1 3751 193 INTAKE OF NATURAL COMPOUNDS AND CIRCULATING MICRORNA EXPRESSION LEVELS: THEIR RELATIONSHIP INVESTIGATED IN HEALTHY SUBJECTS WITH DIFFERENT DIETARY HABITS. DIET HAS A STRONG INFLUENCE ON MANY PHYSIOLOGICAL PROCESSES, WHICH IN TURN HAVE IMPORTANT IMPLICATIONS ON A VARIETY OF PATHOLOGICAL CONDITIONS. IN THIS RESPECT, MICRORNAS (MIRNAS), A CLASS OF SMALL NON-CODING RNAS PLAYING A RELEVANT EPIGENETIC ROLE IN CONTROLLING GENE EXPRESSION, MAY REPRESENT MEDIATORS BETWEEN THE DIETARY INTAKE AND THE HEALTHY STATUS. DESPITE GREAT ADVANCES IN THE FIELD OF NUTRI-EPIGENOMICS, IT REMAINS UNCLEAR HOW MIRNA EXPRESSION IS MODULATED BY THE DIET AND, SPECIFICALLY, THE INTAKE OF SPECIFIC NUTRIENTS. WE INVESTIGATED THE WHOLE CIRCULATING MIRNOME BY SMALL RNA-SEQUENCING PERFORMED ON PLASMA SAMPLES OF 120 HEALTHY VOLUNTEERS WITH DIFFERENT DIETARY HABITS (VEGANS, VEGETARIANS, AND OMNIVORES). DIETARY INTAKES OF SPECIFIC NUTRIENTS WERE ESTIMATED FOR EACH SUBJECT FROM THE INFORMATION REPORTED IN THE FOOD-FREQUENCY QUESTIONNAIRE PREVIOUSLY VALIDATED IN THE EPIC STUDY. WE FOCUSED HEREBY ON THE INTAKE OF 23 NATURAL COMPOUNDS (NCS) OF THE CLASSES OF LIPIDS, MICRO-ELEMENTS, AND VITAMINS. WE IDENTIFIED 78 SIGNIFICANT CORRELATIONS (RHO > 0.300, P-VALUE < 0.05) AMONG THE ESTIMATED DAILY INTAKE OF 13 NCS AND THE EXPRESSION LEVELS OF 58 PLASMA MIRNAS. OVERALL, VITAMIN D, SODIUM, AND VITAMIN E CORRELATED WITH THE LARGEST NUMBER OF MIRNAS. ALL THE IDENTIFIED CORRELATIONS WERE CONSISTENT AMONG THE THREE DIETARY GROUPS AND 22 OF THEM WERE CONFIRMED AS SIGNIFICANT (P-VALUE < 0.05) BY AGE-, GENDER-, AND BODY-MASS INDEX-ADJUSTED GENERALIZED LINEAR REGRESSION MODEL ANALYSIS. MIR-23A-3P EXPRESSION LEVELS WERE RELATED WITH DIFFERENT NCS INCLUDING A SIGNIFICANT POSITIVE CORRELATION WITH SODIUM (RHO = 0.377) AND SIGNIFICANT NEGATIVE CORRELATIONS WITH LIPID-RELATED NCS AND VITAMIN E. CONVERSELY, THE ESTIMATED INTAKE OF VITAMIN D WAS NEGATIVELY CORRELATED WITH THE EXPRESSION OF THE HIGHEST NUMBER OF CIRCULATING MIRNAS, PARTICULARLY MIR-1277-5P (RHO = -0.393) AND MIR-144-3P (RHO = -0.393). FUNCTIONAL ANALYSIS OF THE TARGETS OF SODIUM INTAKE-CORRELATED MIRNAS HIGHLIGHTED TERMS RELATED TO CARDIAC DEVELOPMENT. A SIMILAR APPROACH ON TARGETS OF THOSE MIRNAS CORRELATED WITH VITAMIN D INTAKE SHOWED AN ENRICHMENT IN GENES INVOLVED IN HORMONE METABOLISMS, WHILE THE RESPONSE TO CHRONIC INFLAMMATION WAS AMONG THE TOP ENRICHED PROCESSES INVOLVING TARGETS OF MIRNAS NEGATIVELY RELATED WITH VITAMIN E INTAKE. OUR FINDINGS SHOW THAT NUTRIENTS THROUGH THE HABITUAL DIET INFLUENCE CIRCULATING MIRNA PROFILES AND HIGHLIGHT THAT THIS ASPECT MUST BE CONSIDERED IN THE NUTRI-EPIGENOMIC RESEARCH.	2020	

2 6720  41 VITAMIN D METABOLISM GENES ARE DIFFERENTIALLY METHYLATED IN INDIVIDUALS WITH CHRONIC KNEE PAIN. CONTEXT: RECENT EVIDENCE SUGGESTS THAT VITAMIN D MAY INTERACT WITH THE EPIGENOME AND PLAY A ROLE IN THE PAIN EXPERIENCE. IN ORDER FOR PROPER FUNCTIONING TO OCCUR, THERE MUST BE AN ADEQUATE LEVEL OF VITAMIN D PRESENT, MADE POSSIBLE BY ENZYMATIC REACTIONS THAT ALLOW VITAMIN D TO BE BIOLOGICALLY ACTIVE. THE PURPOSE OF THIS STUDY WAS TO EXPLORE THE EPIGENETIC LANDSCAPE OF GENES INVOLVED IN VITAMIN D METABOLISM IN INDIVIDUALS WITH AND WITHOUT CHRONIC KNEE PAIN. PROCEDURES: COMMUNITY-DWELLING INDIVIDUALS RECRUITED AS PART OF A LARGER STUDY FOCUSED ON KNEE PAIN PROVIDED DEMOGRAPHIC, CLINICAL AND PAIN-RELATED INFORMATION, AS WELL AS AN INTRAVENOUS BLOOD SAMPLE TO DETERMINE DNA METHYLATION LEVELS AT CPG SITES. MAIN FINDINGS: THERE WERE DIFFERENCES IN DNA METHYLATION BETWEEN THOSE WITH AND WITHOUT PAIN IN GENES THAT CODE FOR ENZYMES RELATED TO VITAMIN D METABOLISM: CYP24A1 (24-HYDROXYLASE) AND CYP27B1 (1-?-HYDROXYLASE). THERE WAS ALSO HYPERMETHYLATION ON THE GENE THAT CODES FOR THE VITAMIN D RECEPTOR (VDR). PRINCIPAL CONCLUSIONS: THE PRESENCE OF CHRONIC PAIN IS ASSOCIATED WITH EPIGENETIC MODIFICATIONS IN GENES RESPONSIBLE FOR THE EXPRESSION OF ENZYMES INVOLVED IN VITAMIN D METABOLISM AND CELLULAR FUNCTION. THESE RESULTS LAY GROUNDWORK IN UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION BETWEEN VITAMIN D AND CHRONIC PAIN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3 5638  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
4 5734  46 SMALL NON-CODING RNAS ARE ALTERED BY SHORT-TERM SPRINT INTERVAL TRAINING IN MEN. SMALL NON-CODING RNAS (NCRNAS) ARE EMERGING AS IMPORTANT MOLECULES FOR NORMAL BIOLOGICAL PROCESSES AND ARE DEREGULATED IN DISEASE. EXERCISE TRAINING IS A POWERFUL THERAPEUTIC STRATEGY THAT PREVENTS CARDIOMETABOLIC DISEASE AND IMPROVES CARDIORESPIRATORY FITNESS AND PERFORMANCE. DESPITE THE KNOWN SYSTEMIC HEALTH BENEFITS OF EXERCISE TRAINING, THE UNDERLYING MOLECULAR MECHANISMS ARE INCOMPLETELY UNDERSTOOD. RECENT EVIDENCE SUGGESTS A ROLE FOR EPIGENETIC MECHANISMS, SUCH AS MICRORNAS, BUT WHETHER OTHER SMALL NCRNAS ARE MODULATED BY CHRONIC EXERCISE TRAINING IS UNKNOWN. HERE, WE USED SMALL RNA SEQUENCING TO EXPLORE WHETHER SPRINT INTERVAL TRAINING (SIT) CONTROLS THE ABUNDANCE OF CIRCULATING SMALL NCRNAS IN HUMAN WHOLE BLOOD SAMPLES. TEN HEALTHY MEN PERFORMED SIT THREE TIMES A WEEK FOR 6 WEEKS. AFTER TRAINING, SUBJECTS SHOWED MARKED IMPROVEMENTS IN MAXIMAL OXYGEN CONSUMPTION AND CYCLING PERFORMANCE WITH CONCURRENT CHANGES TO THE ABUNDANCE OF DIVERSE SPECIES OF CIRCULATING SMALL NCRNAS (N = 1266 SMALL NCRNAS, N = 13 MICRORNAS, Q < 0.05). TWELVE MICRORNAS ALTERED BY 6 WEEKS OF SIT WERE UBIQUITOUSLY EXPRESSED MICRORNAS AND TWO REGULATED IMPORTANT SIGNALING PATHWAYS, INCLUDING P53, THYROID HORMONE AND CELL CYCLE SIGNALING. MICRORNAS ALTERED BY 6 WEEKS OF SIT WERE UNCHANGED AFTER A SINGLE SESSION OF SIT (N = 24, ALL P > 0.05). RELATIVE TO OLDER INDIVIDUALS, YOUNGER SUBJECTS EXHIBITED AN INCREASED ACUTE SIT-INDUCED FOLD CHANGE IN MIR-1301-3P (P = 0.02) - A MICRORNA PREDICTED TO TARGET MRNAS INVOLVED IN ALTERNATIVE SPLICING, PHOSPHOPROTEIN AND CHROMOSOMAL REARRANGEMENT PROCESSES (ALL P < 0.001). OUR FINDINGS INDICATE MANY SPECIES OF CIRCULATING SMALL NCRNAS ARE MODULATED BY EXERCISE TRAINING AND THAT THEY COULD CONTROL SIGNALING PATHWAYS RESPONSIBLE FOR HEALTH BENEFITS ACHIEVED FROM EXERCISE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 4367  49 MIRNA-BASED "FITNESS SCORE" TO ASSESS THE INDIVIDUAL RESPONSE TO DIET, METABOLISM, AND EXERCISE. BACKGROUND: REGULAR, ESPECIALLY SUSTAINED EXERCISE PLAYS AN IMPORTANT ROLE IN THE PREVENTION AND TREATMENT OF MULTIPLE CHRONIC DISEASES. SOME OF THE UNDERLYING MOLECULAR AND CELLULAR MECHANISMS BEHIND THE ADAPTIVE RESPONSE TO PHYSICAL ACTIVITY ARE STILL UNCLEAR, BUT RECENT FINDINGS SUGGEST A POSSIBLE ROLE OF EPIGENETIC MECHANISMS, ESPECIALLY MIRNAS, IN THE PROGRESSION AND MANAGEMENT OF EXERCISE-RELATED CHANGES. DUE TO THE COMBINATION OF THE ANALYSIS OF EPIGENETIC BIOMARKERS (MIRNAS), THE INTAKE OF FOOD AND SUPPLEMENTS, AND GENETIC DISPOSITIONS, A "FITNESS SCORE" WAS EVALUATED TO ASSESS THE INDIVIDUAL RESPONSE TO NUTRITION, EXERCISE, AND METABOLIC INFLUENCE. METHODS: IN RESPONSE TO A 12-WEEK SPORTS INTERVENTION, WE ANALYZED GENETIC AND EPIGENETIC BIOMARKERS IN CAPILLARY BLOOD FROM 61 SEDENTARY, HEALTHY PARTICIPANTS (66.1% FEMALES, 33.9% MALES, MEAN AGE 33 YEARS), INCLUDING LINE-1 METHYLATION, THREE SNPS, AND TEN MIRNAS USING HRM AND QPCR ANALYSIS. THESE BIOMARKERS WERE ALSO ANALYZED IN A HEALTHY, AGE- AND SEX-MATCHED CONTROL GROUP (N, 20) WITHOUT INTERVENTION. FOOD FREQUENCY INTAKE, INCLUDING DIETARY SUPPLEMENT INTAKE, AND GENERAL HEALTH QUESTIONNAIRES WERE SURVEYED UNDER THE SUPERVISION OF TRAINED STAFF. RESULTS: EXERCISE TRAINING DECREASED THE EXPRESSION OF MIR-20A-5P, -22-5P, AND -505-3P (P < 0.02) AND IMPROVED THE "FITNESS SCORE," WHICH ESTIMATES EIGHT DIFFERENT LIFESTYLE FACTORS TO ASSESS, NUTRITION, INFLAMMATION, CARDIOVASCULAR FITNESS, INJURY RISK, REGENERATION, MUSCLE AND HYDRATION STATUS, AS WELL AS STRESS LEVEL. IN ADDITION, WE WERE ABLE TO DETERMINE CORRELATIONS BETWEEN INDIVIDUAL MIRNAS, MIR-20A-5P, -22-5P, AND -101-3P (P < 0.04), AND THE GENETIC PREDISPOSITION FOR ENDURANCE AND/OR STRENGTH AND OBESITY RISK (ACE, ACTN3, AND FTO), AS WELL AS BETWEEN MIRNAS AND THE BODY COMPOSITION (P < 0.05). MIR-19B-3P AND -101-3P CORRELATED WITH THE INTAKE OF B VITAMINS. FURTHER, MIR-19B-3P CORRELATED WITH MAGNESIUM AND MIR-378A-3P WITH IRON INTAKE (P < 0.05). CONCLUSIONS: IN SUMMARY, OUR RESULTS INDICATE THAT A COMBINED ANALYSIS OF SEVERAL BIOMARKERS (MIRNAS) CAN PROVIDE INFORMATION ABOUT AN INDIVIDUAL'S TRAINING ADAPTIONS/FITNESS, BODY COMPOSITION, NUTRITIONAL NEEDS, AND POSSIBLE RECOVERY. IN CONTRAST TO MOST STUDIES USING MUSCLE BIOPSIES, WE WERE ABLE TO SHOW THAT THESE BIOMARKERS CAN ALSO BE MEASURED USING A MINIMALLY INVASIVE METHOD.	2022	
                                                                                                                                                                                                
6 6547  44 TRANSCRIPTOMICS OF LONG-TERM MEDITATION PRACTICE: EVIDENCE FOR PREVENTION OR REVERSAL OF STRESS EFFECTS HARMFUL TO HEALTH. BACKGROUND AND OBJECTIVES: STRESS CAN OVERLOAD ADAPTIVE MECHANISMS, LEADING TO EPIGENETIC EFFECTS HARMFUL TO HEALTH. RESEARCH ON THE REVERSAL OF THESE EFFECTS IS IN ITS INFANCY. EARLY RESULTS SUGGEST SOME MEDITATION TECHNIQUES HAVE HEALTH BENEFITS THAT GROW WITH REPEATED PRACTICE. THIS STUDY FOCUSED ON POSSIBLE TRANSCRIPTOMIC EFFECTS OF 38 YEARS OF TWICE-DAILY TRANSCENDENTAL MEDITATION((R)) (TM((R))) PRACTICE. MATERIALS AND METHODS: FIRST, USING ILLUMINA((R)) BEADCHIP MICROARRAY TECHNOLOGY, DIFFERENCES IN GLOBAL GENE EXPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE SOUGHT BETWEEN HEALTHY PRACTITIONERS AND TIGHTLY MATCHED CONTROLS (N = 12, AGE 65). SECOND, THESE MICROARRAY RESULTS WERE VERIFIED ON A SUBSET OF GENES USING QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND WERE VALIDATED USING QPCR IN LARGER TM AND CONTROL GROUPS (N = 45, AGE 63). BIOINFORMATICS INVESTIGATION EMPLOYED INGENUITY((R)) PATHWAY ANALYSIS (IPA((R))), DAVID, GENOMATIX, AND R PACKAGES. RESULTS: THE 200 GENES AND LOCI FOUND TO MEET STRICT CRITERIA FOR DIFFERENTIAL EXPRESSION IN THE MICROARRAY EXPERIMENT SHOWED CONTRASTING PATTERNS OF EXPRESSION THAT DISTINGUISHED THE TWO GROUPS. DIFFERENTIAL EXPRESSION RELATING TO IMMUNE FUNCTION AND ENERGY EFFICIENCY WERE MOST APPARENT. IN THE TM GROUP, RELATIVE TO THE CONTROL, ALL 49 GENES ASSOCIATED WITH INFLAMMATION WERE DOWNREGULATED, WHILE GENES ASSOCIATED WITH ANTIVIRAL AND ANTIBODY COMPONENTS OF THE DEFENSE RESPONSE WERE UPREGULATED. THE LARGEST EXPRESSION DIFFERENCES WERE SHOWN BY SIX GENES RELATED TO ERYTHROCYTE FUNCTION THAT APPEARED TO REFLECT A CONDITION OF LOWER ENERGY EFFICIENCY IN THE CONTROL GROUP. RESULTS SUPPORTING THESE GENE EXPRESSION DIFFERENCES WERE OBTAINED WITH QPCR-MEASURED EXPRESSION BOTH IN THE WELL-MATCHED MICROARRAY GROUPS AND IN THE LARGER, LESS WELL-MATCHED GROUPS. CONCLUSIONS: THESE FINDINGS ARE CONSISTENT WITH PREDICTIONS BASED ON RESULTS FROM EARLIER RANDOMIZED TRIALS OF MEDITATION AND MAY PROVIDE EVIDENCE FOR STRESS-RELATED MOLECULAR MECHANISMS UNDERLYING REDUCTIONS IN ANXIETY, POST-TRAUMATIC STRESS DISORDER (PTSD), CARDIOVASCULAR DISEASE (CVD), AND OTHER CHRONIC DISORDERS AND DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                             
7 1345  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
8 3652  39 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10 2909  40 GENE EXPRESSION PROFILING IN FIBROMYALGIA INDICATES AN AUTOIMMUNE ORIGIN OF THE DISEASE AND OPENS NEW AVENUES FOR TARGETED THERAPY. FIBROMYALGIA IS A CHRONIC DISORDER CHARACTERIZED BY WIDESPREAD PAIN AND BY SEVERAL NON-PAIN SYMPTOMS. AUTOIMMUNITY, SMALL FIBER NEUROPATHY AND NEUROINFLAMMATION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF THE DISEASE. WE HAVE INVESTIGATED THE GENE EXPRESSION PROFILE IN PERIPHERAL BLOOD MONONUCLEAR CELLS OBTAINED FROM TEN PATIENTS AND TEN HEALTHY SUBJECTS. OF THE 545,500 TRANSCRIPTS ANALYZED, 1673 RESULTED MODULATED IN FIBROMYALGIC PATIENTS. THE MAJORITY OF THESE GENES ARE INVOLVED IN BIOLOGICAL PROCESSES AND PATHWAYS LINKED TO THE CLINICAL MANIFESTATIONS OF THE DISEASE. MOREOVER, GENES INVOLVED IN IMMUNOLOGICAL PATHWAYS CONNECTED TO INTERLEUKIN-17 AND TO TYPE I INTERFERON SIGNATURES WERE ALSO MODULATED, SUGGESTING THAT AUTOIMMUNITY PLAYS A ROLE IN THE DISEASE. WE THEN AIMED AT IDENTIFYING DIFFERENTIALLY EXPRESSED LONG NON-CODING RNAS (LNCRNAS) FUNCTIONALLY CONNECTED TO MODULATED GENES BOTH DIRECTLY AND VIA MICRORNA TARGETING. ONLY TWO LNCRNAS OF THE 298 FOUND MODULATED IN PATIENTS, WERE ABLE TO TARGET THE MOST HIGHLY CONNECTED GENES IN THE FIBROMYALGIA INTERACTOME, SUGGESTING THEIR INVOLVEMENT IN CRUCIAL GENE REGULATION. OUR GENE EXPRESSION DATA WERE CONFIRMED BY REAL TIME PCR, BY AUTOANTIBODY TESTING, DETECTION OF SOLUBLE MEDIATORS AND TH-17 POLARIZATION IN A VALIDATION COHORT OF 50 PATIENTS. OUR RESULTS INDICATE THAT GENETIC AND EPIGENETIC MECHANISMS AS WELL AS AUTOIMMUNITY PLAY A PIVOTAL ROLE IN THE PATHOGENESIS OF FIBROMYALGIA.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
11 1193  47 CORRELATION OF CYP2R1 GENE PROMOTER METHYLATION WITH CIRCULATING VITAMIN D LEVELS AMONG HEALTHY ADULTS. BACKGROUND & OBJECTIVES: DESPITE BEING A TROPICAL COUNTRY, VITAMIN D DEFICIENCY IS HIGHLY PREVALENT IN INDIA WITH STUDIES INDICATING 40-99 PER CENT PREVALENCE. APART FROM CALCIUM AND PHOSPHATE METABOLISM, VITAMIN D IS INVOLVED IN CELL CYCLE REGULATION, CARDIOVASCULAR, HEPATOPROTECTION. THE METABOLISM OF VITAMIN D IS REGULATED BY VITAMIN D TOOL GENES (CYP2R1/CYP27B1/CYP24A1/VDR). THE PROMOTER REGIONS OF SOME OF THESE GENES HAVE CPG ISLANDS, MAKING THEM PRONE TO METHYLATION INDUCED GENE SILENCING, WHICH MAY CAUSE A REDUCTION IN CIRCULATING VITAMIN D LEVELS. EPIGENETIC BASIS OF VITAMIN D DEFICIENCY IS YET TO BE STUDIED IN INDIA, AND HENCE, THIS PILOT STUDY WAS AIMED TO ANALYZE WHETHER METHYLATION LEVELS OF CYP2R1 GENE WERE CORRELATED WITH THE LEVELS OF 25(OH)D IN HEALTHY, ADULT INDIVIDUALS IN INDIAN POPULATION. METHODS: IN THIS CROSS-SECTIONAL STUDY, HEALTHY ADULTS OF 18-45 YR OF AGE WITH NO HISTORY OF MALABSORPTION, THYROIDECTOMY, CHRONIC ILLNESS OR THERAPEUTIC VITAMIN D SUPPLEMENTATION WERE RECRUITED. DNA METHYLATION ANALYSIS WAS CARRIED OUT BY METHYLATION SPECIFIC QUANTITATIVE PCR. SERUM CALCIUM, PHOSPHATE AND VITAMIN D LEVELS WERE ALSO QUANTIFIED. STATISTICAL ANALYSIS WAS DONE BY R 4.0.5 SOFTWARE. RESULTS: A TOTAL OF 61 APPARENTLY HEALTHY ADULTS WERE ANALYZED. THE SERUM VITAMIN D LEVELS DID NOT CORRELATE WITH CYP2R1 METHYLATION LEVELS IN OUR STUDY POPULATION. SIGNIFICANT POSITIVE CORRELATION WAS OBSERVED BETWEEN AGE AND SERUM VITAMIN D LEVELS. SIGNIFICANT ASSOCIATION OF GENDER WAS FOUND WITH CYP2R1 METHYLATION LEVELS. INTERPRETATION & CONCLUSIONS: THIS STUDY FOUND NO SIGNIFICANT CORRELATION BETWEEN LEVELS OF CYP2R1 METHYLATION AND CIRCULATING 25(OH)D DEFICIENCY. FURTHER STUDIES ON THE INDIAN POPULATION HAVING A LARGER SAMPLE SIZE INCLUDING ENTIRE VITAMIN D TOOL GENES, AMONG DIFFERENT ETHNIC GROUPS MAY BE CONDUCTED TO ELUCIDATE MOLECULAR ETIOLOGY OF CIRCULATING 25(OH)D DEFICIENCY. THE HIGH PREVALENCE OF NORMAL SERUM CALCIUM AND PHOSPHATE LEVELS AMONG VITAMIN D DEFICIENT SUBJECTS IN THIS STUDY COUPLED WITH THE STRIKINGLY HIGH PREVALENCE OF THE DEFICIENCY AT THE NATIONAL LEVEL, MAY SUGGEST THE NEED TO REVISE THE CUT-OFF CRITERIA FOR VITAMIN D DEFICIENCY IN THE INDIAN POPULATION.	2023	
                                                                                                                                                                                                                                                                                                                                                        
12 1567  37 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13 1607  42 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14 1503  33 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
15 2653  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
16 1025  38 CIRCULATING MIRNAS ARE ASSOCIATED WITH INFLAMMATION BIOMARKERS IN CHILDREN WITH OVERWEIGHT AND OBESITY: RESULTS OF THE I.FAMILY STUDY. INCREASING DATA SUGGEST THAT OVERNUTRITION-INDUCED OBESITY MAY TRIGGER AN INFLAMMATORY PROCESS IN ADIPOSE TISSUE AND UPTURN IN THE INNATE IMMUNE SYSTEM. NUMEROUS PLAYERS HAVE BEEN INVOLVED IN GOVERNING THE INFLAMMATORY RESPONSE, INCLUDING EPIGENETICS. AMONG EPIGENETIC PLAYERS, MIRNAS ARE EMERGING AS CRUCIAL REGULATORS OF IMMUNE CELL DEVELOPMENT, IMMUNE RESPONSES, AUTOIMMUNITY, AND INFLAMMATION. IN THIS STUDY, WE AIMED AT IDENTIFYING THE INVOLVEMENT OF CANDIDATE MIRNAS IN RELATION TO INFLAMMATION-ASSOCIATED BIOMARKERS IN A SUBSAMPLE OF EUROPEAN CHILDREN WITH OVERWEIGHT AND OBESITY PARTICIPATING IN THE I.FAMILY STUDY. THE STUDY SAMPLE INCLUDED INDIVIDUALS WITH INCREASED ADIPOSITY SINCE THIS CONDITION CONTRIBUTES TO THE EARLY OCCURRENCE OF CHRONIC LOW-GRADE INFLAMMATION. WE FOCUSED ON THE ACUTE-PHASE REAGENT C-REACTIVE PROTEIN (CRP) AS THE PRIMARY OUTCOME AND SELECTED CYTOKINES AS PLAUSIBLE BIOMARKERS OF INFLAMMATION. WE FOUND THAT CHRONIC LOW-GRADE CRP ELEVATION SHOWS A HIGHLY SIGNIFICANT ASSOCIATION WITH MIR-26B-3P AND HSA-MIR-576-5P IN BOYS. FURTHERMORE, THE ASSOCIATION OF CRP WITH HSA-MIR-10B-5P AND HSA-MIR-31-5P IS HIGHLY SIGNIFICANT IN GIRLS. WE ALSO OBSERVED MAJOR SEX-RELATED ASSOCIATIONS OF CANDIDATE MIRNAS WITH SELECTED CYTOKINES. EXCEPT FOR IL-6, A SIGNIFICANT ASSOCIATION OF HSA-MIR-26B-3P AND HSA-MIR-576-5P WITH TNF-ALPHA, IL1-RA, IL-8, AND IL-15 LEVELS WAS FOUND EXCLUSIVELY IN BOYS. THE FINDINGS OF THIS EXPLORATORY STUDY SUGGEST SEX DIFFERENCES IN THE ASSOCIATION OF CIRCULATING MIRNAS WITH INFLAMMATORY RESPONSE BIOMARKERS, AND INDICATE A POSSIBLE ROLE OF MIRNAS AMONG THE CANDIDATE EPIGENETIC MECHANISMS RELATED TO THE PROCESS OF LOW-GRADE INFLAMMATION IN CHILDHOOD OBESITY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17 2908  45 GENE EXPRESSION PROFILE OF NORMAL BREAST TISSUE AND BODY MASS INDEX. BACKGROUND: IN HUMAN BREAST, ADIPOSE TISSUE REPRESENTS UP TO 80% OF THE TOTAL VOLUME AND PLAYS A CRITICAL ROLE IN MAMMARY GLAND REMODELING. GIVEN THE EMERGING ROLE OF OBESITY IN BREAST CANCER GROWTH AND DEVELOPMENT, WE EXPLORED THE RELATIONSHIP BETWEEN BODY MASS INDEX (BMI), AS A PROXY OF WOMAN'S OBESITY STATUS, AND THE EXPRESSION IN NORMAL BREAST TISSUE FROM HEALTHY WOMEN OF A SELECTED PANEL OF GENES, KNOWN TO BE INVOLVED IN MAMMARY GLAND HOMEOSTASIS. METHODS: TWO INDEPENDENT PUBLICLY AVAILABLE DATASETS, COMPOSED OF 180 SPECIMENS OF NORMAL BREAST TISSUE FROM REDUCTION MAMMOPLASTY WERE INTERROGATED. DIFFERENTIAL GENE EXPRESSION AMONG BMI CLASSES WAS EVALUATED BY ANOVA, AND PARTIAL CORRELATION COEFFICIENT WAS USED TO ASSAY THE CORRELATION BETWEEN GENES CONTROLLING FOR BMI. RESULTS: DESPITE THE DIFFERENCES IN MICROARRAY PLATFORMS AND ANALYTICAL PROCEDURES, THE TWO DATASETS SHARED A CORE OF 9 GENES DIFFERENTIALLY EXPRESSED IN BMI CLASSES AND SIGNIFICANTLY CORRELATED WITH BMI. FOUR (44%) OF THESE GENES BELONG TO THE FUNCTIONAL CLASS OF CYTOKINES AND CYTOKINE RECEPTORS (IL1R1, IL2RA, IL12A, AND IL12RB2). THE OTHERS BELONG TO THE FUNCTIONAL CLASS OF THE EPIGENETIC REGULATION (MEDAG AND SETD7), SIGNAL TRANSDUCTION (STAT1), CELL ADHESION (ITGAV), AND ENZYMATIC ACTIVITY (STS). CONCLUSIONS: ALTHOUGH EXPLORATORY, PRESENT FINDINGS ARE IN AGREEMENT WITH THE ROLE OF INFLAMMATION MODULATORS IN THE HOMEOSTASIS OF NORMAL BREAST TISSUE AND THE BELIEVE THAT AN INCREASE IN BODY ADIPOSE TISSUE MAY HAVE A POTENTIALLY DANGEROUS LOCAL EFFECT, THROUGH THE INCREASED EXPRESSION OF INFLAMMATION-RELATED GENES AND THE ESTABLISHMENT OF A LOW-GRADE CHRONIC INFLAMMATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18 3503  34 IDENTIFICATION OF POTENTIAL DIFFERENTIALLY METHYLATED GENE-RELATED BIOMARKERS IN ENDOMETRIOSIS. AIM: TO IDENTIFY EPIGENETIC ALTERATIONS OF DIFFERENTIALLY EXPRESSED GENES AND SCREEN OUT TARGETED THERAPEUTIC DRUGS IN ENDOMETRIOSIS. METHODS: BASED ON THE GENE EXPRESSION OMNIBUS DATABASE AND A SERIES OF BIOLOGICAL INFORMATION ANALYSIS TOOLS, SUPPLEMENTED BY VALIDATION OF CLINICAL SAMPLES, ABERRANT DNA METHYLATION-DRIVEN GENES AND THEIR FUNCTIONS WERE EXPLORED, AS WELL AS POSSIBLE TARGETED DRUGS. RESULTS: THIS STUDY SCREENED OUT A RANGE OF DNA METHYLATION-DRIVEN GENES THAT WERE ASSOCIATED WITH POWERFUL PROPERTIES AND CORRESPONDING PATHWAYS. AMONG THEM, BDNF AND CCL2 WERE KEY GENES IN THE DEVELOPMENT OF ENDOMETRIOSIS. FOUR CHEMICAL AGENTS HAVE BEEN FLAGGED AS POTENTIAL TREATMENTS FOR ENDOMETRIOSIS. CONCLUSION: THESE CANDIDATE GENES AND SMALL-MOLECULE AGENTS MAY BE FURTHER EXPLORED AS POTENTIAL TARGETS AND DRUGS FOR ENDOMETRIOSIS DIAGNOSIS AND THERAPY, RESPECTIVELY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
19 2820  28 FINE-MAPPING INFLAMMATORY BOWEL DISEASE LOCI TO SINGLE-VARIANT RESOLUTION. INFLAMMATORY BOWEL DISEASES ARE CHRONIC GASTROINTESTINAL INFLAMMATORY DISORDERS THAT AFFECT MILLIONS OF PEOPLE WORLDWIDE. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED 200 INFLAMMATORY BOWEL DISEASE-ASSOCIATED LOCI, BUT FEW HAVE BEEN CONCLUSIVELY RESOLVED TO SPECIFIC FUNCTIONAL VARIANTS. HERE WE REPORT FINE-MAPPING OF 94 INFLAMMATORY BOWEL DISEASE LOCI USING HIGH-DENSITY GENOTYPING IN 67,852 INDIVIDUALS. WE PINPOINT 18 ASSOCIATIONS TO A SINGLE CAUSAL VARIANT WITH GREATER THAN 95% CERTAINTY, AND AN ADDITIONAL 27 ASSOCIATIONS TO A SINGLE VARIANT WITH GREATER THAN 50% CERTAINTY. THESE 45 VARIANTS ARE SIGNIFICANTLY ENRICHED FOR PROTEIN-CODING CHANGES (N = 13), DIRECT DISRUPTION OF TRANSCRIPTION-FACTOR BINDING SITES (N = 3), AND TISSUE-SPECIFIC EPIGENETIC MARKS (N = 10), WITH THE LAST CATEGORY SHOWING ENRICHMENT IN SPECIFIC IMMUNE CELLS AMONG ASSOCIATIONS STRONGER IN CROHN'S DISEASE AND IN GUT MUCOSA AMONG ASSOCIATIONS STRONGER IN ULCERATIVE COLITIS. THE RESULTS OF THIS STUDY SUGGEST THAT HIGH-RESOLUTION FINE-MAPPING IN LARGE SAMPLES CAN CONVERT MANY DISCOVERIES FROM GENOME-WIDE ASSOCIATION STUDIES INTO STATISTICALLY CONVINCING CAUSAL VARIANTS, PROVIDING A POWERFUL SUBSTRATE FOR EXPERIMENTAL ELUCIDATION OF DISEASE MECHANISMS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20 1508  50 DNA METHYLATION AND MRNA AND MICRORNA EXPRESSION OF SLE CD4+ T CELLS CORRELATE WITH DISEASE PHENOTYPE. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS AN AUTOIMMUNE DISEASE WELL KNOWN FOR ITS CLINICAL HETEROGENEITY, AND ITS ETIOLOGY SECONDARY TO A CROSS-TALK INVOLVING GENETIC PREDISPOSITION AND ENVIRONMENTAL STIMULI. ALTHOUGH GENOME-WIDE ANALYSIS HAS CONTRIBUTED GREATLY TO OUR UNDERSTANDING OF THE GENETIC BASIS OF SLE, THERE IS INCREASING EVIDENCE FOR A ROLE OF EPIGENETICS. INDEED, RECENT DATA HAVE DEMONSTRATED THAT IN PATIENTS WITH SLE, THERE ARE STRIKING ALTERATIONS OF DNA METHYLATION, HISTONE MODIFICATIONS, AND DEREGULATED MICRORNA EXPRESSION, THE SUM OF WHICH CONTRIBUTE TO OVER-EXPRESSION OF SELECT AUTOIMMUNE-RELATED GENES AND LOSS OF TOLERANCE. TO ADDRESS THIS ISSUE AT THE LEVEL OF CLINICAL PHENOTYPE, WE PERFORMED DNA METHYLATION, MRNA AND MICRORNA EXPRESSION SCREENING USING HIGH-THROUGHPUT SEQUENCING OF PURIFIED CD4+ T CELLS FROM PATIENTS WITH SLE, COMPARED TO AGE AND SEX MATCHED CONTROLS. IN PARTICULAR, WE STUDIED 42 PATIENTS WITH SLE AND DIVIDED THIS GROUP INTO THREE CLINICAL PHENOTYPES: A) THE PRESENCE OF SKIN LESIONS WITHOUT SIGNS OF SYSTEMIC PATHOLOGY; B) SKIN LESIONS BUT ALSO CHRONIC RENAL PATHOLOGY; AND C) SKIN LESIONS, CHRONIC RENAL PATHOLOGY AND POLYARTICULAR DISEASE. INTERESTINGLY, AND AS EXPECTED, SEQUENCING DATA REVEALED CHANGES IN DNA METHYLATION IN SLE COMPARED TO CONTROLS. HOWEVER, AND MORE IMPORTANTLY, ALTHOUGH THERE WERE COMMON METHYLATION CHANGES FOUND IN ALL GROUPS OF SLE COMPARED TO CONTROLS, THERE WAS SPECIFIC DNA METHYLATION CHANGES THAT CORRELATED WITH CLINICAL PHENOTYPE. THESE INCLUDED CHANGES IN THE NOVEL KEY TARGET GENES NLRP2, CD300LB AND S1PR3, AS WELL AS CHANGES IN THE CRITICAL PATHWAYS, INCLUDING THE ADHERENS JUNCTION AND LEUKOCYTE TRANSENDOTHELIAL MIGRATION. WE ALSO NOTED THAT A SIGNIFICANT PROPORTION OF GENES UNDERGOING DNA METHYLATION CHANGES WERE INVERSELY CORRELATED WITH GENE EXPRESSION AND THAT MIRNA SCREENING REVEALED THE EXISTENCE OF SUBSETS WITH CHANGES IN EXPRESSION. INTEGRATED ANALYSIS OF THIS DATA HIGHLIGHTS SPECIFIC SETS OF MIRNAS CONTROLLED BY DNA METHYLATION, AND GENES THAT ARE ALTERED BY METHYLATION AND TARGETED BY MIRNAS. IN CONCLUSION, OUR FINDINGS SUGGEST SELECT EPIGENETIC MECHANISMS THAT CONTRIBUTE TO CLINICAL PHENOTYPES AND FURTHER SHED LIGHT ON A NEW VENUE FOR BASIC SLE RESEARCH.	2014