1  1499 113 DNA METHYLATION ANALYSIS IN NONALCOHOLIC FATTY LIVER DISEASE SUGGESTS DISTINCT DISEASE-SPECIFIC AND REMODELING SIGNATURES AFTER BARIATRIC SURGERY. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CHRONIC LIVER DISORDER IN INDUSTRIALIZED COUNTRIES. LIVER SAMPLES FROM MORBIDLY OBESE PATIENTS (N = 45) WITH ALL STAGES OF NAFLD AND CONTROLS (N = 18) WERE ANALYZED BY ARRAY-BASED DNA METHYLATION AND MRNA EXPRESSION PROFILING. NAFLD-SPECIFIC EXPRESSION AND METHYLATION DIFFERENCES WERE SEEN FOR NINE GENES CODING FOR KEY ENZYMES IN INTERMEDIATE METABOLISM (INCLUDING PC, ACLY, AND PLCG1) AND INSULIN/INSULIN-LIKE SIGNALING (INCLUDING IGF1, IGFBP2, AND PRKCE) AND REPLICATED BY BISULFITE PYROSEQUENING (INDEPENDENT N = 39). TRANSCRIPTION FACTOR BINDING SITES AT NAFLD-SPECIFIC CPG SITES WERE >1,000-FOLD ENRICHED FOR ZNF274, PGC1A, AND SREBP2. INTRAINDIVIDUAL COMPARISON OF LIVER BIOPSIES BEFORE AND AFTER BARIATRIC SURGERY SHOWED NAFLD-ASSOCIATED METHYLATION CHANGES TO BE PARTIALLY REVERSIBLE. POSTBARIATRIC AND NAFLD-SPECIFIC METHYLATION SIGNATURES WERE CLEARLY DISTINCT BOTH IN GENE ONTOLOGY AND TRANSCRIPTION FACTOR BINDING SITE ANALYSES, WITH >400-FOLD ENRICHMENT OF NRF1, HSF1, AND ESRRA SITES. OUR FINDINGS PROVIDE AN EXAMPLE OF TREATMENT-INDUCED EPIGENETIC ORGAN REMODELING IN HUMANS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2  1292  34 DECREASED BLOOD PRESSURE IS RELATED TO CHANGES IN NF-KB PROMOTER METHYLATION LEVELS AFTER BARIATRIC SURGERY. BACKGROUND: OBESITY IS CHARACTERIZED BY A CHRONIC, LOW-GRADE INFLAMMATION, AND BARIATRIC SURGERY IS PROPOSED AS AN EFFECTIVE TREATMENT FOR REDUCING THE OBESITY-RELATED CO-MORBIDITIES. EPIGENETIC MODIFICATIONS COULD BE INVOLVED IN THE METABOLIC IMPROVEMENT AFTER SURGERY. OBJECTIVE: THE MAIN AIM OF THIS STUDY WAS TO EVALUATE WHETHER DNA METHYLATION PATTERN FROM GENES RELATED TO INFLAMMATION AND INSULIN RESPONSE IS ASSOCIATED WITH THE METABOLIC IMPROVEMENT AFTER BARIATRIC SURGERY IN MORBIDLY OBESE PATIENTS AND IF THESE CHANGES DEPEND ON THE SURGICAL PROCEDURE. SETTING: UNIVERSITY HOSPITAL, SPAIN. METHODS: WE STUDIED 60 SEVERELY OBESE PATIENTS; 31 UNDERWENT ROUX-EN-Y GASTRIC BYPASS AND 29 UNDERWENT LAPAROSCOPIC SLEEVE GASTRECTOMY. ALL PATIENTS WERE EXAMINED BEFORE AND AT 6 MONTHS AFTER BARIATRIC SURGERY. DNA METHYLATION PROFILE OF GENES RELATED TO THE INFLAMMATORY RESPONSE AND INSULIN SENSITIVITY WAS MEASURED BY PYROSEQUENCING. RESULTS: THE PROMOTER METHYLATION LEVELS OF THE NFKB1 GENE WERE INCREASED SIGNIFICANTLY AFTER SURGERY (2.16 +/- .9 VERSUS 2.8 +/- 1.03). THE DECREASE IN BLOOD PRESSURE, BOTH SYSTOLIC AND DIASTOLIC, AFTER SURGERY WAS SIGNIFICANTLY ASSOCIATED WITH THE CHANGES IN THE PROMOTER METHYLATION LEVELS OF THE NFKB1 GENE (BETA = -.513, P = .003 AND BETA = -.543, P = .004, RESPECTIVELY). A DECREASE IN INFLAMMATION STATUS, MEASURED BY HIGH SENSITIVITY C-REACTIVE PROTEIN VALUES, WAS ASSOCIATED WITH CHANGES IN SLC19A1 METHYLATION LEVELS. CONCLUSION: OUR STUDY SHOWS FOR THE FIRST TIME AN ASSOCIATION BETWEEN NFKB1 METHYLATION LEVELS AND BLOOD PRESSURE AFTER BARIATRIC SURGERY, HIGHLIGHTING THE POSSIBLE FUNCTION OF THIS GENE IN THE REGULATION OF ARTERIAL PRESSURE. REGARDING SLC19A1, THIS GENE COULD POSITION AS A POTENTIAL TARGET LINKING INFLAMMATION AND INSULIN RESISTANCE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
3   240  27 ADIPOCYTE EXPRESSION OF SLC19A1 LINKS DNA HYPERMETHYLATION TO ADIPOSE TISSUE INFLAMMATION AND INSULIN RESISTANCE. CONTEXT: INSULIN RESISTANCE (IR) IS PROMOTED BY A CHRONIC LOW-GRADE INFLAMMATION IN WHITE ADIPOSE TISSUE (WAT). THE LATTER MIGHT BE REGULATED THROUGH EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION. THE ONE CARBON CYCLE (1CC) IS A CENTRAL METABOLIC PROCESS GOVERNING DNA METHYLATION. OBJECTIVE: TO IDENTIFY ADIPOCYTE-EXPRESSED 1CC GENES LINKED TO WAT INFLAMMATION, IR, AND THEIR CAUSAL ROLE. DESIGN: COHORT STUDY. SETTING: OUTPATIENT ACADEMIC CLINIC. PARTICIPANTS: OBESE AND NONOBESE SUBJECTS. METHODS: GENE EXPRESSION AND DNA METHYLATION ARRAYS WERE PERFORMED IN SUBCUTANEOUS WAT AND ISOLATED ADIPOCYTES. IN IN VITRO DIFFERENTIATED HUMAN ADIPOCYTES, GENE KNOCKDOWN WAS ACHIEVED BY SMALL INTERFERING RNA, AND ANALYSES INCLUDED MICROARRAY, QUANTITATIVE POLYMERASE CHAIN REACTION, DNA METHYLATION BY ENZYME-LINKED IMMUNOSORBENT ASSAY AND PYROSEQUENCING, PROTEIN SECRETION BY ENZYME-LINKED IMMUNOSORBENT ASSAY, TARGETED METABOLOMICS, AND LUCIFERASE REPORTER AND THERMAL SHIFT ASSAYS. MAIN OUTCOME MEASURES: EFFECTS ON ADIPOCYTE INFLAMMATION. RESULTS: IN ADIPOCYTES FROM OBESE INDIVIDUALS, GLOBAL DNA HYPERMETHYLATION WAS ASSOCIATED POSITIVELY WITH GENE EXPRESSION OF PROINFLAMMATORY PATHWAYS. AMONG THE 1CC GENES, IR IN VIVO AND PROINFLAMMATORY GENE EXPRESSION IN WAT WERE MOST STRONGLY AND INVERSELY ASSOCIATED WITH SLC19A1, A GENE ENCODING A MEMBRANE FOLATE CARRIER. SLC19A1 KNOCKDOWN IN HUMAN ADIPOCYTES PERTURBED INTRACELLULAR 1CC METABOLISM, INDUCED GLOBAL DNA HYPERMETHYLATION, AND INCREASED EXPRESSION OF PROINFLAMMATORY GENES. SEVERAL CPG LOCI LINKED SLC19A1 TO INFLAMMATION; VALIDATION STUDIES WERE FOCUSED ON THE CHEMOKINE C-C MOTIF CHEMOKINE LIGAND 2 (CCL2) IN WHICH METHYLATION IN THE PROMOTER (CG12698626) REGULATED CCL2 EXPRESSION AND CCL2 SECRETION THROUGH ALTERED TRANSCRIPTIONAL ACTIVITY. CONCLUSIONS: REDUCED SLC19A1 EXPRESSION IN HUMAN ADIPOCYTES INDUCES DNA HYPERMETHYLATION, RESULTING IN INCREASED EXPRESSION OF SPECIFIC PROINFLAMMATORY GENES, INCLUDING CCL2. THIS CONSTITUTES AN EPIGENETIC MECHANISM THAT MIGHT LINK DYSFUNCTIONAL ADIPOCYTES TO WAT INFLAMMATION AND IR.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                
4  2809  33 FGF1 AMELIORATES OBESITY-ASSOCIATED HEPATIC STEATOSIS BY REVERSING IGFBP2 HYPERMETHYLATION. OBESITY IS A MAJOR CONTRIBUTING FACTOR FOR METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD). FIBROBLAST GROWTH FACTOR (FGF) 1 IS THE FIRST PARACRINE FGF FAMILY MEMBER IDENTIFIED TO EXHIBIT PROMISING METABOLIC REGULATORY PROPERTIES CAPABLE OF CONFERRING GLUCOSE-LOWERING AND INSULIN-SENSITIZING EFFECT. THIS STUDY EXPLORES THE ROLE AND MOLECULAR UNDERPINNINGS OF FGF1 IN OBESITY-ASSOCIATED HEPATIC STEATOSIS. IN A MOUSE HIGH-FAT DIET (HFD)-INDUCED MAFLD MODEL, CHRONIC TREATMENT WITH RECOMBINANT FGF1(RFGF1) WAS FOUND TO EFFECTIVELY REDUCE THE SEVERITY OF INSULIN RESISTANCE, HYPERLIPIDEMIA, AND INFLAMMATION. FGF1 TREATMENT DECREASED LIPID ACCUMULATION IN THE MOUSE LIVER AND PALMITIC ACID-TREATED AML12 CELLS. THESE EFFECTS WERE ASSOCIATED WITH DECREASED MATURE FORM SREBF1 EXPRESSION AND ITS TARGET GENES FASN AND SCD1. INTERESTINGLY, WE UNCOVERED THAT RFGF1 SIGNIFICANTLY INDUCED IGFBP2 EXPRESSION AT BOTH MRNA AND PROTEIN LEVELS IN HFD-FED MOUSE LIVERS AND CULTURED HEPATOCYTES TREATED WITH PALMITIC ACID. ADENO-ASSOCIATED VIRUS-MEDIATED IGFBP2 SUPPRESSION SIGNIFICANTLY DIMINISHED THE THERAPEUTIC BENEFIT OF RFGF1 ON MAFLD-ASSOCIATED PHENOTYPES, INDICATING THAT IGFBP2 PLAYS A CRUCIAL ROLE IN THE FGF1-MEDIATED REDUCTION OF HEPATIC STEATOSIS. FURTHER ANALYSIS REVEALED THAT RFGF1 TREATMENT REDUCES THE RECRUITMENT OF DNA METHYLTRANSFERASE 3 ALPHA TO THE IGFBP2 GENOMIC LOCUS, LEADING TO DECREASED IGFBP2 GENE METHYLATION AND INCREASED MRNA AND PROTEIN EXPRESSION. COLLECTIVELY, OUR FINDINGS REVEAL FGF1 MODULATION OF LIPID METABOLISM VIA EPIGENETIC REGULATION OF IGFBP2 EXPRESSION, AND UNRAVEL THE THERAPEUTIC POTENTIAL OF THE FGF1-IGFBP2 AXIS IN METABOLIC DISEASES ASSOCIATED WITH OBESITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5  3583  30 IMPACT OF SHORT- AND LONG-TERM ELECTRICALLY INDUCED MUSCLE EXERCISE ON GENE SIGNALING PATHWAYS, GENE EXPRESSION, AND PGC1A METHYLATION IN MEN WITH SPINAL CORD INJURY. EXERCISE ATTENUATES THE DEVELOPMENT OF CHRONIC NONCOMMUNICABLE DISEASES (NCDS). GENE SIGNALING PATHWAY ANALYSIS OFFERS AN OPPORTUNITY TO DISCOVER IF ELECTRICALLY INDUCED MUSCLE EXERCISE REGULATES KEY PATHWAYS AMONG PEOPLE LIVING WITH SPINAL CORD INJURY (SCI). WE EXAMINED SHORT-TERM AND LONG-TERM DURATIONS OF ELECTRICALLY INDUCED SKELETAL MUSCLE EXERCISE ON COMPLEX GENE SIGNALING PATHWAYS, SPECIFIC GENE REGULATION, AND EPIGENETIC TAGGING OF PGC1A, A MAJOR TRANSCRIPTION FACTOR IN SKELETAL MUSCLE OF MEN WITH SCI. AFTER SHORT- OR LONG-TERM ELECTRICALLY INDUCED EXERCISE TRAINING, PARTICIPANTS UNDERWENT BIOPSIES OF THE TRAINED AND UNTRAINED MUSCLES. RNA WAS HYBRIDIZED TO AN EXON MICROARRAY AND ANALYZED BY A GENE SET ENRICHMENT ANALYSIS. WE DISCOVERED THAT LONG-TERM EXERCISE TRAINING REGULATED THE REACTOME GENE SETS FOR METABOLISM (38 GENE SETS), CELL CYCLE (36 GENE SETS), DISEASE (27 GENE SETS), GENE EXPRESSION AND TRANSCRIPTION (22 GENE SETS), ORGANELLE BIOGENESIS (4 GENE SETS), CELLULAR RESPONSE TO STIMULI (8 GENE SETS), IMMUNE SYSTEM (8 GENE SETS), VESICLE-MEDIATED TRANSPORT (4 GENE SETS), AND TRANSPORT OF SMALL MOLECULES (3 GENE SETS). SPECIFIC GENE EXPRESSION INCLUDED: OXIDATIVE CATABOLISM OF GLUCOSE INCLUDING PDHB (P < 0.001), PDHX (P < 0.001), MPC1 (P < 0.009), AND MPC2 (P < 0.007); OXIDATIVE PHOSPHORYLATION GENES INCLUDING SDHA (P < 0.006), SDHB (P < 0.001), NDUFB1 (P < 0.002), NDUFA2 (P < 0.001); TRANSCRIPTION GENES INCLUDING PGC1ALPHA (P < 0.030) AND PRKAB2 (P < 0.011); HYPERTROPHY GENE MSTN (P < 0.001); AND THE MYOKINE GENERATING FNDC5 GENE (P < 0.008). LONG-TERM ELECTRICALLY INDUCED EXERCISE DEMETHYLATED THE MAJOR TRANSCRIPTION FACTOR PGC1A. TAKEN TOGETHER, THESE FINDINGS SUPPORT THAT LONG-TERM ELECTRICALLY INDUCED MUSCLE ACTIVITY REGULATES KEY PATHWAYS ASSOCIATED WITH MUSCLE HEALTH AND SYSTEMIC METABOLISM.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
6   561  39 BARIATRIC SURGERY-INDUCED WEIGHT LOSS AND ASSOCIATED GENOME-WIDE DNA-METHYLATION ALTERATIONS IN OBESE INDIVIDUALS. BACKGROUND: OBESITY IS A MULTIFACTORIAL AND CHRONIC CONDITION OF GROWING UNIVERSAL CONCERN. IT HAS RECENTLY BEEN REPORTED THAT BARIATRIC SURGERY IS A MORE SUCCESSFUL TREATMENT FOR SEVERE OBESITY THAN OTHER NONINVASIVE INTERVENTIONS, RESULTING IN RAPID SIGNIFICANT WEIGHT LOSS AND ASSOCIATED CHRONIC DISEASE REMISSION. THE IDENTIFICATION OF DISTINCT EPIGENETIC PATTERNS IN PATIENTS WHO ARE OBESE OR HAVE METABOLIC IMBALANCES HAS SUGGESTED A POTENTIAL ROLE FOR EPIGENETIC ALTERATIONS IN CAUSAL OR MEDIATING PATHWAYS IN THE DEVELOPMENT OF OBESITY-RELATED PATHOLOGIES. SPECIFIC CHANGES IN THE EPIGENOME (DNA METHYLOME), ASSOCIATED WITH METABOLIC DISORDERS, CAN BE DETECTED IN THE BLOOD. WE INVESTIGATED WHETHER SUCH EPIGENETIC CHANGES ARE REVERSIBLE AFTER WEIGHT LOSS USING GENOME-WIDE DNA METHYLOME ANALYSIS OF BLOOD SAMPLES FROM INDIVIDUALS WITH SEVERE OBESITY (MEAN BMI ~ 45) UNDERGOING BARIATRIC SURGERY. RESULTS: OUR ANALYSIS REVEALED 41 SIGNIFICANT (BONFERRONI P < 0.05) AND 1169 (FALSE DISCOVERY RATE P < 0.05) SUGGESTIVE DIFFERENTIALLY METHYLATED POSITIONS (DMPS) ASSOCIATED WITH WEIGHT LOSS DUE TO BARIATRIC SURGERY. AMONG THE 41 SIGNIFICANT DMPS, 5 CPGS WERE REPLICATED IN AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS (THE HEAVIER TWIN UNDERWENT DIET-INDUCED WEIGHT LOSS). THE EFFECT SIZES OF THESE 5 CPGS WERE CONSISTENT ACROSS DISCOVERY AND REPLICATION SETS (P < 0.05). WE ALSO IDENTIFIED 192 DIFFERENTIALLY METHYLATED REGIONS (DMRS) AMONG WHICH SMAD6 AND PFKFB3 GENES WERE THE TOP HYPERMETHYLATED AND HYPOMETHYLATED REGIONS, RESPECTIVELY. PATHWAY ENRICHMENT ANALYSIS OF THE DMR-ASSOCIATED GENES SHOWED THAT FUNCTIONAL PATHWAYS RELATED TO IMMUNE FUNCTION AND TYPE 1 DIABETES WERE SIGNIFICANT. WEIGHT LOSS DUE TO BARIATRIC SURGERY ALSO SIGNIFICANTLY DECELERATED EPIGENETIC AGE 12 MONTHS AFTER THE INTERVENTION (MEAN = - 4.29; P = 0.02). CONCLUSIONS: WE IDENTIFIED WEIGHT LOSS-ASSOCIATED DNA-METHYLATION ALTERATIONS TARGETING IMMUNE AND INFLAMMATORY GENE PATHWAYS IN BLOOD SAMPLES FROM BARIATRIC-SURGERY PATIENTS. THE TOP HITS WERE REPLICATED IN SAMPLES FROM AN INDEPENDENT COHORT OF BMI-DISCORDANT MONOZYGOTIC TWINS FOLLOWING A HYPOCALORIC DIET. ENERGY RESTRICTION AND BARIATRIC SURGERY THUS SHARE CPGS THAT MAY REPRESENT EARLY INDICATORS OF RESPONSE TO THE METABOLIC EFFECTS OF WEIGHT LOSS. THE ANALYSIS OF BARIATRIC SURGERY-ASSOCIATED DMRS SUGGESTS THAT EPIGENETIC REGULATION OF GENES INVOLVED IN ENDOTHELIAL AND ADIPOSE TISSUE FUNCTION IS KEY IN THE PATHOPHYSIOLOGY OF OBESITY.	2022	

7   659  22 BLOOD GLOBAL DNA METHYLATION IS DECREASED IN NON-SEVERE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS. BACKGROUND: ALTERATIONS IN GLOBAL DNA METHYLATION HAVE BEEN ASSOCIATED WITH OXIDATIVE STRESS (OS). SINCE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS CHARACTERIZED BY INCREASED OXIDATIVE STRESS WE AIMED TO EVALUATE THE LEVELS OF GLOBAL DNA METHYLATION IN THIS PATIENT GROUP. METHODS: WE ASSESSED METHYLCYTOSINE (MCYT) LEVELS IN DNA FROM BLOOD COLLECTED IN 43 COPD PATIENTS (29 WITH MILD AND 14 WITH MODERATE DISEASE) AND 43 AGE- AND SEX-MATCHED HEALTHY CONTROLS. RESULTS: DNA METHYLATION WAS SIGNIFICANTLY LOWER IN COPD PATIENTS VS. CONTROLS (4.20 +/- 0.18% MCYT VS. 4.29 +/- 0.18% MCYT, P = 0.02). FURTHERMORE, DNA METHYLATION IN COPD PATIENTS WITH MODERATE DISEASE WAS SIGNIFICANTLY LOWER THAN THAT IN PATIENTS WITH MILD DISEASE (4.14 +/- 0.15% MCYT VS. 4.23 +/- 0.19% MCYT, P < 0.05). UNIVARIATE LOGISTIC REGRESSION ANALYSIS SHOWED THAT LOWER DNA METHYLATION LEVELS WERE ASSOCIATED WITH PRESENCE OF COPD (CRUDE OR = 0.06, 95% CI 0.00 TO 0.67, P = 0.023). THIS RELATIONSHIP REMAINED SIGNIFICANT AFTER ADJUSTING FOR SEVERAL CONFOUNDERS (OR 0.03, 95% CI 0.00 TO 0.67; P = 0.028). RECEIVER OPERATING CHARACTERISTICS (ROC) CURVE ANALYSIS DEMONSTRATED THE AREA UNDER THE CURVE OF MCYT WAS 0.646, WITH 46.6% SENSITIVITY AND 79.1% SPECIFICITY FOR PRESENCE OF COPD. CONCLUSIONS: THERE WERE NO SIGNIFICANT CORRELATIONS BETWEEN METHYLATION AND OS INDICES. THE PRESENCE AND SEVERITY OF COPD IS ASSOCIATED WITH PROGRESSIVELY LOWER DNA METHYLATION IN BLOOD. HOWEVER, THIS EPIGENETIC ALTERATION SEEMS INDEPENDENT OF OXIDATIVE STRESS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  3995  28 LONGITUDINAL STUDY OF DNA METHYLATION OF INFLAMMATORY GENES AND CANCER RISK. BACKGROUND: CHRONIC INFLAMMATION PLAYS A KEY ROLE IN CANCER ETIOLOGY. DNA METHYLATION MODIFICATION, ONE OF THE EPIGENETIC MECHANISMS REGULATING GENE EXPRESSION, IS CONSIDERED A HALLMARK OF CANCER. HUMAN AND ANIMAL MODELS HAVE IDENTIFIED NUMEROUS LINKS BETWEEN DNA METHYLATION AND INFLAMMATORY BIOMARKERS. OUR OBJECTIVE WAS TO PROSPECTIVELY AND LONGITUDINALLY EXAMINE ASSOCIATIONS BETWEEN METHYLATION OF FOUR INFLAMMATORY GENES AND CANCER RISK. METHODS: WE INCLUDED 795 NORMATIVE AGING STUDY PARTICIPANTS WITH BLOOD DRAWN ONE TO FOUR TIMES FROM 1999 TO 2012 (MEDIAN FOLLOW-UP, 10.6 YEARS). PROMOTER DNA METHYLATION OF IL6, ICAM-1, IFN, AND TLR2 IN BLOOD LEUKOCYTES WAS MEASURED USING PYROSEQUENCING AT MULTIPLE CPG SITES AND AVERAGED BY GENE FOR DATA ANALYSIS. WE USED COX REGRESSION MODELS TO EXAMINE PROSPECTIVE ASSOCIATIONS OF BASELINE AND TIME-DEPENDENT METHYLATION WITH CANCER RISK AND COMPARED MEAN METHYLATION DIFFERENCES OVER TIME BETWEEN CANCER CASES AND CANCER-FREE PARTICIPANTS. RESULTS: BASELINE IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.49; P = 0.04) AND PROSTATE CANCER INCIDENCE (HR, 1.69; P = 0.02). BASELINE ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.43; P = 0.02; HR, 0.70; P = 0.03, RESPECTIVELY). IN OUR TIME-DEPENDENT ANALYSES, IFN HYPERMETHYLATION WAS ASSOCIATED WITH ALL-CANCER (HR, 1.79; P = 0.007) AND PROSTATE CANCER (HR, 1.57; P = 0.03) INCIDENCE; AND ICAM-1 AND IL6 HYPERMETHYLATION WERE ASSOCIATED WITH PROSTATE CANCER INCIDENCE (HR, 1.39; P = 0.02; HR, 0.69; P = 0.03, RESPECTIVELY). WE DETECTED SIGNIFICANT ICAM-1 HYPERMETHYLATION IN CANCER CASES (P = 0.0003) 10 TO 13 YEARS PREDIAGNOSIS. CONCLUSION: HYPERMETHYLATION OF IFN AND ICAM-1 MAY PLAY IMPORTANT ROLES IN EARLY CARCINOGENESIS, PARTICULARLY THAT OF PROSTATE CANCER. IMPACT: THESE METHYLATION CHANGES COULD INFORM THE DEVELOPMENT OF EARLY DETECTION BIOMARKERS AND POTENTIAL TREATMENTS OF INFLAMMATION-RELATED CARCINOGENESIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9  3783  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10  4244  21 METHYLATION STATUS OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER IN A HIGH-RISK CHINESE POPULATION. BACKGROUND: METHYLATION IS A COMMON EPIGENETIC MODIFICATION WHICH MAY PLAY A CRUCIAL ROLE IN CANCER DEVELOPMENT. TO INVESTIGATE THE ASSOCIATION BETWEEN METHYLATION OF COX-2 IN BLOOD LEUKOCYTE DNA AND RISK OF GASTRIC CANCER (GC), A NESTED CASE-CONTROL STUDY WAS CONDUCTED IN LINQU COUNTY, SHANDONG PROVINCE, A HIGH RISK AREA OF GC IN CHINA. METHODS: ASSOCIATION BETWEEN BLOOD LEUKOCYTE DNA METHYLATION OF COX-2 AND RISK OF GC WAS INVESTIGATED IN 133 GCS AND 285 SUPERFICIAL GASTRITIS (SG)/ CHRONIC ATROPHIC GASTRITIS (CAG). THE TEMPORAL TREND OF COX-2 METHYLATION LEVEL DURING GC DEVELOPMENT WAS FURTHER EXPLORED IN 74 PRE-GC AND 95 POST-GC SAMPLES (INCLUDING 31 CASES WITH BOTH PRE- AND POST-GC SAMPLES). IN ADDITION, THE ASSOCIATION OF DNA METHYLATION AND RISK OF PROGRESSION TO GC WAS EVALUATED IN 74 PRE-GC SAMPLES AND THEIR RELEVANT INTESTINAL METAPLASIA (IM)/DYSPLASIA (DYS) CONTROLS. METHYLATION LEVEL WAS DETERMINED BY QUANTITATIVE METHYLATION-SPECIFIC PCR (QMSP). ODDS RATIOS (ORS) AND 95% CONFIDENCE INTERVALS (CIS) WERE CALCULATED BY UNCONDITIONAL LOGISTIC REGRESSION ANALYSIS. RESULTS: THE MEDIANS OF COX-2 METHYLATION LEVELS WERE 2.3% AND 2.2% IN GC CASES AND CONTROLS, RESPECTIVELY. NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN COX-2 METHYLATION AND RISK OF GC (OR, 1.15; 95% CI: 0.70-1.88). HOWEVER, THE TEMPORAL TREND ANALYSIS SHOWED THAT COX-2 METHYLATION LEVELS WERE ELEVATED AT 1-4 YEARS AHEAD OF CLINICAL GC DIAGNOSIS COMPARED WITH THE YEAR OF GC DIAGNOSIS (3.0% VS. 2.2%, P=0.01). FURTHER VALIDATION IN 31 GCS WITH BOTH PRE- AND POST-GC SAMPLES INDICATED THAT COX-2 METHYLATION LEVELS WERE SIGNIFICANTLY DECREASED AT THE YEAR OF GC DIAGNOSIS COMPARED WITH PRE-GC SAMPLES (1.5% VS. 2.5%, P=0.02). NO SIGNIFICANT ASSOCIATION BETWEEN COX-2 METHYLATION AND RISK OF PROGRESSION TO GC WAS FOUND IN SUBJECTS WITH IM (OR, 0.50; 95% CI: 0.18-1.42) OR DYS (OR, 0.70; 95% CI: 0.23-2.18). ADDITIONALLY, WE FOUND THAT ELDER PEOPLE HAD INCREASED RISK OF COX-2 HYPERMETHYLATION (OR, 1.55; 95% CI: 1.02-2.36) AND SUBJECTS WHO EVER INFECTED WITH H. PYLORI HAD DECREASED RISK OF COX-2 HYPERMETHYLATION (OR, 0.54; 95% CI: 0.34-0.88). CONCLUSIONS: COX-2 METHYLATION EXISTS IN BLOOD LEUKOCYTE DNA BUT AT A LOW LEVEL. COX-2 METHYLATION LEVELS IN BLOOD LEUKOCYTE DNA MAY CHANGE DURING GC DEVELOPMENT.	2015	
                                                                                                                                                                                                            
11  4689  25 NEW-ONSET POSTPARTUM PREECLAMPSIA: EPIGENETIC MECHANISM AND PREDICTION. OBJECTIVE: PLACENTAL CYTOSINE (CPG) METHYLATION WAS MEASURED TO PREDICT NEW-ONSET POSTPARTUM PREECLAMPSIA (NOPP) AND INTERROGATE ITS MOLECULAR PATHOGENESIS. METHODS: NOPP WAS DEFINED AS PATIENTS WITH A NEW DIAGNOSIS OF POSTPARTUM PREECLAMPSIA DEVELOPING >/=48 H TO </=6 WEEKS AFTER DELIVERY WITH NO PRIOR HYPERTENSIVE DISORDERS. PLACENTAL TISSUE WAS OBTAINED FROM 12 NOPP CASES AND 12 NORMOTENSIVE CONTROLS. GENOME-WIDE INDIVIDUAL CYTOSINE (CPG) METHYLATION LEVEL WAS MEASURED WITH THE INFINIUM METHYLATIONEPIC BEADCHIP ARRAY. SIGNIFICANT DIFFERENTIAL METHYLATION (NOPP VS. CONTROLS) FOR INDIVIDUAL CPG LOCI WAS DEFINED AS FALSE DISCOVERY RATE (FDR) P VALUE <.05. GENE FUNCTIONAL ENRICHMENT USING QIAGEN'S INGENUITY PATHWAY ANALYSIS (IPA) WAS PERFORMED TO HELP ELUCIDATE THE MOLECULAR PATHOGENESIS OF NOPP. A LOGISTIC REGRESSION MODEL FOR NOPP PREDICTION BASED ON THE METHYLATION LEVEL IN A COMBINATION OF CPG LOCI WAS GENERATED. THE AREA UNDER THE RECEIVER OPERATING CHARACTERISTIC CURVES (AUC [95% CI]) SENSITIVITY, AND SPECIFICITY FOR NOPP PREDICTION BASED ON THE CPG METHYLATION LEVEL WAS CALCULATED FOR EACH LOCUS. RESULTS: THERE WERE 537 (IN 540 SEPARATE GENES) SIGNIFICANTLY (FDR P<.05 WITH A >/= 2.0-FOLD METHYLATION DIFFERENCE) DIFFERENTIALLY METHYLATED CPG LOCI BETWEEN THE GROUPS. A TOTAL OF 143 INDIVIDUAL CPG MARKERS HAD EXCELLENT INDIVIDUAL PREDICTIVE ACCURACY FOR NOPP PREDICTION (AUC >/=0.80), OF WHICH 14 MARKERS HAD OUTSTANDING ACCURACY (AUC >/=0.90). A LOGISTIC REGRESSION MODEL BASED ON FIVE CPG MARKERS YIELDED AN AUC (95% CI)=0.99 (0.95-0.99) WITH SENSITIVITY 95% AND SPECIFICITY 93% FOR NOPP PREDICTION. IPA REVEALED DYSREGULATION OF CRITICAL PATHWAYS (E.G., ANGIOGENESIS, CHRONIC INFLAMMATION, AND EPITHELIAL-MESENCHYMAL TRANSITION) KNOWN TO BE LINKED TO CLASSIC PREECLAMPSIA, IN ADDITION TO OTHER PREVIOUSLY UNDESCRIBED GENES/PATHWAYS. CONCLUSIONS: THERE WAS SIGNIFICANT PLACENTAL EPIGENETIC DYSREGULATION IN NOPP. NOPP SHARED BOTH COMMON AND UNIQUE MOLECULAR PATHWAYS WITH CLASSIC PREECLAMPSIA. FINALLY, WE HAVE IDENTIFIED NOVEL POTENTIAL BIOMARKERS FOR THE EARLY POST-PARTUM PREDICTION OF NOPP.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  2678  24 EVALUATION OF A PROGNOSTIC EPIGENETIC CLASSIFICATION SYSTEM IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS. BACKGROUND: METHYLATION AT 5 CPG SITES WAS PREVIOUSLY SHOWN TO CLASSIFY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) INTO 3 PROGNOSTIC SUBGROUPS. HERE, WE AIMED TO VALIDATE THE MARKER SET IN AN ADDITIONAL COHORT AND TO EVALUATE ITS CLINICAL UTILITY FOR CLL PATIENT STRATIFICATION. METHODS: WE EVALUATED THIS EPIGENETIC MARKER SET IN 79 GERMAN PATIENTS USING BISULFITE TREATMENT FOLLOWED BY PYROSEQUENCING AND CLASSIFICATION USING A SUPPORT VECTOR MACHINE-LEARNING TOOL. RESULTS: THE N-CLL, I-CLL, AND M-CLL CLASSIFICATION WAS DETECTED IN 28 (35%), 10 (13%), AND 41 (51%) PATIENTS, RESPECTIVELY. EPIGENETIC GROUPING WAS ASSOCIATED WITH IGHV MUTATIONAL STATUS (P = 2 X 10(-12)), ISOLATED DEL13Q (P = 9 X 10(-6)), DEL17P (P = .015), COMPLEX KARYOTYPE (P = .005), VH-USAGE, AND CLINICAL OUTCOME AS TIME TO FIRST TREATMENT (P = 1.4 X 10(-12)) AND OVERALL SURVIVAL (P = .003). MULTIVARIATE COX REGRESSION ANALYSIS IDENTIFIED N-CLL AS A FACTOR FOR EARLIER TREATMENT HAZARD RATIO (HR), 6.3 (95% CONFIDENCE INTERVAL [CI] 2.4-16.4; P = .0002) COMPARED TO IGHV MUTATIONAL STATUS (HR 4.6, 95% CI 1.9-11.3, P = .0008). IN ADDITION, WHEN COMPARING THE PROGNOSTIC VALUE OF THE EPIGENETIC CLASSIFICATION SYSTEM WITH THE IGHV CLASSIFICATION, EPIGENETIC GROUPING PERFORMED BETTER COMPARED TO IGHV MUTATIONAL STATUS USING KAPLAN-MEIER ESTIMATION AND ALLOWED THE IDENTIFICATION OF A THIRD, INTERMEDIATE (I-CLL) GROUP. THUS, OUR STUDY CONFIRMED THE PROGNOSTIC VALUE OF THE EPIGENETIC MARKER SET FOR PATIENT STRATIFICATION IN ROUTINE CLINICAL DIAGNOSTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13   525  22 ASSOCIATIONS OF BODY COMPOSITION AND PHYSICAL ACTIVITY LEVEL WITH MULTIPLE MEASURES OF EPIGENETIC AGE ACCELERATION. EPIGENETIC CLOCKS USE DNA METHYLATION TO ESTIMATE BIOLOGICAL AGE. WHETHER BODY COMPOSITION AND PHYSICAL ACTIVITY ARE ASSOCIATED WITH THESE CLOCKS IS NOT WELL UNDERSTOOD. USING BLOOD SAMPLES COLLECTED AT ENROLLMENT (2003-2009) FROM 2,758 WOMEN IN THE US NATIONWIDE SISTER STUDY, WE CALCULATED 6 EPIGENETIC AGE ACCELERATION METRICS USING 4 EPIGENETIC CLOCKS (HANNUM, HORVATH, PHENOAGE, GRIMAGE). RECREATIONAL PHYSICAL ACTIVITY WAS SELF-REPORTED, AND ADIPOSITY MEASURES WERE ASSESSED BY TRAINED MEDICAL EXAMINERS (BODY MASS INDEX (BMI), WAIST-TO-HIP RATIO (WTH), WAIST CIRCUMFERENCE). IN CROSS-SECTIONAL ANALYSES, ALL ADIPOSITY MEASURES WERE ASSOCIATED WITH EPIGENETIC AGE ACCELERATION. THE STRONGEST ASSOCIATION WAS FOR BMI AND PHENOAGE, A MEASURE OF BIOLOGICAL AGE THAT CORRELATES WITH CHRONIC DISEASE (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 3.15 YEARS, 95% CONFIDENCE INTERVAL (CI): 2.41, 3.90; P FOR TREND < 0.001). IN A MUTUAL-ADJUSTMENT MODEL, BOTH WERE ASSOCIATED WITH PHENOAGE AGE ACCELERATION (BMI OF >/=35.0 VS. 18.5-24.9, BETA = 2.69 YEARS, 95% CI: 1.90, 3.48; P FOR TREND < 0.001; QUARTILE 4 VS.1 WTH, BETA = 1.00 YEARS, 95% CI: 0.34, 1.65; P FOR TREND < 0.008). AFTER ADJUSTMENT, PHYSICAL ACTIVITY WAS ASSOCIATED ONLY WITH GRIMAGE (QUARTILE 4 VS. 1, BETA = -0.42 YEARS, 95% CI: -0.70, -0.14; P FOR TREND = 0.001). PHYSICAL ACTIVITY ATTENUATED THE WAIST CIRCUMFERENCE ASSOCIATIONS WITH PHENOAGE AND GRIMAGE. EXCESS ADIPOSITY WAS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION; PHYSICAL ACTIVITY MIGHT ATTENUATE ASSOCIATIONS WITH WAIST CIRCUMFERENCE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
14  2624  28 EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) OF BMI, BMI CHANGE AND WAIST CIRCUMFERENCE IN AFRICAN AMERICAN ADULTS IDENTIFIES MULTIPLE REPLICATED LOCI. OBESITY IS AN IMPORTANT COMPONENT OF THE PATHOPHYSIOLOGY OF CHRONIC DISEASES. IDENTIFYING EPIGENETIC MODIFICATIONS ASSOCIATED WITH ELEVATED ADIPOSITY, INCLUDING DNA METHYLATION VARIATION, MAY POINT TO GENOMIC PATHWAYS THAT ARE DYSREGULATED IN NUMEROUS CONDITIONS. THE ILLUMINA 450K BEAD CHIP ARRAY WAS USED TO ASSAY DNA METHYLATION IN LEUKOCYTE DNA OBTAINED FROM 2097 AFRICAN AMERICAN ADULTS IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY. MIXED-EFFECTS REGRESSION MODELS WERE USED TO TEST THE ASSOCIATION OF METHYLATION BETA VALUE WITH CONCURRENT BODY MASS INDEX (BMI) AND WAIST CIRCUMFERENCE (WC), AND BMI CHANGE, ADJUSTING FOR BATCH EFFECTS AND POTENTIAL CONFOUNDERS. REPLICATION USING WHOLE-BLOOD DNA FROM 2377 WHITE ADULTS IN THE FRAMINGHAM HEART STUDY AND CD4+ T CELL DNA FROM 991 WHITES IN THE GENETICS OF LIPID LOWERING DRUGS AND DIET NETWORK STUDY WAS FOLLOWED BY TESTING USING ADIPOSE TISSUE DNA FROM 648 WOMEN IN THE MULTIPLE TISSUE HUMAN EXPRESSION RESOURCE COHORT. SEVENTY-SIX BMI-RELATED PROBES, 164 WC-RELATED PROBES AND 8 BMI CHANGE-RELATED PROBES PASSED THE THRESHOLD FOR SIGNIFICANCE IN ARIC (P < 1 X 10(-7); BONFERRONI), INCLUDING PROBES IN THE RECENTLY REPORTED HIF3A, CPT1A AND ABCG1 REGIONS. REPLICATION USING BLOOD DNA WAS ACHIEVED FOR 37 BMI PROBES AND 1 ADDITIONAL WC PROBE. SIXTEEN OF THESE ALSO REPLICATED IN ADIPOSE TISSUE, INCLUDING 15 NOVEL METHYLATION FINDINGS NEAR GENES INVOLVED IN LIPID METABOLISM, IMMUNE RESPONSE/CYTOKINE SIGNALING AND OTHER DIVERSE PATHWAYS, INCLUDING LGALS3BP, KDM2B, PBX1 AND BBS2, AMONG OTHERS. ADIPOSITY TRAITS ARE ASSOCIATED WITH DNA METHYLATION AT NUMEROUS CPG SITES THAT REPLICATE ACROSS STUDIES DESPITE VARIATION IN TISSUE TYPE, ETHNICITY AND ANALYTIC APPROACHES.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  1849  22 EIGHT WEEKS OF PHYSICAL TRAINING DECREASES 2 YEARS OF DNA METHYLATION AGE OF SEDENTARY WOMEN. PURPOSE: THE ACCELERATION OF EPIGENETIC AGE IS A PREDICTOR OF MORTALITY AND CONTRIBUTES TO THE INCREASE IN CHRONIC DISEASES. ADHERENCE TO A HEALTHY LIFESTYLE IS A STRATEGY TO REDUCE EPIGENETIC AGE. THE PRESENT STUDY AIMED TO DETERMINE WHETHER EIGHT WEEKS OF COMBINED (AEROBIC AND STRENGTH) TRAINING (CT) CAN INFLUENCE THE EPIGENETIC AGE OF WOMEN BETWEEN 50 AND 70 YEARS OLD AND THE DIFFERENCES IN SITES AND METHYLATED REGIONS. METHODS: EIGHTEEN WOMEN (AAR(LOW): LOWER AGE ACCELERATION RESIDUAL, N = 10; AAR(HIGH): HIGHER AGE ACCELERATION RESIDUAL, N = 8) PARTICIPATED IN A COMBINED EXERCISE TRAINING PROGRAM (60 MINUTES, 3X A WEEK) FOR EIGHT WEEKS. DNA WAS EXTRACTED FROM WHOLE BLOOD USING THE SALTING OUT TECHNIQUE. DNA METHYLATION WAS PERFORMED USING THE ARRAY TECHNIQUE (ILLUMINA'S INFINIUM METHYLATION BEADCHIP 850K). WE USED THE DNA METHYLATION AGE CALCULATOR PLATFORM TO CALCULATE THE BIOLOGICAL EPIGENETIC AGE. TWO-WAY ANOVA FOLLOWED BY FISHER LSD POSTHOC WAS APPLIED, ADOPTING P < .05. RESULTS: AFTER EIGHT WEEKS OF CT, THERE WERE NO CHANGES TO THE EPIGENETIC AGE ACCELERATION FOR THE AAR(LOW) GROUP (PRE: -2.3 +/- 3.2 TO POST: -2.3 +/- 3.6). HOWEVER, THE AAR(HIGH) GROUP SIGNIFICANTLY DECREASED THE AGE ACCELERATION (PRE: 3.6 +/- 2.6 TO POST: 2.2 +/- 2.7) (GROUP EFFECT, P = .01; TIME EFFECT, P = .31; GROUP VS. TIME EFFECT, P = .005). CONCLUSION: CT FOR EIGHT WEEKS BENEFITS THE EPIGENETIC CLOCK OF WOMEN WITH THE MOST ACCELERATED AGE.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16  1908  34 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION ASSOCIATED WITH CHRONIC POSTSURGICAL PAIN AND ANXIETY IN CHILDREN: A PROSPECTIVE, PILOT STUDY. WE HAVE REPORTED CHILD ANXIETY SENSITIVITY (CHILD ANXIETY SENSITIVITY INDEX [CASI]) PREDICTS CHRONIC POSTSURGICAL PAIN (CPSP). HEREIN, WE EVALUATED DNA METHYLATION PROFILES TO UNDERSTAND THE GENE-ENVIRONMENT INTERACTIONS UNDERLYING CPSP AND CASI, TO IDENTIFY SHARED, ENRICHED, GENOMIC PATHWAYS. IN 73 PROSPECTIVELY RECRUITED ADOLESCENTS UNDERGOING SPINE FUSION, PREOPERATIVE CASI AND PAIN DATA OVER 12 MONTHS AFTER SURGERY WERE COLLECTED. DNA FROM THE PERIPHERAL BLOOD OF EVALUABLE SUBJECTS WITH (N = 16) AND WITHOUT CPSP (N = 40) WERE ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 637 AND 2,445 DIFFERENTIALLY DNA METHYLATED POSITIONS (DMPS) ASSOCIATED WITH CPSP AND CASI, RESPECTIVELY (P </= .05). INGENUITY PATHWAY ANALYSIS OF 39 GENES WITH DMPS FOR BOTH CPSP AND CASI REVEALED ENRICHMENT OF SEVERAL CANONICAL PATHWAYS, INCLUDING GABA RECEPTOR (P = .00016 FOR CPSP; P =.0008 FOR CASI) AND DOPAMINE-DARPP32 FEEDBACK IN CYCLIC ADENOSINE MONOPHOSPHATE (P = .004 FOR CPSP AND P =.00003 FOR CASI) SIGNALING. GENE-GENE INTERACTION NETWORK ENRICHMENT ANALYSIS REVEALED PARTICIPATION OF PATHWAYS IN CELL SIGNALING, MOLECULAR TRANSPORT, METABOLISM, AND NEUROLOGIC DISEASES (P < 10(-8)). BIOINFORMATIC APPROACHES TO IDENTIFY HISTONE MARKS AND TRANSCRIPTION FACTOR (TF) BINDING EVENTS UNDERLYING DMPS, SHOWED THEIR LOCATION IN ACTIVE REGULATORY REGIONS IN PAIN PATHWAY RELEVANT BRAIN CELLS. USING ENRICHR/PINET ENRICHMENT AND LIBRARY OF INTEGRATED NETWORK-BASED CELLULAR SIGNATURES KNOCKDOWN SIGNATURES, WE IDENTIFIED TFS REGULATING GENES WITH DMPS IN ASSOCIATION WITH CPSP AND CASI. IN CONCLUSION, WE IDENTIFIED EPIGENETICALLY ENRICHED PATHWAYS ASSOCIATED WITH CPSP AND ANXIETY SENSITIVITY IN CHILDREN UNDERGOING SURGERY. OUR FINDINGS SUPPORT GABA HYPOFUNCTION AND THE ROLES OF THE DOPAMINE-DARPP32 PATHWAY IN EMOTION/REWARD AND PAIN. THIS PILOT STUDY PROVIDES NEW EPIGENETIC INSIGHTS INTO THE PATHOPHYSIOLOGY OF CPSP AND A BASIS FOR FUTURE STUDIES IN BIOMARKER DEVELOPMENT AND TARGETABLE INTERVENTIONS. PERSPECTIVE: DIFFERENTIAL DNA METHYLATION IN REGULATORY GENOMIC REGIONS ENRICHING SHARED NEURAL PATHWAYS WERE ASSOCIATED WITH CPSP AND CASI IN ADOLESCENTS UNDERGOING SPINE SURGERY. OUR FINDINGS SUPPORT GABA HYPOFUNCTION AND THE ROLES OF THE DOPAMINE-DARPP32 PATHWAY IN EMOTION/REWARD CONTRIBUTING TO BEHAVIORAL MAINTENANCE OF PAIN 10 TO 12 MONTHS AFTER SURGERY.	2019	
                                                                                     
17  4021  24 LOWERED DNA METHYLTRANSFERASE (DNMT-3B) MRNA EXPRESSION IS ASSOCIATED WITH GENOMIC DNA HYPERMETHYLATION IN PATIENTS WITH CHRONIC ALCOHOLISM. DNA METHYLTRANSFERASES (DNMTS) ARE INVOLVED WITHIN THE EPIGENETIC CONTROL OF DNA METHYLATION PROCESSES. RECENTLY, IT HAS BEEN SHOWN THAT THE GENOMIC DNA METHYLATION IN PATIENTS WITH ALCOHOLISM IS INCREASED. IN THE PRESENT CONTROLLED STUDY WE OBSERVED A SIGNIFICANT DECREASE OF MRNA EXPRESSION OF DNMT-3A AND DNMT-3B WHEN COMPARING ALCOHOLIC PATIENTS (N = 59) WITH HEALTHY CONTROLS (N = 66): DNMT-3A (T = -2.38, P = 0.019), DNMT-3B (T = -2.65, P = 0.008). NO SIGNIFICANT DIFFERENCES WERE SEEN FOR DNMT-1 AND MBD-2 (METHYL-CPG-BINDING-DOMAIN PROTEIN 2) EXPRESSION. ADDITIONALLY, WE OBSERVED A SIGNIFICANT NEGATIVE CORRELATION BETWEEN DNMT-3B EXPRESSION AND THE BLOOD ALCOHOL CONCENTRATION (R = -0.45, P = 0.003) WHICH MIGHT EXPLAIN THE DECREASE OF DNMT-3B MRNA EXPRESSION IN ALCOHOLIC PATIENTS. USING A MULTIVARIATE MODEL WE OBSERVED THAT THE INCREASE (10%) OF GENOMIC DNA METHYLATION IN PATIENTS WITH ALCOHOLISM WAS SIGNIFICANTLY ASSOCIATED WITH THEIR LOWERED DNMT-3B MRNA EXPRESSION (MULTIPLE LINEAR REGRESSION, P = 0.014). SINCE METHYLATION OF DNA IS AN IMPORTANT EPIGENETIC FACTOR IN REGULATION OF GENE EXPRESSION THESE FINDINGS MAY HAVE IMPORTANT IMPLICATIONS FOR A POSSIBLE SUBSEQUENT DERANGEMENT OF EPIGENETIC CONTROL IN THESE PATIENTS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18  3460  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  3637  23 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  5909  24 TARGETED DEEP SEQUENCING OF PLASMA CIRCULATING CELL-FREE DNA REVEALS VIMENTIN AND FIBULIN 1 AS POTENTIAL EPIGENETIC BIOMARKERS FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE SECOND MOST COMMON CAUSE OF CANCER DEATH WORLDWIDE, BUT IS STILL LACKING SENSITIVE AND SPECIFIC BIOMARKERS FOR EARLY DIAGNOSIS AND PROGNOSIS. IN THIS STUDY, WE APPLIED TARGETED MASSIVELY PARALLEL SEMICONDUCTOR SEQUENCING TO ASSESS METHYLATION ON A PANEL OF GENES (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM AND YWHAZ) IN PLASMA CIRCULATING CELL-FREE DNA (CFDNA) AND TO EVALUATE THE POTENTIAL OF THESE GENES AS HCC BIOMARKERS IN TWO DIFFERENT SERIES, ONE FROM FRANCE (42 HCC CASES AND 42 CONTROLS) AND ONE FROM THAILAND (42 HCC CASES, 26 CHRONIC LIVER DISEASE CASES AND 42 CONTROLS). WE ALSO ANALYZED A SET OF HCC AND ADJACENT TISSUES AND LIVER CELL LINES TO FURTHER COMPARE WITH 'THE CANCER GENOME ATLAS' (TCGA) DATA. THE METHYLATION IN CFDNA WAS DETECTED FOR FBLN1, PSMA7, PXDN AND VIM, WITH DIFFERENCES IN METHYLATION PATTERNS BETWEEN CASES AND CONTROLS FOR FBLN1 AND VIM. THE AVERAGE METHYLATION LEVEL ACROSS ANALYZED CPG-SITES WAS ASSOCIATED WITH HIGHER ODDS OF HCC FOR VIM (1.48 [1.02, 2.16] FOR FRENCH CASES AND 2.18 [1.28, 3.72] FOR THAI CASES), AND LOWER ODDS OF HCC FOR FBLN1 (0.89 [0.76, 1.03] FOR FRENCH CASES AND 0.75 [0.63, 0.88] FOR THAI CASES). IN CONCLUSION, OUR STUDY PROVIDES EVIDENCE THAT CHANGES IN VIM AND FBLN1 METHYLATION LEVELS IN CFDNA ARE ASSOCIATED WITH HCC AND COULD REPRESENT USEFUL PLASMA-BASED BIOMARKERS. ALSO, THE POTENTIAL TO INVESTIGATE METHYLATION PATTERNS IN CFDNA COULD BRING NEW STRATEGIES FOR HCC DETECTION AND MONITORING HIGH-RISK GROUPS AND RESPONSE TO TREATMENT.	2017