1 5673 119 SHARED EPIGENETIC ALTERATIONS BETWEEN ORAL CANCER AND PERIODONTITIS: A PRELIMINARY STUDY. INTRODUCTION: WE RECENTLY DEVELOPED A NON-INVASIVE SAMPLING PROCEDURE FOR ORAL SQUAMOUS CELL CARCINOMA (OSCC) DETECTION BASED ON DNA METHYLATION ANALYSIS OF A PANEL OF 13 GENES. ORAL CANCER, AS WELL AS ACUTE AND CHRONIC INFLAMMATORY DISEASES, MAY INFLUENCE THE METHYLATION LEVEL OF SEVERAL GENES IN THE ORAL CAVITY. IN THE PRESENT STUDY, WE EVALUATED THE PRESENCE OF PERIODONTAL DISEASE (PD) AND THE METHYLATION STATUS USING OUR 13-GENE PANEL. METHODS: ORAL BRUSHING SPECIMENS WERE COLLECTED FROM THREE DIFFERENT PATIENT GROUPS: 23 GINGIVAL OSCC PATIENTS, 15 PATIENTS AFFECTED BY PD, AND 15 HEALTHY VOLUNTEERS LACKING EVIDENCE OF PD. DNA METHYLATION ANALYSIS WAS PERFORMED AND EACH SAMPLE WAS DETERMINED TO BE POSITIVE OR NEGATIVE BASED ON A PREDEFINED CUT-OFF VALUE. RESULTS: POSITIVE RESULTS WERE FOUND FOR 23/23 OSCC PATIENTS, 3/15 PD PATIENTS, AND 0/15 SAMPLES FROM HEALTHY VOLUNTEERS. THE GP1BB AND MIR193 GENES IN THE PD GROUP EXHIBITED MEAN METHYLATION LEVELS SIMILAR TO OSCC PATIENTS. ZAP70 SHOWED DIFFERENT METHYLATION LEVELS AMONG THREE GROUPS. CONCLUSION: PRELIMINARY DATA IDENTIFIED SHARED EPIGENETIC ALTERATIONS BETWEEN PD AND OSCC PATIENTS IN TWO INFLAMMATORY GENES (GP1BB AND MIR193). THIS STUDY MAY HELP TO IDENTIFY POTENTIAL LINKS BETWEEN THE TWO DISEASES AND SERVE AS A STARTING POINT FOR THE FUTURE RESEARCH FOCUSED ON PATHOGENESIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2 1607  36 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
3 2653  36 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                      
4 1519  29 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5 3954  35 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 2048  37 EPIGENETIC CLUSTERING OF LUNG ADENOCARCINOMAS BASED ON DNA METHYLATION PROFILES IN ADJACENT LUNG TISSUE: ITS CORRELATION WITH SMOKING HISTORY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE AIM OF THIS STUDY WAS TO CLARIFY THE SIGNIFICANCE OF DNA METHYLATION ALTERATIONS DURING LUNG CARCINOGENESIS. INFINIUM ASSAY WAS PERFORMED USING 139 PAIRED SAMPLES OF NON-CANCEROUS LUNG TISSUE (N) AND TUMOROUS TISSUE (T) FROM A LEARNING COHORT OF PATIENTS WITH LUNG ADENOCARCINOMAS (LADCS). FIFTY PAIRED N AND T SAMPLES FROM A VALIDATION COHORT WERE ALSO ANALYZED. DNA METHYLATION ALTERATIONS ON 1,928 PROBES OCCURRED IN N SAMPLES RELATIVE TO NORMAL LUNG TISSUE FROM PATIENTS WITHOUT PRIMARY LUNG TUMORS, AND WERE INHERITED BY, OR STRENGTHENED IN, T SAMPLES. UNSUPERVISED HIERARCHICAL CLUSTERING USING DNA METHYLATION LEVELS IN N SAMPLES ON ALL 26,447 PROBES SUBCLUSTERED PATIENTS INTO CLUSTER I (N = 32), CLUSTER II (N = 35) AND CLUSTER III (N = 72). LADCS IN CLUSTER I DEVELOPED FROM THE INFLAMMATORY BACKGROUND IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN HEAVY SMOKERS AND WERE LOCALLY INVASIVE. MOST PATIENTS IN CLUSTER II WERE NON-SMOKERS AND HAD A FAVORABLE OUTCOME. LADCS IN CLUSTER III DEVELOPED IN LIGHT SMOKERS WERE MOST AGGRESSIVE (FREQUENTLY SHOWING LYMPHATIC AND BLOOD VESSEL INVASION, LYMPH NODE METASTASIS AND AN ADVANCED PATHOLOGICAL STAGE), AND HAD A POOR OUTCOME. DNA METHYLATION LEVELS OF HALLMARK GENES FOR EACH CLUSTER, SUCH AS IRX2, HOXD8, SPARCL1, RGS5 AND EI24, WERE AGAIN CORRELATED WITH CLINICOPATHOLOGICAL CHARACTERISTICS IN THE VALIDATION COHORT. DNA METHYLATION PROFILES REFLECTING CARCINOGENETIC FACTORS SUCH AS SMOKING AND COPD APPEAR TO BE ESTABLISHED IN NON-CANCEROUS LUNG TISSUE FROM PATIENTS WITH LADCS AND MAY DETERMINE THE AGGRESSIVENESS OF TUMORS DEVELOPING IN INDIVIDUAL PATIENTS, AND THUS PATIENT OUTCOME.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
7 1909  36 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                         
8 3125  29 GHSR DNA HYPERMETHYLATION IS A COMMON EPIGENETIC ALTERATION OF HIGH DIAGNOSTIC VALUE IN A BROAD SPECTRUM OF CANCERS. IDENTIFICATION OF A SINGLE MOLECULAR TRAIT THAT IS DETERMINANT OF COMMON MALIGNANCIES MAY SERVE AS A POWERFUL DIAGNOSTIC SUPPLEMENT TO CANCER TYPE-SPECIFIC MARKERS. HERE, WE REPORT A DNA METHYLATION MARK THAT IS CHARACTERISTIC OF SEVEN STUDIED MALIGNANCIES, NAMELY CANCERS OF LUNG, BREAST, PROSTATE, PANCREAS, COLORECTUM, GLIOBLASTOMA AND B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) (N = 137). THIS MARK WAS DEFINED BY SUBSTANTIAL HYPERMETHYLATION AT THE PROMOTER AND FIRST EXON OF GROWTH HORMONE SECRETAGOUGE RECEPTOR (GHSR) THROUGH BISULFITE PYROSEQUENCING. THE DEGREE OF ABERRANT METHYLATION WAS CAPABLE OF ACCURATE DISCRIMINATION BETWEEN CANCER AND CONTROL SAMPLES. THE HIGHEST SENSITIVITY AND SPECIFICITY OF CANCER DETECTION WAS ACHIEVED FOR CANCERS OF PANCREAS, LUNG, BREAST AND CLL YIELDING THE AREA UNDER THE CURVE (AUC) VALUES OF 1.0000, 0.9952, 0.9800 AND 0.9400, RESPECTIVELY. NARROWING TO A SINGLE CPG SITE WITHIN THE GENE'S PROMOTER OR FOUR CONSECUTIVE CPG UNITS OF THE HIGHEST METHYLATION LEVELS WITHIN THE FIRST EXON IMPROVED THE DETECTION POWER. GHSR HYPERMETHYLATION WAS DETECTED ALREADY AT THE EARLY STAGE TUMORS. THE ACCURATE PERFORMANCE OF THIS MARKER WAS FURTHER REPLICATED IN AN INDEPENDENT SET OF PANCREATIC CANCER AND CONTROL SAMPLES (N = 78). THESE FINDINGS SUPPORT THE CANDIDATURE OF GHSR METHYLATION AS A HIGHLY ACCURATE PAN-CANCER MARKER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 1739  41 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT.	2022	
                                                                                                                                                                                                 
10 5638  34 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                 
11 1587  33 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 2637  37 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY.	2022	

13 1345  36 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 6488  37 TP53 R72P POLYMORPHISM MODULATES DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS CHARACTERIZED BY WIDESPREAD EPIDEMIOLOGICAL AND MOLECULAR HETEROGENEITY. PREVIOUS WORK SHOWED THAT IN THE WESTERN PART OF NORTH AFRICA, A REGION OF LOW INCIDENCE OF HCC, MUTATIONS ARE SCARCE FOR THIS TUMOR TYPE. AS EPIGENETIC CHANGES ARE CONSIDERED POSSIBLE SURROGATES TO MUTATIONS IN HUMAN CANCERS, WE DECIDED, THUS, TO CHARACTERIZE DNA METHYLATION IN HCC FROM NORTH-AFRICAN PATIENTS. METHODS: A SET OF 11 LOCI WAS INVESTIGATED IN A SERIES OF 45 TUMOR SPECIMENS USING METHYLATION-SPECIFIC AND COMBINED-BISULFITE RESTRICTION ASSAY PCR. RESULTS OBTAINED ON CLINICAL SAMPLES WERE SUBSEQUENTLY VALIDATED IN LIVER CANCER CELL LINES. RESULTS: DNA METHYLATION AT TUMOR SUPPRESSOR LOCI IS SIGNIFICANTLY HIGHER IN SAMPLES DISPLAYING CHROMOSOME INSTABILITY. MORE IMPORTANTLY, DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN ARG/ARG WHEN COMPARED TO PRO/PRO GENOTYPE CARRIERS AT CODON 72 RS1042522 OF TP53 (65% VS 20% METHYLATED LOCI, P = 0.0006), A POLYMORPHISM ALREADY KNOWN TO AFFECT SOMATIC MUTATION RATE IN HUMAN CARCINOMAS. IN VITRO EXPERIMENTS IN CELL LINES INDICATED THAT ENZYMES CONTROLLING DNA METHYLATION WERE DIFFERENTIALLY REGULATED BY CODON 72 ARG OR PRO ISOFORMS OF P53. FURTHERMORE, THE ARG72-CARRYING VERSION OF P53 WAS SHOWN TO RE-METHYLATE DNA MORE RAPIDLY THAN THE PRO-HARBORING ISOFORM. FINALLY, PRO-CARRYING CELL LINES WERE SHOWN TO BE SIGNIFICANTLY MORE RESISTANT TO DECITABINE TREATMENT (TWO-FOLD, P = 0.005). CONCLUSIONS: OUR DATA SUGGEST THAT ARG72PRO POLYMORPHISM IN A WT P53 CONTEXT MAY ACT AS A PRIMARY DRIVER OF EPIGENETIC CHANGES IN HCC. IT SUGGESTS, IN ADDITION, THAT RS1042522 GENOTYPE MAY PREDICT SENSITIVITY TO EPIGENETIC-TARGETED THERAPY. THIS MODEL OF LIVER TUMORIGENESIS THAT ASSOCIATES LOW PENETRANCE GENETIC PREDISPOSITION TO EPIGENETIC CHANGES EMERGES FROM A REGION OF LOW HCC INCIDENCE AND IT MAY, THEREFORE, APPLY ESSENTIALLY TO POPULATION LIVING IN SIMILAR AREAS. SURVEYS ON POPULATIONS SUBMITTED TO HIGHLY MUTAGENIC CONDITIONS AS PERINATALLY-ACQUIRED CHRONIC HEPATITIS B OR AFLATOXIN B1 EXPOSURE REMAINED TO BE CONDUCTED TO VALIDATE OUR OBSERVATIONS AS A GENERAL MODEL.	2015	
                                                                                         
15 1591  42 DNA METHYLATION PROFILING IN PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH COPD. BACKGROUND: EPIGENETICS CHANGES HAVE BEEN SHOWN TO BE AFFECTED BY CIGARETTE SMOKING. CIGARETTE SMOKE (CS)-MEDIATED DNA METHYLATION CAN POTENTIALLY AFFECT SEVERAL CELLULAR AND PATHOPHYSIOLOGICAL PROCESSES, ACUTE EXACERBATIONS, AND COMORBIDITY IN THE LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE SOUGHT TO DETERMINE WHETHER GENOME-WIDE LUNG DNA METHYLATION PROFILES OF SMOKERS AND PATIENTS WITH COPD WERE SIGNIFICANTLY DIFFERENT FROM NON-SMOKERS. WE ISOLATED DNA FROM PARENCHYMAL LUNG TISSUES OF PATIENTS INCLUDING EIGHT LIFELONG NON-SMOKERS, EIGHT CURRENT SMOKERS, AND EIGHT PATIENTS WITH COPD AND ANALYZED THE SAMPLES USING ILLUMINA'S INFINIUM HUMANMETHYLATION450 BEADCHIP. RESULTS: OUR DATA REVEALED THAT THE DIFFERENTIALLY METHYLATED GENES WERE RELATED TO TOP CANONICAL PATHWAYS (E.G., G BETA GAMMA SIGNALING, MECHANISMS OF CANCER, AND NNOS SIGNALING IN NEURONS), DISEASE AND DISORDERS (ORGANISMAL INJURY AND ABNORMALITIES, CANCER, AND RESPIRATORY DISEASE), AND MOLECULAR AND CELLULAR FUNCTIONS (CELL DEATH AND SURVIVAL, CELLULAR ASSEMBLY AND ORGANIZATION, CELLULAR FUNCTION AND MAINTENANCE) IN PATIENTS WITH COPD. THE GENOME-WIDE DNA METHYLATION ANALYSIS IDENTIFIED SUGGESTIVE GENES, SUCH AS NOS1AP, TNFAIP2, BID, GABRB1, ATXN7, AND THOC7 WITH DNA METHYLATION CHANGES IN COPD LUNG TISSUES THAT WERE FURTHER VALIDATED BY PYROSEQUENCING. PYROSEQUENCING VALIDATION CONFIRMED HYPER-METHYLATION IN SMOKERS AND PATIENTS WITH COPD AS COMPARED TO NON-SMOKERS. HOWEVER, WE DID NOT DETECT SIGNIFICANT DIFFERENCES IN DNA METHYLATION FOR TNFAIP2, ATXN7, AND THOC7 GENES IN SMOKERS AND COPD GROUPS DESPITE THE CHANGES OBSERVED IN THE GENOME-WIDE ANALYSIS. CONCLUSIONS: OUR STUDY SUGGESTS THAT DNA METHYLATION IN SUGGESTIVE GENES, SUCH AS NOS1AP, BID, AND GABRB1 MAY BE USED AS EPIGENETIC SIGNATURES IN SMOKERS AND PATIENTS WITH COPD IF THE SAME IS VALIDATED IN A LARGER COHORT. FUTURE STUDIES ARE REQUIRED TO CORRELATE DNA METHYLATION STATUS WITH TRANSCRIPTOMICS OF SELECTIVE GENES IDENTIFIED IN THIS STUDY AND ELUCIDATE THEIR ROLE AND INVOLVEMENT IN THE PROGRESSION OF COPD AND ITS EXACERBATIONS.	2017	
                                                                                                               
16 1729  25 DYSREGULATION OF MIR-155 EXPRESSION IN PROFESSIONAL MIXED MARTIAL ARTS (MMA) FIGHTERS. PSYCHOLOGICAL AND PHYSICAL STRESS CAN INDUCE DYSREGULATION OF GENE EXPRESSION VIA CHANGES IN DNA METHYLATION AND MICRORNA (MIRNA) EXPRESSION. SUCH EPIGENETIC MODIFICATIONS ARE YET TO BE INVESTIGATED IN PROFESSIONAL MIXED MARTIAL ARTS (MMA) FIGHTERS SUBJECT TO HIGHLY STRESSFUL TRAINING INVOLVING REPETITIVE HEAD IMPACTS. THIS STUDY EXAMINED DIFFERENCES IN DNA METHYLATION AND MIRNA EXPRESSION IN ELITE MMA FIGHTERS COMPARED TO ACTIVE CONTROLS. GLOBAL METHYLATION DIFFERENCES BETWEEN GROUPS WERE ASSESSED VIA A LINE-1 ASSAY. AT THE SAME TIME, PCR ARRAYS WERE USED TO ESTIMATE DIFFERENTIAL EXPRESSION IN SAMPLES OF 21 FIGHTERS AND 15 CONTROLS FOR 192 DIFFERENT MIRNAS ASSOCIATED WITH INFLAMMATORY DISEASES. AN INDEPENDENT-SAMPLES T-TEST FOUND NO SIGNIFICANT DIFFERENCE IN LINE-1 METHYLATION BETWEEN GROUPS. HOWEVER, AN INDEPENDENT-SAMPLES MANN-WHITNEY U TEST REVEALED A SIGNIFICANT UPREGULATION IN THE EXPRESSION OF MIR-155 IN MMA FIGHTER PLASMA. SINCE MIR-155 HAS BEEN RECOGNIZED AS AN IMPORTANT REGULATOR OF NEUROINFLAMMATION, THIS DYSREGULATION SUGGESTS A POSSIBLE EPIGENETIC MECHANISM RESPONSIBLE FOR CHRONIC INFLAMMATION ASSOCIATED WITH PROFESSIONAL-LEVEL MMA TRAINING. CONSISTENT WITH OTHER PUBLISHED WORKS, THIS STUDY HIGHLIGHTS THE POTENTIAL OF MIR-155 NOT ONLY AS A BIOMARKER FOR MONITORING LONG-TERM HEALTH RISKS LINKED TO HEAD TRAUMA BUT ALSO AS A TARGET TO REMEDIATE THE IMPACT OF CHRONIC NEUROINFLAMMATION.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17  177  33 ACCELERATED EPIGENETIC AGING AND INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) IN PATIENTS WITH CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). THIS FAILURE CAN BE RELATED TO A PHENOTYPE OF ACCELERATED AGING. IN THIS WORK, WE CONSIDERED 76 PATIENTS WITH END-STAGE RENAL DISEASE (ESRD) AND 83 HEALTHY CONTROLS. WE CONCOMITANTLY EVALUATED FOR THE FIRST TIME TWO MEASURES THAT CAN BE INFORMATIVE OF THE RATE OF AGING, I.E., WHOLE BLOOD DNA METHYLATION USING THE ILLUMINA INFINIUM EPIC ARRAY AND PLASMA LEVELS OF A SELECTION OF INFLAMMATORY/IMMUNOLOGICAL PROTEINS USING MULTIPLEX IMMUNOASSAYS. FIRST OF ALL, WE DEMONSTRATED ACCELERATED AGING IN TERMS OF THE MOST COMMON EPIGENETIC AGE ESTIMATORS IN CKD PATIENTS. MOREOVER, WE DEVELOPED A NEW CLOCK/PREDICTOR OF AGE BASED ON THE INFLAMMATORY/IMMUNOLOGICAL PROFILE (IPAGE) AND IDENTIFIED THE INFLAMMATORY/IMMUNOLOGICAL BIOMARKERS DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS. IPAGE APPEARED TO BE MORE SENSITIVE THAN EPIGENETIC CLOCKS IN QUANTIFYING THE ACCELERATED AGING PHENOTYPE OF ESRD PATIENTS. INTERESTINGLY, WE DID NOT FIND ANY CORRELATION BETWEEN THE AGE ACCELERATION EVALUATED ACCORDING TO THE EPIGENETIC CLOCKS AND IPAGE IN EITHER THE ESRD GROUP OR THE CONTROL GROUP. ON THE WHOLE, OUR DATA SHOW A CONSISTENT ACCELERATED AGING PHENOTYPE IN ESRD PATIENTS, WHICH IS BETTER APPRECIATED BY QUANTIFYING THE UNDERLYING INFLAMMATORY PROCESSES (INFLAMMAGING) BY IPAGE THAN BY USING EPIGENETIC CLOCKS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18 1590  28 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19 2620  37 EPIGENOME-WIDE ASSOCIATION DATA IMPLICATES DNA METHYLATION-MEDIATED GENETIC RISK IN PSORIASIS. BACKGROUND: PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPROLIFERATION AND ALTERED KERATINOCYTE DIFFERENTIATION AND INFLAMMATION AND IS CAUSED BY THE INTERPLAY OF GENETIC AND ENVIRONMENTAL FACTORS. PREVIOUS STUDIES HAVE REVEALED THAT DNA METHYLATION (DNAM) AND GENETIC MAKERS ARE CLOSELY ASSOCIATED WITH PSORIASIS, AND STRONG EVIDENCES HAVE SHOWN THAT DNAM CAN BE CONTROLLED BY GENETIC FACTORS, WHICH ATTRACTED US TO EVALUATE THE RELATIONSHIP AMONG DNAM, GENETIC MAKERS, AND DISEASE STATUS. METHODS: WE UTILIZED THE GENOME-WIDE METHYLATION DATA OF PSORIATIC SKIN (PP, N = 114) AND UNAFFECTED CONTROL SKIN (NN, N = 62) TISSUE SAMPLES IN OUR PREVIOUS STUDY, AND WE PERFORMED WHOLE-GENOME GENOTYPING WITH PERIPHERAL BLOOD OF THE SAME SAMPLES TO EVALUATE THE UNDERLYING GENETIC EFFECT ON SKIN DNA METHYLATION. CAUSAL INFERENCE TEST (CIT) WAS USED TO ASSESS WHETHER DNAM REGULATE GENETIC VARIATION AND GAIN A BETTER UNDERSTANDING OF THE EPIGENETIC BASIS OF PSORIASIS SUSCEPTIBILITY. RESULTS: WE IDENTIFIED 129 SNP-CPG PAIRS ACHIEVING THE SIGNIFICANT ASSOCIATION THRESHOLD, WHICH CONSTITUTED 28 UNIQUE METHYLATION QUANTITATIVE TRAIT LOCI (METHQTL) AND 34 UNIQUE CPGS. THERE ARE 18 SNPS WERE ASSOCIATED WITH PSORIASIS AT A BONFERONI-CORRECTED P < 0.05, AND THESE 18 SNPS FORMED 93 SNP-CPG PAIRS WITH 17 UNIQUE CPG SITES. WE FOUND THAT 11 OF 93 SNP-CPG PAIRS, COMPOSED OF 5 UNIQUE SNPS AND 3 CPG SITES, PRESENTED A METHYLATION-MEDIATED RELATIONSHIP BETWEEN SNPS AND PSORIASIS. THE 3 CPG SITES WERE LOCATED ON THE BODY OF C1ORF106, THE TSS1500 PROMOTER REGION OF DMBX1 AND THE BODY OF SIK3. CONCLUSIONS: THIS STUDY REVEALED THAT DNAM OF SOME GENES CAN BE CONTROLLED BY GENETIC FACTORS AND ALSO MEDIATE RISK VARIATION FOR PSORIASIS IN CHINESE HAN POPULATION AND PROVIDED NOVEL MOLECULAR INSIGHTS INTO THE PATHOGENESIS OF PSORIASIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                         
20 2024  39 EPIGENETIC CHANGES CAUSED BY DIABETES AND THEIR POTENTIAL ROLE IN THE DEVELOPMENT OF PERIODONTITIS. AIMS/INTRODUCTION: PERIODONTAL DISEASE, A CHRONIC INFLAMMATION INDUCED BY BACTERIA, IS CLOSELY LINKED WITH DIABETES MELLITUS. MANY COMPLICATIONS ASSOCIATED WITH DIABETES ARE RELATED TO EPIGENETIC CHANGES. HOWEVER, THE EXACT EPIGENETIC CHANGES WHEREBY DIABETES AFFECTS PERIODONTAL DISEASE REMAIN LARGELY UNKNOWN. THUS, WE SOUGHT TO INVESTIGATE THE ROLE OF DIABETES-DEPENDENT EPIGENETIC CHANGES OF GINGIVAL TISSUE IN THE SUSCEPTIBILITY TO PERIODONTAL DISEASE. MATERIALS AND METHODS: WE STUDIED THE EFFECT OF STREPTOZOTOCIN-INDUCED DIABETES IN MINIPIGS ON GINGIVAL MORPHOLOGICAL AND EPIGENETIC TISSUE CHANGES. ACCORDINGLY, WE RANDOMLY DIVIDED SIX MINIPIGS INTO TWO GROUPS: STREPTOZOTOCIN-INDUCED DIABETES GROUP, N = 3; AND NON-DIABETES HEALTHY CONTROL GROUP, N = 3. AFTER 85 DAYS, ALL ANIMALS WERE KILLED, AND GINGIVAL TISSUE WAS COLLECTED FOR HISTOLOGY, DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS AND IMMUNOHISTOCHEMISTRY. RESULTS: A DIABETES MELLITUS MODEL WAS SUCCESSFULLY CREATED, AS EVIDENCED BY SIGNIFICANTLY INCREASED BLOOD GLUCOSE LEVELS, REDUCTION OF PANCREATIC INSULIN-PRODUCING BETA-CELLS AND HISTOPATHOLOGICAL CHANGES IN THE KIDNEYS. THE GINGIVAL TISSUES IN THE DIABETES GROUP PRESENTED ACANTHOSIS OF BOTH GINGIVAL SQUAMOUS EPITHELIUM AND SULCULAR/JUNCTIONAL EPITHELIUM, AND A SIGNIFICANT REDUCTION IN THE NUMBER AND LENGTH OF RETE PEGS. DEOXYRIBONUCLEIC ACID METHYLATION ANALYSIS SHOWED A TOTAL OF 1,163 AFFECTED GENES, OF WHICH 599 AND 564 WERE SIGNIFICANTLY HYPERMETHYLATED AND HYPOMETHYLATED, RESPECTIVELY. IMMUNOHISTOCHEMISTRY STAINING SHOWED THAT THE HYPOMETHYLATED GENES - TUMOR NECROSIS FACTOR-ALPHA AND INTERLEUKIN-6 - WERE POSITIVELY EXPRESSED UNDER THE JUNCTIONAL EPITHELIUM AREA IN THE DIABETES GROUP. CONCLUSIONS: DIABETES MELLITUS INDUCES MORPHOLOGICAL AND EPIGENETIC CHANGES IN PERIODONTAL TISSUE, WHICH MIGHT CONTRIBUTE TO THE INCREASED SUSCEPTIBILITY OF PERIODONTAL DISEASES IN PATIENTS WITH DIABETES.	2021