1 3592 150 IMPAIRED VASCULAR FUNCTION CONTRIBUTES TO EXERCISE INTOLERANCE IN CHRONIC KIDNEY DISEASE. BACKGROUND: EXERCISE INTOLERANCE IS AN IMPORTANT FEATURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE (CKD) AND IS PROGNOSTIC FOR BOTH INCREASED MORBIDITY AND MORTALITY. LITTLE IS KNOWN ABOUT THE UNDERLYING MECHANISMS IN PREDIALYSIS CKD. THIS STUDY AIMED TO GAIN MORE INSIGHT INTO THE ROLE OF VASCULAR DYSFUNCTION IN THE EXERCISE INTOLERANCE OF PREDIALYSIS CKD. IN ADDITION, VASCULAR-RELATED MICRORNAS (MIRNAS)-AS EPIGENETIC REGULATORS OF EXERCISE CAPACITY-WERE ANALYSED. METHODS: SIXTY-THREE PATIENTS WITH CKD STAGES 1-5 AND 18 HEALTHY CONTROLS WERE INCLUDED. PEAK OXYGEN CONSUMPTION (VO(2)PEAK) WAS DETERMINED BY CARDIOPULMONARY EXERCISE TESTING, ENDOTHELIAL FUNCTION BY FLOW-MEDIATED DILATION (FMD) AND ARTERIAL STIFFNESS BY CAROTID-FEMORAL PULSE WAVE VELOCITY (PWV). PLASMA MIRNA LEVELS (MIR-21, MIR-126, MIR-146A, MIR-150 AND MIR-210) WERE QUANTIFIED BY QUANTITATIVE RT-PCR. RESULTS: VO(2)PEAK WAS ALREADY IMPAIRED IN MILD CKD (STAGES 1-3A) AND SIGNIFICANTLY CORRELATED WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR; R = 0.525, P < 0.001). LIKEWISE, BOTH FMD AND PWV WERE SIGNIFICANTLY CORRELATED WITH EGFR (R = 0.319, P = 0.007 AND R = -0.365, P = 0.001, RESPECTIVELY). IN MULTIPLE REGRESSION ANALYSIS, PWV REMAINED ONE OF THE STRONGEST INDEPENDENT DETERMINANTS OF VO(2)PEAK (BETA = -0.301, P = 0.01). OF THE STUDIED MIRNA, CIRCULATING LEVELS OF MIR-146A AND MIR-150 CORRELATED WITH EGFR, PWV AND VO(2)PEAK, BUT THE ASSOCIATION WITH THE LATTER WAS LOST WHEN CORRECTING FOR PWV. CONCLUSIONS: ARTERIAL STIFFNESS CONTRIBUTES TO THE OBSERVED REDUCED AEROBIC CAPACITY IN PREDIALYSIS CKD, INDEPENDENT OF AGE, HAEMOGLOBIN LEVELS AND ENDOTHELIAL FUNCTION AND REPRESENTS A PROMISING THERAPEUTIC TARGET FOR IMPROVING EXERCISE CAPACITY IN THIS POPULATION. FUTURE WORK IS REQUIRED TO ELUCIDATE WHY HIGHER CIRCULATING LEVELS OF MIR-146A AND MIR-150 ARE ASSOCIATED WITH IMPAIRED RENAL FUNCTION AND INCREASED ARTERIAL STIFFNESS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2  782  43 CELL-FREE MICRORNA-148A IS ASSOCIATED WITH RENAL ALLOGRAFT DYSFUNCTION: IMPLICATION FOR BIOMARKER DISCOVERY. BACKGROUND: CHRONIC ALLOGRAFT DYSFUNCTION (CAD), THE FOREMOST CAUSE OF RENAL GRAFT LOSS WORLDWIDE, IS A SERIOUS CHALLENGE FOR MOST OF THE RECIPIENTS. AS THE EPIGENETIC ERA IS EMERGING, EPIGENETIC BIOMARKERS ESPECIALLY MICRORNAS (MIRNAS) MAY REFLECT THE CURRENT STAGE OF THE DISEASE AND PATIENT'S THERAPY RESPONSE. THE CURRENT STUDY INVESTIGATED THE POTENTIAL SIGNIFICANCE OF CIRCULATING MIRNA-148A IN PREDICTING THE RENAL GRAFT FUNCTION. DESIGN AND METHODS: CIRCULATING MIRNAS WERE ISOLATED FROM 53 PLASMA SAMPLES OF RECIPIENTS WITH HISTOLOGICALLY VALIDATED INTERSTITIAL FIBROSIS AND TUBULAR ATROPHY (IFTA, N = 26), AND RECIPIENTS WITH STABLE GRAFT FUNCTION (SGF, N = 27), AND ALSO HEALTHY INDIVIDUALS ( N = 15). THE LEVEL OF MIRNA-148A WAS EVALUATED BY THE QUANTITATIVE POLYMERASE CHAIN REACTION (QPCR) AND CORRELATED WITH CLINICAL AND HISTOLOGICAL PARAMETERS. RESULTS: SIGNIFICANTLY, MIRNA-148A DECREASED IN IFTA COMPARED WITH SGF SUBJECTS (P < 0.001). MIRNA-148A LEVELS INDICATED A SIGNIFICANT ASSOCIATION WITH SERUM CREATININE LEVELS ( R = 0.451, P = 0.021) AND GLOMERULAR FILTRATION RATE ( R = -0.520, P = 0.006). MIRNA-148A EXPRESSION LEVELS COULD DISCRIMINATE IFTA CASES FROM SGF INDIVIDUALS WITH AN AREA UNDER THE CURVE OF 0.89 ( P < 0.001), 97% SENSITIVITY, AND 72% SPECIFICITY. A NUMBER OF PREDICTED TARGETS THAT MIGHT BE INVOLVED IN CAD BY MIRNA-148A WERE PREDICTED. CONCLUSION: PLASMA CELL-FREE MIRNA-148A CORRELATED WITH RENAL FUNCTION AND HISTOLOGICAL GRADES; THEREFORE, IT MAY BE FURTHER INVESTIGATED AS A NOVEL NONINVASIVE MOLECULAR MARKER OF THE PROGRESSION TO IFTA IN RENAL TRANSPLANT RECIPIENTS; MOREOVER, THE EMERGING BIOMARKER MAY BECOME A THERAPEUTIC TARGET IN THE FUTURE CLINIC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3 3568  37 IMPACT OF INFLAMMATION ON EPIGENETIC DNA METHYLATION - A NOVEL RISK FACTOR FOR CARDIOVASCULAR DISEASE? OBJECTIVE: THE LIFESPAN OF DIALYSIS PATIENTS IS AS SHORT AS IN PATIENTS WITH METASTATIC CANCER DISEASE, MAINLY DUE TO CARDIOVASCULAR DISEASE (CVD). DNA METHYLATION IS AN IMPORTANT CELLULAR MECHANISM MODULATING GENE EXPRESSION ASSOCIATED WITH AGEING, INFLAMMATION AND ATHEROSCLEROTIC PROCESSES. DESIGN: DNA METHYLATION WAS ANALYSED IN PERIPHERAL BLOOD LEUCOCYTES FROM THREE DIFFERENT GROUPS OF CHRONIC KIDNEY DISEASE (CKD) POPULATIONS (37 CKD STAGES 3 AND 4 PATIENTS, 98 CKD STAGE 5 PATIENTS AND 20 PREVALENT HAEMODIALYSIS PATIENTS). THIRTY-SIX HEALTHY SUBJECTS SERVED AS CONTROLS. CLINICAL CHARACTERISTICS (DIABETES MELLITUS, NUTRITIONAL STATUS AND PRESENCE OF CLINICAL CVD), INFLAMMATION AND OXIDATIVE STRESS BIOMARKERS, HOMOCYSTEINE AND GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES (DEFINED AS HPAII/MSPI RATIO BY THE LUMINOMETRIC METHYLATION ASSAY METHOD) WERE EVALUATED. CKD STAGE 5 PATIENTS (N=98) STARTING DIALYSIS TREATMENT WERE FOLLOWED FOR A PERIOD OF 36 +/- 2 MONTHS. RESULTS: INFLAMED PATIENTS HAD LOWER RATIOS OF HPAII/MSPI, INDICATING GLOBAL DNA HYPERMETHYLATION. ANALYSIS BY THE COX REGRESSION MODEL DEMONSTRATED THAT DNA HYPERMETHYLATION (HPAII/MSPI RATIO <MEDIAN) WAS SIGNIFICANTLY ASSOCIATED WITH BOTH ALL-CAUSE (RR 5.0; 95% CI: 1.7-14.8; P<0.01) AND CARDIOVASCULAR (RR 13.9; 95% CI: 1.8-109.3; P<0.05) MORTALITY, EVEN FOLLOWING THE ADJUSTMENT FOR AGE, CVD, DIABETES MELLITUS AND INFLAMMATION. CONCLUSION: THE PRESENT STUDY DEMONSTRATES THAT GLOBAL DNA HYPERMETHYLATION IS ASSOCIATED WITH INFLAMMATION AND INCREASED MORTALITY IN CKD.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
4  177  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
5 1023  46 CIRCULATING MICRORNA PROFILES FOR PREMATURE CARDIOVASCULAR DEATH IN PATIENTS WITH KIDNEY FAILURE WITH REPLACEMENT THERAPY. INTRODUCTION: PATIENTS WITH KIDNEY FAILURE WITH REPLACEMENT THERAPY (KFRT) SUFFER FROM A DISPROPORTIONATELY HIGH CARDIOVASCULAR DISEASE BURDEN. CIRCULATING SMALL NON-CODING RNAS (C-SNCRNAS) HAVE EMERGED AS NOVEL EPIGENETIC REGULATORS AND ARE SUGGESTED AS NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR CARDIOVASCULAR DISEASE; HOWEVER, LITTLE IS KNOWN ABOUT THE ASSOCIATIONS OF C-SNCRNAS WITH PREMATURE CARDIOVASCULAR DEATH IN KFRT. METHODS: IN A PILOT CASE-CONTROL STUDY OF 50 HEMODIALYSIS PATIENTS WHO DIED OF CARDIOVASCULAR EVENTS AS CASES, AND 50 MATCHED HEMODIALYSIS CONTROLS WHO REMAINED ALIVE DURING A MEDIAN FOLLOW-UP OF 2.0 YEARS, WE PERFORMED C-SNCRNAS PROFILES USING NEXT-GENERATION SEQUENCING TO IDENTIFY DIFFERENTIALLY EXPRESSED CIRCULATING MICRORNAS (C-MIRNAS) BETWEEN THE PLASMA OF CASES AND THAT OF CONTROLS. MRNA TARGET PREDICTION AND PATHWAY ENRICHMENT ANALYSIS WERE PERFORMED TO EXAMINE THE FUNCTIONAL RELEVANCE OF DIFFERENTIALLY EXPRESSED C-MIRNAS TO CARDIOVASCULAR PATHOPHYSIOLOGY. THE ASSOCIATION OF DIFFERENTIALLY EXPRESSED C-MIRNAS WITH CARDIOVASCULAR MORTALITY WAS EXAMINED USING MULTIVARIABLE CONDITIONAL LOGISTIC REGRESSION. RESULTS: THE PATIENT CHARACTERISTICS WERE SIMILAR BETWEEN CASES AND CONTROLS, WITH A MEAN AGE OF 63 YEARS, 48% MALE, AND 54% AFRICAN AMERICAN IN BOTH GROUPS. WE DETECTED A TOTAL OF 613 MIRNAS IN THE PLASMA, AMONG WHICH FIVE MIRNAS (I.E., MIR-129-1-5P, MIR-500B-3P, MIR-125B-1-3P, MIR-3648-2-5P, AND MIR-3150B-3P) WERE IDENTIFIED TO BE DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS WITH CUT-OFFS OF P < 0.05 AND LOG2 FOLD-CHANGE (LOG2FC) > 1. WHEN USING MORE STRINGENT CUT-OFFS OF P-ADJUSTED < 0.05 AND LOG2FC > 1, ONLY MIR-129-1-5P REMAINED SIGNIFICANTLY DIFFERENTIALLY EXPRESSED, WITH HIGHER LEVELS OF MIR-129-1-5P IN THE CASES THAN IN THE CONTROLS. THE PATHWAY ENRICHMENT ANALYSIS USING PREDICTED MIR-129-1-5P MRNA TARGETS DEMONSTRATED ENRICHMENT IN ADRENERGIC SIGNALING IN CARDIOMYOCYTES, ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, AND OXYTOCIN SIGNALING PATHWAYS. IN PARALLEL, THE CIRCULATING MIR-129-1-5P LEVELS WERE SIGNIFICANTLY ASSOCIATED WITH THE RISK OF CARDIOVASCULAR DEATH (ADJUSTED OR [95% CI], 1.68 [1.01-2.81] FOR ONE INCREASE IN LOG-TRANSFORMED MIR-129-1-5P COUNTS), INDEPENDENT OF POTENTIAL CONFOUNDERS. CONCLUSIONS: CIRCULATING MIR-129-1-5P MAY SERVE AS A NOVEL BIOMARKER FOR PREMATURE CARDIOVASCULAR DEATH IN KFRT.	2023	
           
6 1271  36 CYTOSINE METHYLATION PREDICTS RENAL FUNCTION DECLINE IN AMERICAN INDIANS. DIABETIC NEPHROPATHY ACCOUNTS FOR MOST OF THE EXCESS MORTALITY IN INDIVIDUALS WITH DIABETES, BUT THE MOLECULAR MECHANISMS BY WHICH NEPHROPATHY DEVELOPS ARE LARGELY UNKNOWN. HERE WE TESTED CYTOSINE METHYLATION LEVELS AT 397,063 GENOMIC CPG SITES FOR ASSOCIATION WITH DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OVER A SIX YEAR PERIOD IN 181 DIABETIC PIMA INDIANS. METHYLATION LEVELS AT 77 SITES SHOWED SIGNIFICANT ASSOCIATION WITH EGFR DECLINE AFTER CORRECTION FOR MULTIPLE COMPARISONS. A MODEL INCLUDING METHYLATION LEVEL AT TWO PROBES (CG25799291 AND CG22253401) IMPROVED PREDICTION OF EGFR DECLINE IN ADDITION TO BASELINE EGFR AND THE ALBUMIN TO CREATININE RATIO WITH THE PERCENT OF VARIANCE EXPLAINED SIGNIFICANTLY IMPROVING FROM 23.1% TO 42.2%. CG22253401 WAS ALSO SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE IN A CASE-CONTROL STUDY DERIVED FROM THE CHRONIC RENAL INSUFFICIENCY COHORT. PROBES AT WHICH METHYLATION SIGNIFICANTLY ASSOCIATED WITH EGFR DECLINE WERE LOCALIZED TO GENE REGULATORY REGIONS AND ENRICHED FOR GENES WITH METABOLIC FUNCTIONS AND APOPTOSIS. THREE OF THE 77 PROBES THAT WERE ASSOCIATED WITH EGFR DECLINE IN BLOOD SAMPLES SHOWED DIRECTIONALLY CONSISTENT AND SIGNIFICANT ASSOCIATION WITH FIBROSIS IN MICRODISSECTED HUMAN KIDNEY TISSUE, AFTER CORRECTION FOR MULTIPLE COMPARISONS. THUS, CYTOSINE METHYLATION LEVELS MAY PROVIDE BIOMARKERS OF DISEASE PROGRESSION IN DIABETIC NEPHROPATHY AND EPIGENETIC VARIATIONS CONTRIBUTE TO THE DEVELOPMENT OF DIABETIC KIDNEY DISEASE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7 4024  29 LUNG ALLOGRAFT EPITHELIUM DNA METHYLATION AGE IS ASSOCIATED WITH GRAFT CHRONOLOGIC AGE AND PRIMARY GRAFT DYSFUNCTION. ADVANCED DONOR AGE IS A RISK FACTOR FOR POOR SURVIVAL FOLLOWING LUNG TRANSPLANTATION. HOWEVER, RECENT WORK IDENTIFYING EPIGENETIC DETERMINANTS OF AGING HAS SHOWN THAT BIOLOGIC AGE MAY NOT ALWAYS REFLECT CHRONOLOGIC AGE AND THAT STRESSORS CAN ACCELERATE BIOLOGIC AGING. WE HYPOTHESIZED THAT LUNG ALLOGRAFTS THAT EXPERIENCED PRIMARY GRAFT DYSFUNCTION (PGD), CHARACTERIZED BY POOR OXYGENATION IN THE FIRST THREE POST-TRANSPLANT DAYS, WOULD HAVE INCREASED BIOLOGIC AGE. WE CULTURED AIRWAY EPITHELIAL CELLS ISOLATED BY TRANSBRONCHIAL BRUSH AT 1-YEAR BRONCHOSCOPIES FROM 13 SUBJECTS WITH SEVERE PGD AND 15 CONTROLS MATCHED ON AGE AND TRANSPLANT INDICATION. WE MEASURED EPIGENETIC AGE USING THE HORVATH EPIGENETIC CLOCK. LINEAR MODELS WERE USED TO DETERMINE THE ASSOCIATION OF AIRWAY EPIGENETIC AGE WITH CHRONOLOGIC AGES AND PGD STATUS, ADJUSTED FOR RECIPIENT PGD RISK FACTORS. SURVIVAL MODELS ASSESSED THE ASSOCIATION WITH CHRONIC LUNG ALLOGRAFT DYSFUNCTION (CLAD) OR DEATH. DISTRIBUTIONS OF PROMOTER METHYLATION WITHIN PATHWAYS WERE COMPARED BETWEEN GROUPS. DNA METHYLTRANSFERASE (DNMT) ACTIVITY WAS QUANTIFIED IN AIRWAY EPITHELIAL CELLS UNDER HYPOXIC OR NORMOXIC CONDITIONS. AIRWAY EPIGENETIC AGE APPEARED YOUNGER BUT WAS STRONGLY ASSOCIATED WITH THE AGE OF THE ALLOGRAFT (SLOPE 0.38 PER YEAR, 95% CI 0.27-0.48). THERE WAS NO CORRELATION BETWEEN EPIGENETIC AGE AND RECIPIENT AGE (P = 0.96). EPIGENETIC AGE WAS 6.5 YEARS GREATER (95% CI 1.7-11.2) IN SUBJECTS WHO HAD EXPERIENCED PGD, AND THIS EFFECT REMAINED SIGNIFICANT AFTER ADJUSTING FOR DONOR AND RECIPIENT CHARACTERISTICS (P = 0.03). EPIGENETIC AGE WAS NOT ASSOCIATED WITH CLAD-FREE SURVIVAL RISK (P = 0.11). ANALYSIS OF DIFFERENTIAL METHYLATION OF PROMOTERS OF KEY BIOLOGIC PATHWAYS REVEALED HYPOMETHYLATION IN REGIONS RELATED TO HYPOXIA, INFLAMMATION, AND METABOLISM-ASSOCIATED PATHWAYS. ACCORDINGLY, AIRWAY EPITHELIAL CELLS CULTURED IN HYPOXIC CONDITIONS SHOWED SUPPRESSED DNMT ACTIVITY. WHILE AIRWAY METHYLATION AGE WAS PRIMARILY DETERMINED BY DONOR CHRONOLOGIC AGE, EARLY INJURY IN THE FORM OF PGD WAS ASSOCIATED WITH INCREASED ALLOGRAFT EPIGENETIC AGE. THESE DATA SHOW HOW PGD MIGHT SUPPRESS KEY PROMOTER METHYLATION RESULTING IN LONG-TERM IMPACTS ON THE ALLOGRAFT.	2021	
                                                                                                                                                                                             
8  658  30 BLOOD DNA METHYLATION PREDICTS DIABETIC KIDNEY DISEASE PROGRESSION IN HIGH FAT DIET-FED MICE. DIABETIC KIDNEY DISEASE (DKD) PROGRESSES AT DIFFERENT RATES AMONG PATIENTS WITH TYPE 2 DIABETES MELLITUS (T2D). EARLY IDENTIFICATION OF PATIENTS WITH A HIGHER RISK OF DKD PROGRESSION IS ESSENTIAL TO IMPROVE PROGNOSIS. EPIGENETIC MODIFICATIONS, PARTICULARLY DNA METHYLATION, HAVE BEEN INDEPENDENTLY IMPLICATED IN T2D AND CHRONIC KIDNEY DISEASE. THE CURRENT STUDY AIMED TO DETERMINE CHANGES IN BLOOD DNA METHYLATION THAT REFLECTS AND PREDICTS DKD PROGRESSION. C57BL/6 MICE WERE FED A HIGH-FAT DIET (HFD) FROM WEANING AND SUBCLASSIFIED INTO TWO GROUPS, HFD-1 AND HFD-2, ACCORDING TO URINARY KIDNEY INJURY MARKER KIM-1/CREATININE RATIOS (LOW VS. HIGH) AND HISTOLOGICAL ABNORMALITIES (MILD-MODERATE VS. ADVANCED). DNA METHYLATION PROFILES WERE DETERMINED BY REDUCED REPRESENTATIVE BISULFIDE SEQUENCING (RRBS). OUR RESULTS CONFIRMED EARLY AND ESTABLISHED DKD AT WEEK 9 AND WEEK 32, RESPECTIVELY. AT WEEK 32, ADVANCED KIDNEY INJURY WAS ASSOCIATED WITH DYSREGULATION OF METHYLATION AND DEMETHYLATION ENZYMES IN THE KIDNEY. BLOOD RRBS REVEALED 579 AND 203 DIFFERENTIALLY METHYLATED SITES (DMS) BETWEEN HFD-1 AND HFD-2 ANIMALS AT WEEK 32 AND WEEK 9, RESPECTIVELY, AMONG WHICH 11 WERE COMMON. THE DMS IN BLOOD AND KIDNEY AT WEEK 32 WERE BOTH RELATED TO ORGAN DEVELOPMENT, NEUROGENESIS, CELL JUNCTION, AND WNT SIGNALLING, WHILE THE DMS IN BLOOD AT WEEK 9 SUGGESTED A SPECIFIC ENRICHMENT OF KIDNEY DEVELOPMENT PROCESSES. IN CONCLUSION, OUR DATA STRONGLY SUPPORT THE IMPLICATION OF EARLY BLOOD DNA METHYLATION MODIFICATIONS AND DKD PROGRESSION IN T2D THAT COULD BE USED TO IMPROVE THE DISEASE'S PROGNOSTICATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
9 6080  38 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION.	2023	
                                                                                                                                                                                                                                            
10 2629  31 EPIGENOME-WIDE ASSOCIATION STUDY OF DIABETIC CHRONIC KIDNEY DISEASE PROGRESSION IN THE KOREAN POPULATION: THE KNOW-CKD STUDY. SINCE THE ETIOLOGY OF DIABETIC CHRONIC KIDNEY DISEASE (CKD) IS MULTIFACTORIAL, STUDIES ON DNA METHYLATION FOR KIDNEY FUNCTION DETERIORATION HAVE RARELY BEEN PERFORMED DESPITE THE NEED FOR AN EPIGENETIC APPROACH. THEREFORE, THIS STUDY AIMED TO IDENTIFY EPIGENETIC MARKERS ASSOCIATED WITH CKD PROGRESSION BASED ON THE DECLINE IN THE ESTIMATED GLOMERULAR FILTRATION RATE IN DIABETIC CKD IN KOREA. AN EPIGENOME-WIDE ASSOCIATION STUDY WAS PERFORMED USING WHOLE BLOOD SAMPLES FROM 180 CKD RECRUITED FROM THE KNOW-CKD COHORT. PYROSEQUENCING WAS ALSO PERFORMED ON 133 CKD PARTICIPANTS AS AN EXTERNAL REPLICATION ANALYSIS. FUNCTIONAL ANALYSES, INCLUDING THE ANALYSIS OF DISEASE-GENE NETWORKS, REACTOME PATHWAYS, AND PROTEIN-PROTEIN INTERACTION NETWORKS, WERE CONDUCTED TO IDENTIFY THE BIOLOGICAL MECHANISMS OF CPG SITES. A PHENOME-WIDE ASSOCIATION STUDY WAS PERFORMED TO DETERMINE THE ASSOCIATIONS BETWEEN CPG SITES AND OTHER PHENOTYPES. TWO EPIGENETIC MARKERS, CG10297223 ON AGTR1 AND CG02990553 ON KRT28 INDICATED A POTENTIAL ASSOCIATION WITH DIABETIC CKD PROGRESSION. BASED ON THE FUNCTIONAL ANALYSES, OTHER PHENOTYPES (BLOOD PRESSURE AND CARDIAC ARRHYTHMIA FOR AGTR1) AND BIOLOGICAL PATHWAYS (KERATINIZATION AND CORNIFIED ENVELOPE FOR KRT28) RELATED TO CKD WERE ALSO IDENTIFIED. THIS STUDY SUGGESTS A POTENTIAL ASSOCIATION BETWEEN THE CG10297223 AND CG02990553 AND THE PROGRESSION OF DIABETIC CKD IN KOREANS. NEVERTHELESS, FURTHER VALIDATION IS NEEDED THROUGH ADDITIONAL STUDIES.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
11 4238  34 METHYLATION PATTERN OF URINARY DNA AS A MARKER OF KIDNEY FUNCTION DECLINE IN DIABETES. INTRODUCTION: RENAL TUBULAR INJURY CONTRIBUTES TO THE DECLINE IN KIDNEY FUNCTION IN PATIENTS WITH DIABETES. CELL TYPE-SPECIFIC DNA METHYLATION PATTERNS HAVE BEEN USED TO CALCULATE PROPORTIONS OF PARTICULAR CELL TYPES. IN THIS STUDY, WE DEVELOPED A METHOD TO DETECT RENAL TUBULAR INJURY IN PATIENTS WITH DIABETES BY DETECTING EXFOLIATED TUBULAR CELLS SHED INTO THE URINE BASED ON TUBULAR CELL-SPECIFIC DNA METHYLATION PATTERNS. RESEARCH DESIGN AND METHODS: WE IDENTIFIED DNA METHYLATION PATTERNS SPECIFIC FOR HUMAN RENAL PROXIMAL TUBULAR CELLS THROUGH COMPARTMENT-SPECIFIC METHYLOME ANALYSIS. WE NEXT DETERMINED THE METHYLATION LEVELS OF PROXIMAL TUBULE-SPECIFIC LOCI IN URINE SEDIMENT OF PATIENTS WITH DIABETES AND ANALYZED CORRELATION WITH CLINICAL VARIABLES. RESULTS: WE IDENTIFIED GENOMIC LOCI IN SMTNL2 AND G6PC TO BE SELECTIVELY UNMETHYLATED IN HUMAN PROXIMAL TUBULAR CELLS. THE METHYLATION LEVELS OF SMTNL2 AND G6PC IN URINE SEDIMENT, DEEMED TO REFLECT THE PROPORTION OF EXFOLIATED PROXIMAL TUBULAR CELLS DUE TO INJURY, CORRELATED WELL WITH EACH OTHER. METHYLATION LEVELS OF SMTNL2 IN URINE SEDIMENT SIGNIFICANTLY CORRELATED WITH THE ANNUAL DECLINE IN ESTIMATED GLOMERULAR FILTRATION RATE. MOREOVER, ADDITION OF URINARY SMTNL2 METHYLATION TO A MODEL CONTAINING KNOWN RISK FACTORS SIGNIFICANTLY IMPROVED DISCRIMINATION OF PATIENTS WITH DIABETES WITH FASTER ESTIMATED GLOMERULAR FILTRATION RATE DECLINE. CONCLUSIONS: THIS STUDY DEMONSTRATES THAT PATIENTS WITH DIABETES WITH CONTINUAL LOSS IN KIDNEY FUNCTION MAY BE STRATIFIED BY A SPECIFIC DNA METHYLATION SIGNATURE THROUGH EPIGENETIC URINALYSIS AND PROVIDES FURTHER EVIDENCE AT THE LEVEL OF EXFOLIATED CELLS IN THE URINE THAT INJURY OF PROXIMAL TUBULAR CELLS MAY CONTRIBUTE TO PATHOGENESIS OF DIABETIC KIDNEY DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 1576  37 DNA METHYLATION PROFILE ASSOCIATED WITH RAPID DECLINE IN KIDNEY FUNCTION: FINDINGS FROM THE CRIC STUDY. BACKGROUND: EPIGENETIC MECHANISMS MAY BE IMPORTANT IN THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD). METHODS: WE STUDIED THE GENOME-WIDE DNA METHYLATION PATTERN ASSOCIATED WITH RAPID LOSS OF KIDNEY FUNCTION USING THE INFINIUM HUMANMETHYLATION 450 K BEADCHIP IN 40 CHRONIC RENAL INSUFFICIENCY (CRIC) STUDY PARTICIPANTS (N = 3939) WITH THE HIGHEST AND LOWEST RATES OF DECLINE IN ESTIMATED GLOMERULAR FILTRATION RATE. RESULTS: THE MEAN EGFR SLOPE WAS 2.2 (1.4) AND -5.1 (1.2) ML/MIN/1.73 M(2) IN THE STABLE KIDNEY FUNCTION GROUP AND THE RAPID PROGRESSION GROUP, RESPECTIVELY. CPG ISLANDS IN NPHP4, IQSEC1 AND TCF3 WERE HYPERMETHYLATED TO A LARGER EXTENT IN SUBJECTS WITH STABLE KIDNEY FUNCTION (P-VALUES OF 7.8E-05 TO 9.5E-05). THESE GENES ARE INVOLVED IN PATHWAYS KNOWN TO PROMOTE THE EPITHELIAL TO MESENCHYMAL TRANSITION AND RENAL FIBROSIS. OTHER CKD-RELATED GENES THAT WERE DIFFERENTIALLY METHYLATED ARE NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 AND TGFBI, WHICH ARE INVOLVED IN OXIDATIVE STRESS AND INFLAMMATORY PATHWAYS (P-VALUES OF 4.5E-03 TO 0.046). PATHWAY ANALYSIS USING INGENUITY PATHWAY ANALYSIS SHOWED THAT GENE NETWORKS RELATED TO CELL SIGNALING, CARBOHYDRATE METABOLISM AND HUMAN BEHAVIOR ARE EPIGENETICALLY REGULATED IN CKD. CONCLUSIONS: EPIGENETIC MODIFICATIONS MAY BE IMPORTANT IN DETERMINING THE RATE OF LOSS OF KIDNEY FUNCTION IN PATIENTS WITH ESTABLISHED CKD.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
13 1607  24 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  749  39 CARDIAC EPIGENETIC CHANGES IN VEGF SIGNALING GENES ASSOCIATE WITH MYOCARDIAL MICROVASCULAR RAREFACTION IN EXPERIMENTAL CHRONIC KIDNEY DISEASE. CHRONIC KIDNEY DISEASE (CKD) IS COMMON IN PATIENTS WITH HEART FAILURE AND OFTEN RESULTS IN LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (LVDD). HOWEVER, THE MECHANISMS RESPONSIBLE FOR CARDIAC DAMAGE IN CKD-LVDD REMAIN TO BE ELUCIDATED. EPIGENETIC ALTERATIONS MAY IMPOSE LONG-LASTING EFFECTS ON CELLULAR TRANSCRIPTION AND FUNCTION, BUT THEIR EXACT ROLE IN CKD-LVDD IS UNKNOWN. WE INVESTIGATE WHETHER CHANGES IN CARDIAC SITE-SPECIFIC DNA METHYLATION PROFILES MIGHT BE IMPLICATED IN CARDIAC ABNORMALITIES IN CKD-LVDD. CKD-LVDD AND NORMAL CONTROL PIGS (N = 6 EACH) WERE STUDIED FOR 14 WK. RENAL AND CARDIAC HEMODYNAMICS WERE QUANTIFIED BY MULTIDETECTOR CT AND ECHOCARDIOGRAPHY. IN RANDOMLY SELECTED PIGS (N = 3/GROUP), CARDIAC SITE-SPECIFIC 5-METHYLCYTOSINE (5MC) IMMUNOPRECIPITATION (MEDIP)- AND MRNA-SEQUENCING (SEQ) WERE PERFORMED, FOLLOWED BY INTEGRATED (MEDIP-SEQ/MRNA-SEQ ANALYSIS), AND CONFIRMATORY EX VIVO STUDIES. MEDIP-SEQ ANALYSIS REVEALED 261 GENES WITH HIGHER (FOLD CHANGE > 1.4; P < 0.05) AND 162 GENES WITH LOWER (FOLD CHANGE < 0.7; P < 0.05) 5MC LEVELS IN CKD-LVDD VERSUS NORMAL PIGS, WHICH WERE PRIMARILY IMPLICATED IN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-RELATED SIGNALING AND ANGIOGENESIS. INTEGRATED MEDIP-SEQ/MRNA-SEQ ANALYSIS IDENTIFIED A SELECT GROUP OF VEGF-RELATED GENES IN WHICH 5MC LEVELS WERE HIGHER, BUT MRNA EXPRESSION WAS LOWER IN CKD-LVDD VERSUS NORMAL PIGS. CARDIAC VEGF SIGNALING GENE AND VEGF PROTEIN EXPRESSION WERE BLUNTED IN CKD-LVDD COMPARED WITH CONTROLS AND WERE ASSOCIATED WITH DECREASED SUBENDOCARDIAL MICROVASCULAR DENSITY. CARDIAC EPIGENETIC CHANGES IN VEGF-RELATED GENES ARE ASSOCIATED WITH IMPAIRED ANGIOGENESIS AND CARDIAC MICROVASCULAR RAREFACTION IN SWINE CKD-LVDD. THESE OBSERVATIONS MAY ASSIST IN DEVELOPING NOVEL THERAPIES TO AMELIORATE CARDIAC DAMAGE IN CKD-LVDD.NEW & NOTEWORTHY CHRONIC KIDNEY DISEASE (CKD) OFTEN LEADS TO LEFT VENTRICULAR DIASTOLIC DYSFUNCTION (LVDD) AND HEART FAILURE. USING A NOVEL TRANSLATIONAL SWINE MODEL OF CKD-LVDD, WE CHARACTERIZE THE CARDIAC EPIGENETIC LANDSCAPE, IDENTIFYING SITE-SPECIFIC 5-METHYLCYTOSINE CHANGES IN VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF)-RELATED GENES ASSOCIATED WITH IMPAIRED ANGIOGENESIS AND CARDIAC MICROVASCULAR RAREFACTION. THESE OBSERVATIONS SHED LIGHT ON THE MECHANISMS OF CARDIAC MICROVASCULAR DAMAGE IN CKD-LVDD AND MAY ASSIST IN DEVELOPING NOVEL THERAPIES FOR THESE PATIENTS.	2023	

15 1729  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 2331  38 EPIGENETIC REGULATION OF INFLAMMATION BY MICRORNAS IN POST-INFECTIOUS BRONCHIOLITIS OBLITERANS. OBJECTIVES: POST-INFECTIOUS BRONCHIOLITIS OBLITERANS (PIBO) IS A RARE, CHRONIC DISEASE INITIATED BY SEVERE INFECTION AND FOLLOWED BY PERPETUATING INFLAMMATION AND OBLITERATION OF THE SMALL AIRWAYS. MICRORNAS (MIRNAS) HAVE BEEN PROPOSED TO PLAY A CENTRAL ROLE AS EPIGENETIC REGULATORS, WHICH CONTROL RESOLUTION AND PREVENT THE UNCONTROLLED PROGRESS OF INFLAMMATION. THE AIM OF THIS STUDY WAS TO DEFINE BIOMARKERS ON THE LEVEL OF POST-TRANSCRIPTIONAL GENE REGULATION IN ORDER TO CHARACTERISE PIBO. METHODS: A TOTAL OF 39 PATIENTS WITH WELL-DEFINED PIBO AND 31 CONTROLS FROM TWO CENTRES, BARCELONA, SPAIN, AND FRANKFURT, GERMANY, WERE ANALYSED BY NEXT-GENERATION SEQUENCING (NGS). THE EVALUATION OF THE BIOLOGICAL TARGETS OF THE MIRNAS WAS PERFORMED BY PATHWAY ENRICHMENT ANALYSIS AND PROTEIN-PROTEIN INTERACTION NETWORK ANALYSIS RESPECTIVELY. RESULTS: PATIENTS WITH PIBO HAD SIGNIFICANTLY LOWER LUNG FUNCTION VALUES AND INCREASED AIRWAY INFLAMMATION IN INDUCED SPUTUM AS INDICATED BY TOTAL CELL COUNTS, NEUTROPHILS, IL-1BETA, IL-6, IL-8 AND TGF-BETA COMPARED TO CONTROLS.NEXT-GENERATION SEQUENCING ANALYSIS REVEALED A TOTAL OF 22 DYSREGULATED MIRNAS, WHICH PASSED SIGNIFICANCE THRESHOLD FOR PADJ </= 0.001 WITH 17 BEING UPREGULATED AND 5 BEING DOWNREGULATED. OF THESE DYSREGULATED MIRNAS, MIR-335-5P, MIR-186-5P, MIR-30B-5P AND MIR-30C-5P WERE FURTHER VALIDATED USING QRT-PCR. INTERESTINGLY, THESE MIRNAS ARE FUNCTIONALLY IMPLICATED IN CYTOKINE-CYTOKINE RECEPTOR INTERACTION, TGF-BETA SIGNALLING AND FOXO SIGNALLING PATHWAY AND SIGNIFICANTLY CORRELATED WITH LUNG FUNCTION VALUES (FEV1). CONCLUSION: OUR RESULTS DEMONSTRATE AN ABERRANT MIRNA EXPRESSION PROFILE IN PIBO, WHICH IMPACTS PATHWAYS RESPONSIBLE FOR THE REGULATION OF INFLAMMATION AND FIBROSIS. THE DEFINED MIRNAS ARE USEFUL BIOMARKERS AND SHOULD BE ASSESSED AS POTENTIAL TARGET IN THE FIELD OF MIRNA THERAPEUTICS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17 2627  32 EPIGENOME-WIDE ASSOCIATION STUDY OF ADIPOSITY AND FUTURE RISK OF OBESITY-RELATED DISEASES. BACKGROUND: OBESITY IS AN ESTABLISHED RISK FACTOR FOR SEVERAL COMMON CHRONIC DISEASES SUCH AS BREAST AND COLORECTAL CANCER, METABOLIC AND CARDIOVASCULAR DISEASES; HOWEVER, THE BIOLOGICAL BASIS FOR THESE RELATIONSHIPS IS NOT FULLY UNDERSTOOD. TO EXPLORE THE ASSOCIATION OF OBESITY WITH THESE CONDITIONS, WE INVESTIGATED PERIPHERAL BLOOD LEUCOCYTE (PBL) DNA METHYLATION MARKERS FOR ADIPOSITY AND THEIR CONTRIBUTION TO RISK OF INCIDENT BREAST AND COLORECTAL CANCER AND MYOCARDIAL INFARCTION. METHODS: DNA METHYLATION PROFILES (ILLUMINA INFINIUM((R)) HUMANMETHYLATION450 BEADCHIP) FROM 1941 INDIVIDUALS FROM FOUR POPULATION-BASED EUROPEAN COHORTS WERE ANALYSED IN RELATION TO BODY MASS INDEX, WAIST CIRCUMFERENCE, WAIST-HIP AND WAIST-HEIGHT RATIO WITHIN A META-ANALYTICAL FRAMEWORK. IN A SUBSET OF THESE INDIVIDUALS, DATA ON GENOME-WIDE GENE EXPRESSION LEVEL, BIOMARKERS OF GLUCOSE AND LIPID METABOLISM WERE ALSO AVAILABLE. VALIDATION OF METHYLATION MARKERS ASSOCIATED WITH ALL ADIPOSITY MEASURES WAS PERFORMED IN 358 INDIVIDUALS. FINALLY, WE INVESTIGATED THE ASSOCIATION OF OBESITY-RELATED METHYLATION MARKS WITH BREAST, COLORECTAL CANCER AND MYOCARDIAL INFARCTION WITHIN RELEVANT SUBSETS OF THE DISCOVERY POPULATION. RESULTS: WE IDENTIFIED 40 CPG LOCI WITH METHYLATION LEVELS ASSOCIATED WITH AT LEAST ONE ADIPOSITY MEASURE. OF THESE, ONE CPG LOCUS (CG06500161) IN ABCG1 WAS ASSOCIATED WITH ALL FOUR ADIPOSITY MEASURES (P = 9.07X10(-)(8) TO 3.27X10(-18)) AND LOWER TRANSCRIPTIONAL ACTIVITY OF THE FULL-LENGTH ISOFORM OF ABCG1 (P = 6.00X10(-7)), HIGHER TRIGLYCERIDE LEVELS (P = 5.37X10(-)(9)) AND HIGHER TRIGLYCERIDES-TO-HDL CHOLESTEROL RATIO (P = 1.03X10(-10)). OF THE 40 INFORMATIVE AND OBESITY-RELATED CPG LOCI, TWO (IN IL2RB AND FGF18) WERE SIGNIFICANTLY ASSOCIATED WITH COLORECTAL CANCER (INVERSELY, P < 1.6X10(-3)) AND ONE INTERGENIC LOCUS ON CHROMOSOME 1 WAS INVERSELY ASSOCIATED WITH MYOCARDIAL INFARCTION (P < 1.25X10(-3)), INDEPENDENTLY OF OBESITY AND ESTABLISHED RISK FACTORS. CONCLUSION: OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES, IN PARTICULAR ALTERED DNA METHYLATION PATTERNS, MAY BE AN INTERMEDIATE BIOMARKER AT THE INTERSECTION OF OBESITY AND OBESITY-RELATED DISEASES, AND COULD OFFER CLUES AS TO UNDERLYING BIOLOGICAL MECHANISMS.	2018	
                                                                                                                                                                                                
18 1193  38 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	
                                                                                                                                                                                                                
19  663  23 BLOOD ORANGE JUICE INTAKE MODULATES PLASMA AND PBMC MICRORNA EXPRESSION IN OVERWEIGHT AND INSULIN-RESISTANT WOMEN: IMPACT ON MAPK AND NFKAPPAB SIGNALING PATHWAYS. BLOOD ORANGE CONSUMPTION PRESENTS POTENTIAL HEALTH BENEFITS AND MAY MODULATE EPIGENETIC MECHANISMS SUCH AS MICRORNAS (MIRNAS) EXPRESSION. MIRNAS ARE NON-CODING RNAS RESPONSIBLE FOR POST-TRANSCRIPTIONAL GENE REGULATION, AND THESE MOLECULES CAN ALSO BE USED AS BIOMARKERS IN BODY FLUIDS. THIS STUDY WAS DESIGNED TO INVESTIGATE THE EFFECT OF CHRONIC BLOOD ORANGE JUICE (BOJ) INTAKE ON THE INFLAMMATORY RESPONSE AND MIRNA EXPRESSION PROFILE IN PLASMA AND BLOOD CELLS IN OVERWEIGHT WOMEN. THE STUDY COHORT WAS COMPRISED OF TWENTY WOMEN AGED 18-40 YEARS OLD, DIAGNOSED AS OVERWEIGHT, WHO CONSUMED 500 ML/D OF BOJ FOR FOUR WEEKS. CLINICAL DATA WERE COLLECTED AT BASELINE AND AFTER 4 WEEKS OF JUICE CONSUMPTION, E.G., ANTHROPOMETRIC AND HEMODYNAMIC PARAMETERS, FOOD INTAKE, BLOOD CELL COUNT, AND METABOLIC AND INFLAMMATORY BIOMARKERS. BOJ SAMPLES WERE ANALYZED AND CHARACTERIZED. ADDITIONALLY, PLASMA AND BLOOD CELLS WERE ALSO COLLECTED FOR MIRNA EXPRESSION PROFILING AND EVALUATION OF THE EXPRESSION OF GENES AND PROTEINS IN THE MAPK AND NFKAPPAB SIGNALING PATHWAYS. BOJ INTAKE INCREASED THE EXPRESSION OF MIR-144-3P IN PLASMA AND THE EXPRESSION OF MIR-424-5P, MIR-144-3P, AND MIR-130B-3P IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMC). CONVERSELY, THE BEVERAGE INTAKE DECREASED THE EXPRESSION OF LET-7F-5P AND MIR-126-3P IN PBMC. COMPUTATIONAL ANALYSES IDENTIFIED DIFFERENT TARGETS OF THE DYSREGULATED MIRNA ON INFLAMMATORY PATHWAYS. FURTHERMORE, BOJ INTAKE INCREASED VITAMIN C CONSUMPTION AND THE PJNK/JNK RATIO AND DECREASED THE EXPRESSION OF IL6 MRNA AND NFKAPPAB PROTEIN. THESE RESULTS DEMONSTRATE THAT BOJ REGULATES THE EXPRESSION OF GENES INVOLVED IN THE INFLAMMATORY PROCESS AND DECREASES NFSMALL KA, CYRILLICB-PROTEIN EXPRESSION IN PBMC.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
20 5845  34 STUDY PROTOCOL FOR THE EPIGENETIC CHARACTERIZATION OF ANGOR PECTORIS ACCORDING TO THE AFFECTED CORONARY COMPARTMENT: GLOBAL AND COMPREHENSIVE ASSESSMENT OF THE RELATIONSHIP BETWEEN INVASIVE CORONARY PHYSIOLOGY AND MICRORNAS. BACKGROUND: MICRORNAS (MIRNAS) ARE NONCODING RNAS INVOLVED IN POST-TRANSCRIPTIONAL GENETIC REGULATION WITH A PROPOSED ROLE IN INTERCELLULAR COMMUNICATION. MIRNAS ARE CONSIDERED PROMISING BIOMARKERS IN ISCHEMIC HEART DISEASE. INVASIVE PHYSIOLOGICAL EVALUATION ALLOWS A PRECISE ASSESSMENT OF EACH AFFECTED CORONARY COMPARTMENT. ALTHOUGH SOME STUDIES HAVE ASSOCIATED THE EXPRESSION OF CIRCULATING MIRNAS WITH INVASIVE PHYSIOLOGICAL INDEXES, THEIR GLOBAL RELATIONSHIP WITH CORONARY COMPARTMENTS HAS NOT BEEN ASSESSED. HERE, WE WILL EVALUATE CIRCULATING MIRNAS PROFILES ACCORDING TO THE CORONARY PATTERN OF THE VASCULAR COMPARTMENT AFFECTATION. STUDY AND DESIGN: THIS IS AN INVESTIGATOR-INITIATED, MULTICENTRE, DESCRIPTIVE STUDY TO BE CONDUCTED AT THREE CENTRES IN SPAIN (NCT05374694). THE STUDY WILL INCLUDE ONE HUNDRED CONSECUTIVE PATIENTS OLDER THAN 18 YEARS WITH CHEST PAIN OF PRESUMED CORONARY CAUSE UNDERGOING INVASIVE PHYSIOLOGICAL EVALUATION, INCLUDING FRACTIONAL FLOW RESERVE (FFR) AND INDEX OF MICROVASCULAR RESISTANCE (IMR). PATIENTS WILL BE INITIALLY CLASSIFIED INTO FOUR GROUPS, ACCORDING TO FFR AND IMR: MACROVASCULAR AND MICROVASCULAR AFFECTATION (FFR</=0.80 / IMR>/=25), ISOLATED MACROVASCULAR AFFECTATION (FFR</=0.80 / IMR<25), ISOLATED MICROVASCULAR AFFECTATION (FFR>0.80 / IMR >/=25) AND NORMAL CORONARY INDEXES (FFR>0.80 / IMR<25). PATIENTS WITH ISOLATED MICROVASCULAR AFFECTATION OR NORMAL INDEXES WILL ALSO UNDERGO THE ACETYLCHOLINE TEST AND MAY BE RECLASSIFIED AS A FIFTH GROUP IN THE PRESENCE OF SPASM. A PANEL OF MIRNAS PREVIOUSLY ASSOCIATED WITH MOLECULAR MECHANISMS LINKED TO CHRONIC CORONARY SYNDROME WILL BE ANALYSED USING RT-QPCR. CONCLUSIONS: THE RESULTS OF THIS STUDY WILL IDENTIFY MIRNA PROFILES ASSOCIATED WITH PATTERNS OF CORONARY AFFECTATION AND WILL CONTRIBUTE TO A BETTER UNDERSTANDING OF THE MECHANISTIC PATHWAYS OF CORONARY PATHOLOGY.	2023