETRIOSIS STAGE IV (SEVERE) HAD FREQUENCIES MORE ALIKE TO THE CTR GROUP IN THE IL1RN*2 ALLELE FREQUENCY (31.2% VS. 27.2%) AND CARRIAGE RATE (37.5% VS. 41.9%). CONCLUSION: ALTHOUGH THESE POLYMORPHISMS ARE NOT ASSOCIATED WITH THE RISK OF ENDOMETRIOSIS, MEXICAN MESTIZO WOMEN WITH SEVERE STAGE OF ENDOMETRIOSIS HAVE HIGHER FREQUENCIES OF TNF*2-, IL1B*2- AND IL1RN*2-ALLELES, WHICH MAY EXPLAIN A POSSIBLE CORRELATION WITH DISEASE SEVERITY RATHER THAN PREDISPOSITION OR RISK.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4  3456  41 HYPOMETHYLATION OF IL1RN AND NFKB1 GENES IS LINKED TO THE DYSBALANCE IN IL1BETA/IL-1RA AXIS IN FEMALE PATIENTS WITH TYPE 2 DIABETES MELLITUS. INFLAMMATION HAS RECEIVED CONSIDERABLE ATTENTION IN THE PATHOGENESIS OF TYPE 2 DIABETES MELLITUS (T2DM). SUPPORTING THIS CONCEPT, ENHANCED EXPRESSION OF INTERLEUKIN (IL)-1BETA AND INCREASED INFILTRATION OF MACROPHAGES ARE OBSERVED IN PANCREATIC ISLETS OF PATIENTS WITH T2DM. ALTHOUGH IL-1 RECEPTOR ANTAGONIST (IL-1RA) PLAYS A MAJOR ROLE IN CONTROLLING OF IL-1BETA-MEDIATED INFLAMMATION, ITS COUNTERACTION EFFECTS AND EPIGENETIC ALTERATIONS IN T2DM ARE LESS STUDIED. THUS, WE AIMED TO ANALYZE THE DNA METHYLATION STATUS IN IL1RN, RELA (P65) AND NFKB1 (P50) GENES IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM TREATED T2DM PATIENTS (N = 35) AND AGE-/SEX- MATCHED HEALTHY CONTROLS (N = 31). PRODUCTION OF IL-1BETA AND IL-1RA WAS ANALYZED IN PLASMA AND SUPERNATANTS FROM LPS-INDUCED PBMCS. IMMUNOMODULATORY EFFECTS OF IL-1BETA AND IL-1RA WERE STUDIED ON THP-1 CELLS. AVERAGE DNA METHYLATION LEVEL OF IL1RN AND NFKB1 GENE PROMOTERS WAS SIGNIFICANTLY DECREASED IN T2DM PATIENTS IN COMPARISON WITH HEALTHY CONTROLS (P< 0.05), WHICH WAS ASSOCIATED WITH THE INCREASED IL-1RA (P< 0.001) AND IL-1BETA (P = 0.039) PLASMA LEVELS IN T2DM PATIENTS. NEGATIVE ASSOCIATION BETWEEN AVERAGE METHYLATION OF IL1RN GENE AND IL-1RA PLASMA LEVELS WERE OBSERVED IN FEMALE T2DM PATIENTS. METHYLATION OF NFKB1 GENE WAS NEGATIVELY CORRELATED WITH IL-1RA LEVELS IN THE PATIENTS AND POSITIVELY WITH IL-1BETA LEVELS IN FEMALE PATIENTS. LPS-STIMULATED PBMCS FROM FEMALE PATIENTS FAILED TO RAISE IL-1BETA PRODUCTION, WHILE THE CELLS FROM HEALTHY FEMALES INCREASED IL-1BETA PRODUCTION IN COMPARISON WITH UNSTIMULATED CELLS (P< 0.001). TAKEN TOGETHER, THE FINDINGS SUGGEST THAT HYPOMETHYLATION OF IL1RN AND NFKB1 GENE PROMOTERS MAY PROMOTE THE INCREASED IL-1BETA/IL-1RA PRODUCTION AND REGULATE CHRONIC INFLAMMATION IN T2DM. FURTHER STUDIES ARE NECESSARY TO ELUCIDATE THE CAUSAL DIRECTION OF THESE ASSOCIATIONS AND POTENTIAL ROLE OF IL-1RA IN ANTI-INFLAMMATORY PROCESSES IN TREATED PATIENTS WITH T2DM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
5  1189  58 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
6  3294  48 HIGH INCIDENCE OF MGMT AND RARBETA PROMOTER METHYLATION IN PRIMARY GLIOBLASTOMAS: ASSOCIATION WITH HISTOPATHOLOGICAL CHARACTERISTICS, INFLAMMATORY MEDIATORS AND CLINICAL OUTCOME. GLIOBLASTOMAS, THE MOST FREQUENT PRIMARY BRAIN TUMORS IN ADULTS, ARE CHARACTERIZED BY A HIGHLY AGGRESSIVE, INFLAMMATORY AND ANGIOGENIC PHENOTYPE. METHYLATION OF CPG ISLANDS IN CANCER-RELATED GENES MAY SERVE AS AN EPIGENETIC BIOMARKER FOR GLIOBLASTOMA DIAGNOSIS AND PROGNOSIS. THE AIM OF THIS STUDY WAS TO ANALYZE THE METHYLATION STATUS OF FOUR CRITICAL TUMOR-ASSOCIATED GENES (MGMT, RARBETA, RASSF1A, CDH13), AND INVESTIGATE POSSIBLE LINKS WITH INFLAMMATORY (INTERLEUKIN [IL]-6, IL-8) AND ANGIOGENIC MEDIATORS (VASCULAR ENDOTHELIAL GROWTH FACTOR [VEGF], CYCLOOXYGENASE [COX]-2) AND CLINICAL OUTCOME IN 23 GLIOMA SAMPLES (6 GRADE II ASTROCYTOMAS, 17 GRADE IV GLIOBLASTOMAS). RARBETA AND MGMT GENES WERE MORE FREQUENTLY METHYLATED IN 70.58% AND 58.8% OF GLIOBLASTOMAS, RESPECTIVELY. RASSF1A AND CDH13 DISPLAYED A SIMILAR METHYLATION FREQUENCY (23.52%) IN GLIOBLASTOMAS. NO GENE METHYLATION WAS OBSERVED IN GRADE II ASTROCYTOMAS. TUMOR GRADE CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION (P = 0.005 AND P = 0.019, RESPECTIVELY) AND THE EXTENT OF NECROSIS (P = 0.001 AND P = 0.003). INTERESTINGLY, THE MARKER OF CHRONIC INFLAMMATION, IL-6, WAS POSITIVELY ASSOCIATED WITH METHYLATION OF MGMT (P = 0.004), RARBETA (P = 0.002), AND RASSF1A (P = 0.0081) AS WELL AS THE TOTAL NUMBER OF METHYLATED GENES (P < 0.0001), INDICATING THE IMPORTANT ROLE OF IL-6 IN MAINTAINING PROMOTER METHYLATION OF THESE GENES. VEGF EXPRESSION CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION ALTHOUGH THESE RELATIONSHIPS WERE OF MARGINAL SIGNIFICANCE (P = 0.0679 AND P = 0.0757). KAPLAN-MEIER UNIVARIATE SURVIVAL ANALYSIS INDICATED AN UNFAVORABLE SURVIVAL PERIOD IN PATIENTS WITH MGMT METHYLATION COMPARED WITH THOSE WITHOUT METHYLATION (P = 0.0474). OUR STUDY HIGHLIGHTS THE IMPLICATION OF MGMT AND RARBETA METHYLATION IN THE AGGRESSIVE PHENOTYPE OF PRIMARY GLIOBLASTOMAS. THE ASSOCIATION OF MGMT METHYLATION WITH CLINICAL OUTCOME INDICATES ITS POTENTIAL PROGNOSTIC VALUE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
7  3460  39 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
8  3624  45 IN VIVO FUNCTION OF FLOW-RESPONSIVE CIS-DNA ELEMENTS OF ENOS GENE: A ROLE FOR CHROMATIN-BASED MECHANISMS. BACKGROUND: ENOS (ENDOTHELIAL NITRIC OXIDE SYNTHASE) IS AN ENDOTHELIAL CELL (EC)-SPECIFIC GENE PREDOMINANTLY EXPRESSED IN MEDIUM- TO LARGE-SIZED ARTERIES WHERE ECS EXPERIENCE ATHEROPROTECTIVE LAMINAR FLOW WITH HIGH SHEAR STRESS. DISTURBED FLOW WITH LOWER AVERAGE SHEAR STRESS DECREASES ENOS TRANSCRIPTION, WHICH LEADS TO THE DEVELOPMENT OF ATHEROSCLEROSIS, ESPECIALLY AT BIFURCATIONS AND CURVATURES OF ARTERIES. THIS PROTOTYPIC ARTERIAL EC GENE CONTAINS 2 DISTINCT FLOW-RESPONSIVE CIS-DNA ELEMENTS IN THE PROMOTER, THE SHEAR STRESS RESPONSE ELEMENT (SSRE) AND THE KLF (KRUPPEL-LIKE FACTOR) ELEMENT. PREVIOUS IN VITRO STUDIES SUGGESTED THEIR POSITIVE REGULATORY FUNCTIONS ON FLOW-INDUCED TRANSCRIPTION OF EC GENES INCLUDING ENOS. HOWEVER, THE IN VIVO FUNCTION OF THESE CIS-DNA ELEMENTS REMAINS UNKNOWN. METHODS: INSERTIONAL TRANSGENIC MICE WITH A MUTATION AT EACH FLOW-RESPONSIVE CIS-DNA ELEMENT WERE GENERATED USING A MURINE ENOS PROMOTER-BETA-GALACTOSIDASE REPORTER BY LINKER-SCANNING MUTAGENESIS AND COMPARED WITH EPISOMAL-BASED MUTATIONS IN VITRO. DNA METHYLATION AT THE ENOS PROXIMAL PROMOTER IN MOUSE ECS WAS ASSESSED BY BISULFITE SEQUENCING OR PYROSEQUENCING. RESULTS: WILD TYPE MICE WITH A FUNCTIONAL ENOS PROMOTER-REPORTER TRANSGENE EXHIBITED REDUCED ENDOTHELIAL REPORTER EXPRESSION IN THE ATHEROPRONE REGIONS OF DISTURBED FLOW (N=5). IT IS SURPRISING THAT THE SSRE MUTATION ABROGATED REPORTER EXPRESSION IN ECS AND WAS ASSOCIATED WITH ABERRANT HYPERMETHYLATION AT THE ENOS PROXIMAL PROMOTER (N=7). REPORTER GENE SILENCING WAS INDEPENDENT OF TRANSGENE COPY NUMBER AND INTEGRATION POSITION, INDICATING THAT THE SSRE IS A CRITICAL CIS-ELEMENT NECESSARY FOR ENOS TRANSCRIPTION IN VIVO. THE KLF MUTATION DEMONSTRATED AN INTEGRATION SITE-SPECIFIC DECREASE IN ENOS TRANSCRIPTION, AGAIN WITH MARKED PROMOTER METHYLATION (N=8), SUGGESTING THAT THE SSRE ALONE IS NOT SUFFICIENT FOR ENOS TRANSCRIPTION IN VIVO. IN WILD TYPE MICE, THE NATIVE ENOS PROMOTER WAS SIGNIFICANTLY HYPERMETHYLATED IN ECS FROM THE ATHEROPRONE REGIONS WHERE ENOS EXPRESSION WAS MARKEDLY REPRESSED BY CHRONIC DISTURBED FLOW, DEMONSTRATING THAT ENOS EXPRESSION IS REGULATED BY FLOW-DEPENDENT DNA METHYLATION THAT IS REGION-SPECIFIC IN THE ARTERIAL ENDOTHELIUM IN VIVO. CONCLUSIONS: WE REPORT, FOR THE FIRST TIME, THAT THE SSRE AND KLF ELEMENTS ARE CRITICAL FLOW SENSORS NECESSARY FOR A TRANSCRIPTIONALLY PERMISSIVE, HYPOMETHYLATED ENOS PROMOTER IN ECS UNDER CHRONIC SHEAR STRESS IN VIVO. MOREOVER, ENOS EXPRESSION IS REGULATED BY FLOW-DEPENDENT EPIGENETIC MECHANISMS, WHICH OFFERS NOVEL MECHANISTIC INSIGHT ON ENOS GENE REGULATION IN ATHEROGENESIS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
9  4349  41 MIR-155 AND MIR-122 EXPRESSION OF SPERMATOZOA IN OBESE SUBJECTS. OBESITY IS CHARACTERIZED BY MILD CHRONIC INFLAMMATION THAT IS LINKED WITH IMPAIRED IRON HOMEOSTASIS. STUDIES IN HUMAN AND MURINE SHOW THAT THERE IS A TRANSGENERATIONAL EPIGENETIC INHERITANCE VIA THE GAMETES IN OBESITY; HOWEVER, THERE IS LITTLE INFORMATION ON CHANGES IN THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION AND IRON HOMEOSTASIS IN SPERMATOZOA FROM OBESE SUBJECTS. THE PRESENT STUDY INVESTIGATED THE EXPRESSION OF MICRORNAS RELATED TO INFLAMMATION (MIR-21 Y MIR-155) AND IRON NUTRITION (MIR-122 AND MIR-200B) IN PLASMA, PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC) AND SPERMATOZOA FROM NORMOZOOSPERMIC CONTROLS (CN; N = 17; BMI: 24.6 +/- 2.0) AND OBESE (OB; N = 17; BMI: 32.6 +/- 4.4) MEN. TO DETERMINE THE INFLAMMATION LEVELS, WE MEASURED IL-6, TNF-ALPHA, AND MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP1) BY MAGNETIC LUMINEX((R)) ASSAY. MRNA EXPRESSION OF IL6, TNF-ALPHA, AND HEPCIDIN (HAMP) IN PBMC WERE EVALUATED BY RT-QPCR. THE ANALYSIS OF MICRORNAS WAS PERFORMED USING THE TAQMAN((R)) ASSAYS. THE IRON CONTENT IN PBMC, SEMINAL PLASMA, AND SPERMATOZOA WAS DETERMINED BY INDUCTIVELY COUPLED PLASMA MASS SPECTROMETRY (ICP-MS). HIGH SERUM IL6, TNF-ALPHA, AND MCP1 LEVELS WERE OBSERVED IN OB GROUP (P < 0.05). GENE EXPRESSION ANALYSIS SHOWED AN INCREASED ABUNDANCE RELATIVE OF TNF-ALPHA (P = 0.018), HAMP (P = 0.03), AND IL6 (P = 0.02) IN PBMC FROM OBESE SUBJECTS. ALSO, WE OBSERVED HIGH LEVELS OF SERUM FERRITIN (P = 0.03), IRON CONTENT IN SEMINAL PLASMA (P = 0.04), AND SPERMATOZOA (P = 0.002), BUT LOWER SERUM FE (P = 0.007) IN OBESE SUBJECTS. IN THE OB GROUP, A HIGH EXPRESSION OF MIR-155 (P = 0.02) AND MIR-21 (P = 0.03) WAS OBSERVED IN PBMC AND MIR-122 (P = 0.03) IN PLASMA. IN SPERM, BOTH MIR-155 (P = 0.004) AND MIR-122 (P = 0.028) WERE HIGH IN THE OB GROUP. OUR RESULTS SHOWED THAT OBESE SUBJECTS HAVE INCREASED EXPRESSIONS OF MIR-155 AND MIR-122, TWO MICRORNAS THAT WERE PREVIOUSLY RELATED WITH INFLAMMATION AND IRON METABOLISM, RESPECTIVELY, AT BOTH THE SYSTEMIC AND SPERM LEVELS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  6415  40 THE STUDY OF P16 AND P15 GENE METHYLATION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA AND THEIR QUANTITATIVE EVALUATION IN PLASMA BY REAL-TIME PCR. EPIGENETIC SILENCING OF THE P16 AND P15 GENES BY PROMOTER METHYLATION ARE COMMONLY OBSERVED IN HUMAN EPITHELIAL MALIGNANCIES, INCLUDING HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC). IN THIS STUDY, A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) WAS USED TO EVALUATE THE METHYLATION STATUS OF THE P16 AND P15 GENES IN 73 HNSCC SURGICAL SPECIMENS. P16 AND P15 GENE METHYLATION WAS ALSO EXAMINED IN 29 PAIRED METASTATIC LYMPH NODES AND 29 PAIRED HISTOLOGICALLY, NORMAL RESECTION MARGIN MUCOSAE. THE QUANTITY OF CELL-FREE METHYLATED P16 AND P15 DNA IN THE PLASMA SAMPLES OF 20 HNSCC PATIENTS AND 24 HEALTHY CONTROLS WAS ALSO EXAMINED USING A FLUORESCENCE-BASED REAL-TIME PCR ASSAY. THE FREQUENCIES OF P16 AND P15 METHYLATION IN THE PRIMARY TUMOUR WERE 49% AND 60%, RESPECTIVELY. CONCORDANT METHYLATION OF P16 AND P15 IN TUMOUR SAMPLES AND METASTATIC LYMPH NODES WAS FOUND IN 59 AND 38% OF CASES, RESPECTIVELY. A SIGNIFICANTLY HIGHER PREVALENCE OF P15 METHYLATION WAS FOUND IN HISTOLOGICALLY-NORMAL SURGICAL MARGIN EPITHELIA OF HNSCC PATIENTS WITH CHRONIC SMOKING AND DRINKING HABITS COMPARED WITH NON-SMOKERS AND NON-DRINKERS. IN ADDITION, METHYLATED P16 AND P15 DNA LEVELS WERE SIGNIFICANTLY HIGHER IN THE PLASMA OF HNSCC PATIENTS (MEAN 56 COPIES/ML PLASMA AND 65 COPIES/ML PLASMA, RESPECTIVELY) COMPARED WITH NORMAL CONTROLS (MEAN 6 COPIES/ML PLASMA AND 16 COPIES/ML PLASMA, RESPECTIVELY). IN CONCLUSION, PROMOTER METHYLATION OF THE P16 AND P15 GENES IS INVOLVED IN THE PATHOGENESIS OF HNSCC AND MAY BE RELATED TO CHRONIC SMOKING AND DRINKING. THE DIFFERENTIAL LEVELS OF METHYLATED P16 AND P15 DNA IN PLASMA MIGHT BE POTENTIAL USEFUL MARKERS IN SCREENING HIGH-RISK POPULATIONS FOR EARLY HNSCC AND MONITORING THEIR TREATMENT RESPONSE.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
11   352  51 ALTERED GENE EXPRESSION OF VEGF, IGFS AND H19 LNCRNA AND EPIGENETIC PROFILE OF H19-DMR REGION IN ENDOMETRIAL TISSUES OF WOMEN WITH ENDOMETRIOSIS. BACKGROUND: ENDOMETRIOSIS, AS CHRONIC ESTROGEN-DEPENDENT DISEASE, IS DEFINED BY THE PRESENCE OF ENDOMETRIAL-LIKE TISSUE OUTSIDE THE UTERUS. PROLIFERATION OF ENDOMETRIAL TISSUE AND NEOANGIOGENESIS ARE CRITICAL FACTORS IN DEVELOPMENT OF ENDOMETRIOSIS. HENCE, VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) AS WELL AS INSULIN-LIKE GROWTH FACTOR 1 AND 2 (IGF1, 2) MAY BE INVOLVED AS INDUCERS OF CELLULAR PROLIFERATION OR NEOANGIOGENESIS. IMPRINTED LONG NONCODING RNA H19 (LNCRNA H19) HAS BEEN SUGGESTED TO BE INVOLVED IN PATHOGENESIS OF ENDOMETRIOSIS VIA REGULATION OF CELLULAR PROLIFERATION AND DIFFERENTIATION. EPIGENETIC ABERRATIONS APPEAR TO PLAY AN IMPORTANT ROLE IN ITS PATHOGENESIS. THE PRESENT STUDY WAS DESIGNED TO ELUCIDATE VEGF, IGF1, IGF2 AND H19 LNCRNA GENES EXPRESSION AND EPIGENETIC ALTERATIONS OF DIFFERENTIALLY METHYLATED REGION (DMR) OF H19 (H19-DMR) REGULATORY REGION IN ENDOMETRIAL TISSUES OF PATIENTS WITH ENDOMETRIOSIS, IN COMPARISON WITH CONTROL WOMEN. METHODS: IN THIS CASE-CONTROL STUDY, 24 WOMEN WITH AND WITHOUT ENDOMETRIOSIS WERE STUDIED FOR THE RELATIVE EXPRESSION OF VEGF, IGF1, IGF2 AND H19 LNCRNA GENES USING REAL-TIME POLYMERASE CHAIN REACTION (PCR) TECHNIQUE. OCCUPANCY OF THE MECP2 ON DMR REGION OF H19 GENE WAS ASSESSED USING CHROMATIN IMMUNOPRECIPITATION (CHIP), FOLLOWED BY REAL-TIME PCR. RESULTS: GENES EXPRESSION PROFILE OF H19, IGF1 AND IGF2 WAS DECREASED IN EUTOPIC AND ECTOPIC ENDOMETRIAL TISSUES OF ENDOMETRIOSIS GROUP, COMPARED TO THE CONTROL TISSUES. DECREASED EXPRESSION OF H19 IN ECTOPIC SAMPLES WAS SIGNIFICANT IN COMPARISON WITH THE CONTROLS (P < 0.05). GENE EXPRESSION OF VEGF WAS INCREASED IN EUTOPIC TISSUES OF ENDOMETRIOSIS GROUP, COMPARED TO CONTROL GROUP. WHEREAS ITS EXPRESSION LEVEL WAS LOWER IN ECTOPIC LESIONS VERSUS EUTOPIC AND CONTROL ENDOMETRIAL SAMPLES. CHIP ANALYSIS REVEALED SIGNIFICANT AND NEARLY SIGNIFICANT HYPOMETHYLATION OF H19-DMR REGION II IN EUTOPIC AND ECTOPIC SAMPLES, COMPARED TO THE CONTROL GROUP RESPECTIVELY. THIS EPIGENETIC CHANGE WAS ALIGNED WITH EXPRESSION OF IGF2. WHILE METHYLATION OF H19-DMR REGION I WAS NOT SIGNIFICANTLY DIFFERENT BETWEEN THE EUTOPIC, ECTOPIC AND CONTROL ENDOMETRIAL SAMPLES. CONCLUSION: THESE DATA SHOWED THAT VEGF, IGF1, IGF2 AND H19 LNCRNA GENES EXPRESSION AND EPIGENETIC ALTERATIONS OF H19 LNCRNA HAVE DYNAMIC ROLE IN THE PATHOGENESIS OF ENDOMETRIOSIS, SPECIFICALLY IN THE WAY THAT HYPOMETHYLATION OF H19-DMR REGION II CAN BE INVOLVED IN IGF2 DYSREGULATION IN ENDOMETRIOSIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
12  3941  34 LNCRNA DRAIR IS DOWNREGULATED IN DIABETIC MONOCYTES AND MODULATES THE INFLAMMATORY PHENOTYPE VIA EPIGENETIC MECHANISMS. LONG NONCODING RNAS (LNCRNAS) ARE INCREASINGLY IMPLICATED IN THE PATHOLOGY OF DIABETIC COMPLICATIONS. HERE, WE EXAMINED THE ROLE OF LNCRNAS IN MONOCYTE DYSFUNCTION AND INFLAMMATION ASSOCIATED WITH HUMAN TYPE 2 DIABETES MELLITUS (T2D). RNA SEQUENCING ANALYSIS OF CD14+ MONOCYTES FROM PATIENTS WITH T2D VERSUS HEALTHY CONTROLS REVEALED DOWNREGULATION OF ANTIINFLAMMATORY AND ANTIPROLIFERATIVE GENES, ALONG WITH SEVERAL LNCRNAS, INCLUDING A POTENTIALLY NOVEL DIVERGENT LNCRNA DIABETES REGULATED ANTIINFLAMMATORY RNA (DRAIR) AND ITS NEARBY GENE CPEB2. HIGH GLUCOSE AND PALMITIC ACID DOWNREGULATED DRAIR IN CULTURED CD14+ MONOCYTES, WHEREAS ANTIINFLAMMATORY CYTOKINES AND MONOCYTE-TO-MACROPHAGE DIFFERENTIATION UPREGULATED DRAIR VIA KLF4 TRANSCRIPTION FACTOR. DRAIR OVEREXPRESSION INCREASED ANTIINFLAMMATORY AND MACROPHAGE DIFFERENTIATION GENES BUT INHIBITED PROINFLAMMATORY GENES. CONVERSELY, DRAIR KNOCKDOWN ATTENUATED ANTIINFLAMMATORY GENES, PROMOTED INFLAMMATORY RESPONSES, AND INHIBITED PHAGOCYTOSIS. DRAIR REGULATED TARGET GENE EXPRESSION THROUGH INTERACTION WITH CHROMATIN, AS WELL AS INHIBITION OF THE REPRESSIVE EPIGENETIC MARK H3K9ME2 AND ITS CORRESPONDING METHYLTRANSFERASE G9A. MOUSE ORTHOLOGOUS DRAIR AND CPEB2 WERE ALSO DOWNREGULATED IN PERITONEAL MACROPHAGES FROM T2D DB/DB MICE, AND DRAIR KNOCKDOWN IN NONDIABETIC MICE ENHANCED PROINFLAMMATORY GENES IN MACROPHAGES. THUS, DRAIR MODULATES THE INFLAMMATORY PHENOTYPE OF MONOCYTES/MACROPHAGES VIA EPIGENETIC MECHANISMS, AND ITS DOWNREGULATION IN T2D MAY PROMOTE CHRONIC INFLAMMATION. AUGMENTATION OF ENDOGENOUS LNCRNAS LIKE DRAIR COULD SERVE AS NOVEL ANTIINFLAMMATORY THERAPIES FOR DIABETIC COMPLICATIONS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13  1785  33 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14   401  50 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15  2759  46 EXPRESSION OF IL-17 AND ITS GENE PROMOTER METHYLATION STATUS ARE ASSOCIATED WITH THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS INFECTION. TO EXPLORE INTERLEUKIN-17 (IL-17) AND ITS EPIGENETIC REGULATION DURING THE PROGRESSION OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION.A TOTAL OF 162 PATIENTS WITH CHRONIC HBV INFECTION, INCLUDING 75 WITH CHRONIC HEPATITIS B (CHB), 54 WITH HEPATITIS B-ASSOCIATED LIVER CIRRHOSIS AND 33 WITH HEPATITIS B-ASSOCIATED HEPATOCELLULAR CARCINOMA (HBV-HCC), WERE ENROLLED IN THIS STUDY. THIRTY HEALTHY ADULTS OF THE SAME ETHNICITY WERE ENROLLED IN THE CONTROL GROUP. WHOLE VENOUS BLOOD WAS OBTAINED FROM THE PATIENTS AND NORMAL CONTROLS (N = 30). CLINICAL AND LABORATORY PARAMETERS WERE ASSESSED, AND WE PERFORMED ENZYME-LINKED IMMUNOSORBENT ASSAY AND QUANTITATIVE REAL-TIME PCR TO MEASURE THE SERUM LEVELS AND RELATIVE MRNA EXPRESSION OF IL-17, RESPECTIVELY. IL-17 PROMOTER METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS WAS ASSESSED BY METHYLATION-SPECIFIC PCR. WE ANALYZED THE SERUM AND MRNA LEVELS OF IL-17 AND IL-17 PROMOTER METHYLATION IN THE 4 GROUPS AS WELL AS THE EFFECT OF METHYLATION ON SERUM IL-17 LEVELS. CORRELATIONS BETWEEN THE IL-17 PROMOTER METHYLATION STATUS AND CLINICAL PARAMETERS WERE ANALYZED BY SPEARMAN CORRELATION ANALYSIS.COMPARED TO THE NORMAL CONTROL GROUP, THE PATIENT GROUPS EXHIBITED SIGNIFICANTLY HIGHER SERUM AND RELATIVE MRNA LEVELS OF IL-17. THE METHYLATION DISTRIBUTION AMONG THE PATIENTS WAS SIGNIFICANTLY LOWER THAN THAT AMONG THE NORMAL CONTROLS (P < .05), WITH THE HBV-HCC GROUP SHOWING THE LOWEST IL-17 GENE METHYLATION FREQUENCY. THE AVERAGE IL-17 PROMOTER CG METHYLATION LEVEL WAS NEGATIVELY CORRELATED WITH IL-17 MRNA EXPRESSION (R = -0.39, P = .03), AND NEGATIVE CORRELATIONS BETWEEN IL-17 PROMOTER METHYLATION AND PROTHROMBIN TIME ACTIVITY (R = -0.585, P = .035), ALANINE AMINOTRANSFERASE (R = -0.522, P < .01), ASPARTATE AMINOTRANSFERASE (R = -0.315, P < .05), AND THE MODEL FOR END-STAGE LIVER DISEASE SCORE (R = -0.461, P < .05) WERE OBSERVED. IL-17 SERUM LEVELS IN THE METHYLATED-PROMOTER GROUPS WERE SIGNIFICANTLY LOWER THAN THOSE IN THE UNMETHYLATED-PROMOTER GROUPS.IL-17 EXPRESSION AND PROMOTER METHYLATION WERE ASSOCIATED WITH CHRONIC HBV INFECTION PROGRESSION, ESPECIALLY IN THE HBV-HCC GROUP. THE IL-17 PROMOTER STATUS MAY HELP CLINICIANS INITIATE THE CORRECT TREATMENT STRATEGY AT THE CHB STAGE.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16  6589  43 TUMOR NECROSIS FACTOR-ALPHA GENE PROMOTER METHYLATION IN JAPANESE ADULTS WITH CHRONIC PERIODONTITIS AND RHEUMATOID ARTHRITIS. BACKGROUND AND OBJECTIVE: OVER-EXPRESSION OF TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA) PLAYS A PATHOLOGICAL ROLE IN CHRONIC PERIODONTITIS (CP) AND RHEUMATOID ARTHRITIS (RA), WHICH MIGHT BE REGULATED BY THE EPIGENETIC MECHANISM. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE WHETHER THERE IS A UNIQUE METHYLATION PROFILE OF THE TNF-ALPHA GENE PROMOTER IN BLOOD CELLS OF INDIVIDUALS WITH CP AND RA. MATERIAL AND METHODS: THE STUDY PARTICIPANTS CONSISTED OF 30 JAPANESE ADULTS WITH RA (RA GROUP), 30 RACE-MATCHED ADULTS WITH CP ONLY (CP GROUP) AND 30 RACE-MATCHED HEALTHY CONTROLS (H GROUP). GENOMIC DNA ISOLATED FROM PERIPHERAL BLOOD WAS MODIFIED BY SODIUM BISULFITE AND ANALYZED, BY DIRECT SEQUENCING, TO INVESTIGATE DNA METHYLATION OF THE TNF-ALPHA GENE PROMOTER REGION. THE LEVEL OF TNF-ALPHA PRODUCED IN MONONUCLEAR CELLS STIMULATED WITH PORPHYROMONAS GINGIVALIS LIPOPOLYSACCHARIDE WAS DETERMINED USING ELISA. RESULTS: TWELVE CYTOSINE-GUANINE DINUCLEOTIDE (CPG) MOTIFS WERE IDENTIFIED IN THE TNF-ALPHA PROMOTER FRAGMENT FROM -343 TO +57 BP. THE CP GROUP SHOWED A SIGNIFICANTLY HIGHER METHYLATION RATE AND FREQUENCY AT -72 BP THAN THE H GROUP (P < 0.01). THE RA GROUP EXHIBITED SIGNIFICANTLY HIGHER METHYLATION RATES AT SEVEN CPG MOTIFS (-302, -163, -119, -72, -49, -38 AND +10 BP), AND SIGNIFICANTLY HIGHER METHYLATION FREQUENCIES AT SIX CPG MOTIFS (-163, -119, -72, -49, -38 AND +10 BP), THAN THE H GROUP (P < 0.01 FOR ALL COMPARISONS). THE LEVELS OF TNF-ALPHA PRODUCED WERE SIGNIFICANTLY DIFFERENT BETWEEN INDIVIDUALS WITH AND WITHOUT METHYLATION AT -163 BP (P = 0.03). CONCLUSION: THESE RESULTS SUGGEST THAT THE HYPERMETHYLATED STATUS OF CPG MOTIFS IN THE TNF-ALPHA GENE PROMOTER IN BLOOD CELLS MAY BE UNIQUE TO JAPANESE ADULTS WITH CP AND RA.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  5118  45 POSSIBLE ASSOCIATION BETWEEN GERMLINE METHYLENETETRAHYDROFOLATE REDUCTASE GENE POLYMORPHISMS AND PSORIASIS RISK IN A TURKISH POPULATION. BACKGROUND: PSORIASIS IS A COMMON CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY GENETIC AND EPIGENETIC FACTORS. THERE ARE CONFLICTING RESULTS IN THE LITERATURE ABOUT THE ASSOCIATION BETWEEN PSORIASIS AND THE METHYLENETETRAHYDROFOLATE REDUCTASE GENE (MTHFR), RANGING FROM STRONG LINKAGE TO NO ASSOCIATION. AIM: TO INVESTIGATE THE ASSOCIATION BETWEEN THE GERMLINE MTHFR POLYMORPHISMS C677T AND A1298C WITH PSORIASIS RISK IN A TURKISH POPULATION. METHODS: THE STUDY ENROLLED 84 PATIENTS WITH PSORIASIS AND 212 HEALTHY CONTROLS (HCS) WITHOUT ANY HISTORY OF PSORIASIS. DNA WAS EXTRACTED FROM PERIPHERAL BLOOD SAMPLES OF PATIENTS AND HCS, AND REAL-TIME PCR WAS USED FOR GENOTYPING. RESULTS WERE COMPARED BY PEARSON CHI(2) TEST AND MULTIPLE LOGISTIC REGRESSION MODELS. RESULTS: THE FREQUENCY OF BOTH THE MTHFR 677TT AND A1298C (HOMOZYGOUS) GENOTYPES WAS STATISTICALLY SIGNIFICANTLY DIFFERENT FROM HCS. POINT MUTATIONS WERE DETECTED IN ALL PATIENTS WITH EARLY-ONSET PSORIASIS (BEFORE THE AGE OF 20 YEARS). THE T ALLELE OF MTHFR 677 AND THE C ALLELE OF MTHFR 1298 INCREASED PSORIASIS RISK BY 12.4- AND 17.0-FOLD, RESPECTIVELY, IN PATIENTS COMPARED WITH HCS. CONCLUSION: A POSSIBLE ASSOCIATION WAS DETECTED BETWEENGERMLINE MTHFR 677 C>T AND 1298 A>C GENOTYPES AND PSORIASIS RISK IN A TURKISH POPULATION. THESE RESULTS NEED TO BE CONFIRMED IN FURTHER STUDIES WITH LARGER SAMPLE SIZES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  3046  41 GENOME-WIDE ANALYSIS OF DNA METHYLATION IDENTIFIES S100A13 AS AN EPIGENETIC BIOMARKER IN INDIVIDUALS WITH CHRONIC (>/= 30 YEARS) TYPE 2 DIABETES WITHOUT DIABETIC RETINOPATHY. BACKGROUND: THIS STUDY AIMED TO DETERMINE THE EPIGENETIC BIOMARKERS OF DIABETIC RETINOPATHY (DR) IN SUBJECTS WITH TYPE 2 DIABETES MELLITUS (T2DM). THIS RETROSPECTIVE STUDY IS BASED ON THE SHANGHAI XINJING COMMUNITY PREVENTION AND TREATMENT ADMINISTRATIVE SYSTEM OF CHRONIC DISEASES. THE SUBJECTS ENROLLED HEREIN WERE T2DM PATIENTS WHO HAD UNDERGONE LONG-TERM FOLLOW-UP EVALUATION IN THE SYSTEM. TWO CONSECUTIVE STUDIES WERE CONDUCTED. IN THE DISCOVERY COHORT, AMONG 19 SUBJECTS WHO HAD DEVELOPED DR WITH A DM DURATION < 3 YEARS AND 21 SUBJECTS WITHOUT DR > 30 YEARS AFTER BEING DIAGNOSED WITH DM, AN INFINIUM HUMAN METHYLATION 850 BEADCHIP WAS USED TO IDENTIFY DIFFERENTIAL METHYLATION REGIONS (DMRS) AND DIFFERENTIAL METHYLATION SITES (DMSS). THE FUNCTION OF THE GENES WAS ASSESSED THROUGH KEGG ENRICHMENT ANALYSIS, GENE ONTOLOGY (GO) ANALYSIS, AND PATHWAY NETWORK ANALYSIS. IN THE REPLICATION COHORT, 87 DR PATIENTS WITH A SHORT DM DURATION AND 89 PATIENTS WITHOUT DR OVER A DM DURATION > 20 YEARS WERE COMPARED TO ASSESS THE ASSOCIATION BETWEEN DMSS AND DR UPON PYROSEQUENCING. RESULTS: A TOTAL OF 34 DMRS WERE IDENTIFIED. GENES CONTAINING DMSS WITH THE TOP 5 HIGHEST BETA VALUE DIFFERENCES BETWEEN DR AND NON-DR PARTICIPANTS WERE LOCATED ON CHROMOSOME 1 AND WERE PRESENT IN THE S100A13 GENE, WHICH WAS ASSOCIATED WITH 71 GO TERMS. TWO S100A13 GENE SITES, I.E., CG02873163 AND CG11343894, DISPLAYED A GOOD CORRELATION WITH DR ON PYROSEQUENCING. CONCLUSIONS: DMSS IN THE S100A13 GENE MAY BE POTENTIAL BIOMARKERS OF DR.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  4234  49 METHYLATION OF SPECIFIC CPG SITES IN IL-1BETA AND IL1R1 GENES IS AFFECTED BY HYPERGLYCAEMIA IN TYPE 2 DIABETIC PATIENTS. OBJECTIVE: TYPE 2 DIABETES (T2D), WHICH IS THE MOST COMMON METABOLIC DISORDER IN THE WORLD, RESULTS FROM INSULIN RESISTANCE OF TARGET TISSUES AND REDUCED PRODUCTION OF INSULIN FROM PANCREATIC BETA CELLS WITH GENETIC AND ENVIRONMENTAL FACTORS BOTH PLAYING ROLES IN THE PATHOGENESIS. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EFFECT OF BLOOD GLUCOSE LEVELS ON DNA METHYLATION OF IL-1BETA AND IL1R1 GENES IN THE PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF NON-DIABETIC, TYPE 2 PRE-DIABETIC AND DIABETIC INDIVIDUALS.METHODS: IN THIS CASE-CONTROL STUDY, 54 NON-DIABETIC, PRE-DIABETIC AND TYPE 2 DIABETIC INDIVIDUALS WERE ENROLLED AND CATEGORIZED BASED ON THEIR FASTING PLASMA GLUCOSE (FPG) AND GLYCATED HEMOGLOBIN (A1C) LEVELS. DNA WAS EXTRACTED FROM PBMCS AND SUBJECTED TO BISULFITE TREATMENT. THE METHYLATION STATUS OF TWO CPG SITES IN THE IL-1BETA GENE AND THREE CPG SITES IN IL1R1 GENE WAS THEN DETERMINED USING SANGER SEQUENCING.RESULTS: OUR RESULTS SHOW THAT THE METHYLATION OF IL-1BETA GENE IS DECREASED AND THE METHYLATION OF IL1R1 GENE IS INCREASED IN DIABETIC INDIVIDUALS WITH HYPERGLYCEMIA. FURTHER ANALYSIS REVEALED THAT BOTH CPG SITES IN IL-1BETA GENE ARE AFFECTED BY HYPERGLYCEMIA AND DISPLAY DECREASED METHYLATION WHILE ONLY ONE CPG SITE IN IL1R1 GENE IS AFFECTED BY HYPERGLYCEMIA.CONCLUSION: WE PROPOSE THAT THE DNA METHYLATION STATUS OF THE CPG SITES CG18773937 AND CG23149881 IN IL-1BETA GENE AND THE CPG SITE CG13399261 IN IL1R1 GENE COULD SERVE AS AN EPIGENETIC MARKER OF CHRONIC INFLAMMATION AND T2D DEVELOPMENT. THESE CPG SITES CAN ALSO BE CONSIDERED FOR STUDIES ON METABOLIC MEMORY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
20  3783  36 INTERFERON-GAMMA PROMOTER HYPOMETHYLATION AND INCREASED EXPRESSION IN CHRONIC PERIODONTITIS. AIM: THE GOAL OF THIS INVESTIGATION WAS TO DETERMINE WHETHER EPIGENETIC MODIFICATIONS IN THE IFNG PROMOTER ARE ASSOCIATED WITH AN INCREASE OF IFNG TRANSCRIPTION IN DIFFERENT STAGES OF PERIODONTAL DISEASES. MATERIALS AND METHODS: DNA WAS EXTRACTED FROM GINGIVAL BIOPSY SAMPLES COLLECTED FROM 47 TOTAL SITES FROM 47 DIFFERENT SUBJECTS: 23 PERIODONTALLY HEALTHY SITES, 12 EXPERIMENTALLY INDUCED GINGIVITIS SITES AND 12 CHRONIC PERIODONTITIS SITES. LEVELS OF DNA METHYLATION WITHIN THE IFNG PROMOTER CONTAINING SIX CPG DINUCLEOTIDES WERE DETERMINED USING PYROSEQUENCING TECHNOLOGY. INTERFERON GAMMA MRNA EXPRESSION WAS ANALYSED BY QUANTITATIVE POLYMERASE CHAIN REACTIONS USING ISOLATED RNA FROM PART OF THE BIOLOGICAL SAMPLES MENTIONED ABOVE. RESULTS: THE METHYLATION LEVEL OF ALL SIX ANALYSED CPG SITES WITHIN THE IFNG PROMOTER REGION IN THE PERIODONTITIS BIOPSIES 52% [INTERQUARTILE RANGE, IQR (43.8%, 63%)] WAS SIGNIFICANTLY LOWER THAN PERIODONTALLY HEALTHY SAMPLES 62% [IQR (51.3%, 74%)], P=0.007 AND GINGIVITIS BIOPSIES 63% [IQR (55%, 74%)], P=0.02. THE TRANSCRIPTIONAL LEVEL OF IFNG IN PERIODONTITIS BIOPSIES WAS 1.96-FOLD AND SIGNIFICANTLY HIGHER THAN TISSUES WITH PERIODONTAL HEALTH (P=0.04). ALTHOUGH THE MRNA LEVEL FROM EXPERIMENTAL GINGIVITIS SAMPLES EXHIBITED AN 8.5-FOLD INCREASE AS COMPARED WITH PERIODONTALLY HEALTHY SAMPLES, NO SIGNIFICANT METHYLATION DIFFERENCE WAS OBSERVED IN EXPERIMENTAL GINGIVITIS SAMPLE. CONCLUSIONS: A HYPOMETHYLATION PROFILE WITHIN IFNG PROMOTER REGION IS RELATED TO AN INCREASE OF IFNG TRANSCRIPTION PRESENT IN THE CHRONIC PERIODONTITIS BIOPSIES, WHILE SUCH AN INCREASE OF IFNG IN EXPERIMENTALLY INDUCED GINGIVITIS SEEMS INDEPENDENT OF PROMOTER METHYLATION ALTERATION.	2010