1  448 145 APABETALONE MEDIATED EPIGENETIC MODULATION IS ASSOCIATED WITH FAVORABLE KIDNEY FUNCTION AND ALKALINE PHOSPHATASE PROFILE IN PATIENTS WITH CHRONIC KIDNEY DISEASE. BACKGROUND/AIMS: THE ASSOCIATION BETWEEN SERUM ALKALINE PHOSPHATASE (ALP) WITH ADVERSE CARDIOVASCULAR OUTCOMES, IN CHRONIC KIDNEY DISEASE (CKD) PATIENTS HAS PREVIOUSLY BEEN REPORTED AND MAY BE A RESULT OF INCREASED VASCULAR CALCIFICATION AND INFLAMMATION. HERE WE REPORT, FOR THE FIRST TIME, THE EFFECTS OF PHARMACOLOGIC EPIGENETIC MODULATION ON LEVELS OF ALP AND KIDNEY FUNCTION VIA A NOVEL ORAL SMALL MOLECULE BET INHIBITOR, APABETALONE, IN CKD PATIENTS. METHODS: A POST-HOC ANALYSIS EVALUATED PATIENTS WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) <60 ML/MIN/1.73M2, WHO PARTICIPATED IN THE APABETALONE PHASE 2 RANDOMIZED CONTROLLED TRIALS (SUSTAIN AND ASSURE). 48 CKD SUBJECTS WITH A HISTORY OF CARDIOVASCULAR DISEASE (CVD) WERE TREATED WITH 100MG TWICE-DAILY OF 24 AND 26 WEEKS OF APABETALONE OR PLACEBO. ALP AND EGFR WERE MEASURED PRIOR TO RANDOMIZATION AND AT FINAL VISITS. RESULTS: PATIENTS WHO RECEIVED APABETALONE (N=35) VERSUS PLACEBO (N=13) OVER 6 MONTHS SHOWED SIGNIFICANTLY (P=0.02) LOWERED SERUM ALP -14.0% (P<0.0001 VERSUS BASELINE) VERSUS -6.3% (P=0.9 VERSUS BASELINE). THE EGFR IN THE APABETALONE GROUP INCREASED BY 3.4% (1.7 ML/MIN/1.73 M2) (P=0.04 VERSUS BASELINE) AND DECREASED BY 5.8% (2.9 ML/MIN/1.73 M2) (P=0.6 VERSUS BASELINE) IN THE PLACEBO GROUP. APABETALONE WAS WELL TOLERATED. CONCLUSION: A POST-HOC ANALYSIS OF CKD SUBJECTS FROM THE SUSTAIN AND ASSURE RANDOMIZED CONTROLLED TRIALS DEMONSTRATED FAVORABLE EFFECTS OF APABETALONE ON ALP AND EGFR, AND GENERATED THE HYPOTHESIS THAT EPIGENETIC MODULATION BY BET INHIBITION MAY POTENTIALLY OFFER A NOVEL THERAPEUTIC STRATEGY TO TREAT CVD AND PROGRESSIVE KIDNEY FUNCTION LOSS IN CKD PATIENTS. THIS IS BEING EXAMINED IN THE PHASE III TRIAL BETONMACE.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  447  52 APABETALONE LOWERS SERUM ALKALINE PHOSPHATASE AND IMPROVES CARDIOVASCULAR RISK IN PATIENTS WITH CARDIOVASCULAR DISEASE. BACKGROUND AND AIMS: IN PATIENTS WITH CARDIOVASCULAR DISEASE, CONSIDERABLE RESIDUAL RISK REMAINS DESPITE EVIDENCE-BASED SECONDARY PREVENTION MEASURES. ALKALINE PHOSPHATASE (ALP) HAS BEEN SUGGESTED AS A MODIFIABLE CARDIOVASCULAR RISK FACTOR. WE SOUGHT TO DETERMINE WHETHER CARDIOVASCULAR RISK REDUCTION BY THE BROMODOMAIN AND EXTRA-TERMINAL (BET) PROTEIN INHIBITOR APABETALONE IS ASSOCIATED WITH THE CONCOMITANT LOWERING OF SERUM ALP. METHODS: IN A POST-HOC ANALYSIS OF 795 PATIENTS WITH ESTABLISHED CORONARY HEART DISEASE AND STATIN TREATMENT, WHO PARTICIPATED IN PHASE 2 PLACEBO-CONTROLLED TRIALS OF APABETALONE, WE DETERMINED THE EFFECT OF ASSIGNED TREATMENT FOR UP TO 24 WEEKS ON THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) AND SERUM ALP. RESULTS: BASELINE ALP (MEDIAN 72 U/L) PREDICTED MACE (DEATH, NON-FATAL MYOCARDIAL INFARCTION, CORONARY REVASCULARIZATION, OR HOSPITALIZATION FOR CARDIOVASCULAR CAUSES), INDEPENDENT OF HIGH-SENSITIVITY C-REACTIVE PROTEIN (HSCRP), SEX, AGE, RACE, STUDY, CARDIOVASCULAR RISK FACTORS, CHRONIC KIDNEY DISEASE (CKD), LIVER FUNCTION MARKERS AND TREATMENT ALLOCATION (HAZARD RATIO [HR] PER STANDARD DEVIATION [SD] 1.6, 95% CI 1.19-2.16, P = 0.002). MEAN PLACEBO-CORRECTED DECREASES IN ALP FROM BASELINE WERE 9.2% (P < 0.001) AFTER 12-14 WEEKS AND 7.7% (P < 0.001) AFTER 24-26 WEEKS OF APABETALONE TREATMENT. IN THE APABETALONE GROUP, A 1-SD REDUCTION IN ALP WAS ASSOCIATED WITH A HR FOR MACE OF 0.64 (95% CI 0.46-0.90, P = 0.009). CONCLUSIONS: SERUM ALP PREDICTS RESIDUAL CARDIOVASCULAR RISK, INDEPENDENT OF HSCRP, ESTABLISHED CARDIOVASCULAR RISK FACTORS AND CKD, IN PATIENTS WITH CARDIOVASCULAR DISEASE ON STATIN TREATMENT. APABETALONE LOWERS SERUM ALP, WHICH WAS ASSOCIATED WITH A LOWER RISK OF CARDIOVASCULAR EVENTS. WHETHER THE BENEFICIAL CARDIOVASCULAR EFFECTS OF APABETALONE ARE CAUSALLY RELATED TO ALP REDUCTION REMAINS UNDETERMINED.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
3 1785  52 EFFECT OF APABETALONE ON CARDIOVASCULAR EVENTS IN DIABETES, CKD, AND RECENT ACUTE CORONARY SYNDROME: RESULTS FROM THE BETONMACE RANDOMIZED CONTROLLED TRIAL. BACKGROUND AND OBJECTIVES: CKD AND TYPE 2 DIABETES MELLITUS INTERACT TO INCREASE THE RISK OF MAJOR ADVERSE CARDIOVASCULAR EVENTS (I.E., CARDIOVASCULAR DEATH, NONFATAL MYOCARDIAL INFARCTION, OR STROKE) AND CONGESTIVE HEART FAILURE. A MALADAPTIVE EPIGENETIC RESPONSE MAY BE A CARDIOVASCULAR RISK DRIVER AND AMENABLE TO MODIFICATION WITH APABETALONE, A SELECTIVE MODULATOR OF THE BROMODOMAIN AND EXTRATERMINAL DOMAIN TRANSCRIPTION SYSTEM. WE EXAMINED THIS QUESTION IN A PRESPECIFIED ANALYSIS OF BETONMACE, A PHASE 3 TRIAL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: BETONMACE WAS AN EVENT-DRIVEN, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL COMPARING EFFECTS OF APABETALONE VERSUS PLACEBO ON MAJOR ADVERSE CARDIOVASCULAR EVENTS AND HEART FAILURE HOSPITALIZATIONS IN 2425 PARTICIPANTS WITH TYPE 2 DIABETES AND A RECENT ACUTE CORONARY SYNDROME, INCLUDING 288 PARTICIPANTS WITH CKD WITH EGFR <60 ML/MIN PER 1.73 M(2) AT BASELINE. THE PRIMARY END POINT IN BETONMACE WAS THE TIME TO THE FIRST MAJOR ADVERSE CARDIOVASCULAR EVENT, WITH A SECONDARY END POINT OF TIME TO HOSPITALIZATION FOR HEART FAILURE. RESULTS: MEDIAN FOLLOW-UP WAS 27 MONTHS (INTERQUARTILE RANGE, 20-32 MONTHS). IN PARTICIPANTS WITH CKD, APABETALONE COMPARED WITH PLACEBO WAS ASSOCIATED WITH FEWER MAJOR ADVERSE CARDIOVASCULAR EVENTS (13 EVENTS IN 124 PATIENTS [11%] VERSUS 35 EVENTS IN 164 PATIENTS [21%]; HAZARD RATIO, 0.50; 95% CONFIDENCE INTERVAL, 0.26 TO 0.96) AND FEWER HEART FAILURE-RELATED HOSPITALIZATIONS (THREE HOSPITALIZATIONS IN 124 PATIENTS [3%] VERSUS 14 HOSPITALIZATIONS IN 164 PATIENTS [9%]; HAZARD RATIO, 0.48; 95% CONFIDENCE INTERVAL, 0.26 TO 0.86). IN THE NON-CKD GROUP, THE CORRESPONDING HAZARD RATIO VALUES WERE 0.96 (95% CONFIDENCE INTERVAL, 0.74 TO 1.24) FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND 0.76 (95% CONFIDENCE INTERVAL, 0.46 TO 1.27) FOR HEART FAILURE-RELATED HOSPITALIZATION. INTERACTION OF CKD ON TREATMENT EFFECT WAS P=0.03 FOR MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND P=0.12 FOR HEART FAILURE-RELATED HOSPITALIZATION. PARTICIPANTS WITH CKD SHOWED SIMILAR NUMBERS OF ADVERSE EVENTS, REGARDLESS OF RANDOMIZATION TO APABETALONE OR PLACEBO (119 [73%] VERSUS 88 [71%] PATIENTS), AND THERE WERE FEWER SERIOUS ADVERSE EVENTS (29% VERSUS 43%; P=0.02) IN THE APABETALONE GROUP. CONCLUSIONS: APABETALONE MAY REDUCE THE INCIDENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH CKD AND TYPE 2 DIABETES WHO HAVE A HIGH BURDEN OF CARDIOVASCULAR DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
4  587  52 BENEFIT OF APABETALONE ON PLASMA PROTEINS IN RENAL DISEASE. INTRODUCTION: APABETALONE, A SMALL MOLECULE INHIBITOR, TARGETS EPIGENETIC READERS TERMED BET PROTEINS THAT CONTRIBUTE TO GENE DYSREGULATION IN HUMAN DISORDERS. APABETALONE HAS IN VITRO AND IN VIVO ANTI-INFLAMMATORY AND ANTIATHEROSCLEROTIC PROPERTIES. IN PHASE 2 CLINICAL TRIALS, THIS DRUG REDUCED THE INCIDENCE OF MAJOR ADVERSE CARDIAC EVENTS IN PATIENTS WITH CARDIOVASCULAR DISEASE. CHRONIC KIDNEY DISEASE IS ASSOCIATED WITH A PROGRESSIVE LOSS OF RENAL FUNCTION AND A HIGH RISK OF CARDIOVASCULAR DISEASE. WE STUDIED THE IMPACT OF APABETALONE ON THE PLASMA PROTEOME IN PATIENTS WITH IMPAIRED KIDNEY FUNCTION. METHODS: SUBJECTS WITH STAGE 4 OR 5 CHRONIC KIDNEY DISEASE AND MATCHED CONTROLS RECEIVED A SINGLE DOSE OF APABETALONE. PLASMA WAS COLLECTED FOR PHARMACOKINETIC ANALYSIS AND FOR PROTEOMICS PROFILING USING THE SOMASCAN 1.3K PLATFORM. PROTEOMICS DATA WERE ANALYZED WITH INGENUITY PATHWAY ANALYSIS TO IDENTIFY DYSREGULATED PATHWAYS IN DISEASED PATIENTS, WHICH WERE TARGETED BY APABETALONE. RESULTS: AT BASELINE, 169 PLASMA PROTEINS (ADJUSTED P VALUE <0.05) WERE DIFFERENTIALLY ENRICHED IN RENALLY IMPAIRED PATIENTS VERSUS CONTROL SUBJECTS, INCLUDING CYSTATIN C AND BETA(2) MICROGLOBULIN, WHICH CORRELATE WITH RENAL FUNCTION. BIOINFORMATICS ANALYSIS OF THE PLASMA PROTEOME REVEALED A SIGNIFICANT ACTIVATION OF 42 PATHWAYS THAT CONTROL IMMUNITY AND INFLAMMATION, OXIDATIVE STRESS, ENDOTHELIAL DYSFUNCTION, VASCULAR CALCIFICATION, AND COAGULATION. AT 12 HOURS POSTDOSE, APABETALONE COUNTERED THE ACTIVATION OF PATHWAYS ASSOCIATED WITH RENAL DISEASE AND REDUCED THE ABUNDANCE OF DISEASE MARKERS, INCLUDING INTERLEUKIN-6, PLASMINOGEN ACTIVATOR INHIBITOR-1, AND OSTEOPONTIN. CONCLUSION: THESE DATA DEMONSTRATED PLASMA PROTEOME DYSREGULATION IN RENALLY IMPAIRED PATIENTS AND THE BENEFICIAL IMPACT OF APABETALONE ON PATHWAYS LINKED TO CHRONIC KIDNEY DISEASE AND ITS CARDIOVASCULAR COMPLICATIONS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
5 6043  39 THE COMBINED PROGNOSTIC SIGNIFICANCE OF ALKALINE PHOSPHATASE AND INTRACRANIAL ARTERIAL CALCIFICATIONS IN HEMODIALYSIS PATIENTS. INTRODUCTION: THE PREVALENCE OF INTRACRANIAL ARTERIAL CALCIFICATION (ICAC) IN MAINTENANCE HEMODIALYSIS (MHD) PATIENTS IS ABOUT 90%, AND ITS SEVERITY IS CORRELATED WITH AGE, HEMODIALYSIS VINTAGE, AND MINERAL BONE DISEASE. ELEVATED CONCENTRATIONS OF CALCIUM AND PHOSPHORUS ARE NOT SUFFICIENT FOR MEDIAL CALCIFICATION BECAUSE OF INHIBITION BY PYROPHOSPHATE. ALKALINE PHOSPHATASE (ALP) PROMOTES CALCIFICATION BY HYDROLYZING EXTRACELLULAR PYROPHOSPHATE. EPIGENETIC MECHANISMS INVOLVING ALP INHIBITION BY APABETALONE WERE INVESTIGATED AS A POTENTIAL TARGET FOR PREVENTING VASCULAR CALCIFICATIONS (VCS). THIS STUDY ASSESSED THE COMBINED IMPACT OF VCS AND ELEVATED SERUM ALP ON MORTALITY AMONG CHRONIC HD PATIENTS. METHODS: VCS REPRESENTED BY ICAC WERE MEASURED SIMULTANEOUSLY WITH MINERAL BONE DISEASE PARAMETERS INCLUDING SERUM ALP OF MHD PATIENTS WHO UNDERWENT NONCONTRAST BRAIN COMPUTED TOMOGRAPHY FROM 2015 TO 2018 IN OUR INSTITUTION. RESULTS: THIS RETROSPECTIVE STUDY INCLUDED 150 MHD PATIENTS (MEAN AGE 71.3 +/- 12.1 YEARS, 60.1% MALE). OF THE TOTAL COHORT, 12 (7.8%) HAD NO BRAIN CALCIFICATIONS AND 69 (45.1%) HAD MULTIPLE INTRACRANIAL CALCIFICATIONS. CONSIDERING THE PATIENTS WITH NORMAL ALP AND NO CALCIFICATION AS THE REFERENCE GROUP YIELDED ADJUSTED ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 4.6 (95% CI: 1.7-12.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND NORMAL ALP (P = 0.003) AND ODDS RATIOS FOR ALL-CAUSE MORTALITY OF 6.1 (95% CI: 2.1-17.7) AMONG PATIENTS WITH BRAIN CALCIFICATIONS AND ELEVATED ALP (P= 0.001). CONCLUSION: WE FOUND AN INDEPENDENT ASSOCIATION BETWEEN ICAC AND THE RISK OF DEATH AMONG MHD PATIENTS. THE COMBINED EFFECT OF ICAC AND ELEVATED ALP WAS ASSOCIATED WITH A HIGHER ODDS RATIO FOR ALL-CAUSE MORTALITY IN MHD PATIENTS AND MAY CONTRIBUTE TO THE RISK STRATIFICATION OF THESE PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
6 5045  38 PHARMACOLOGIC EPIGENETIC MODULATORS OF ALKALINE PHOSPHATASE IN CHRONIC KIDNEY DISEASE. PURPOSE OF REVIEW: IN CHRONIC KIDNEY DISEASE (CKD), DISTURBANCE OF SEVERAL METABOLIC REGULATORY MECHANISMS CAUSE PREMATURE AGEING, ACCELERATED CARDIOVASCULAR DISEASE (CVD), AND MORTALITY. SINGLE-TARGET INTERVENTIONS HAVE REPEATEDLY FAILED TO IMPROVE THE PROGNOSIS FOR CKD PATIENTS. EPIGENETIC INTERVENTIONS HAVE THE POTENTIAL TO MODULATE SEVERAL PATHOGENETIC PROCESSES SIMULTANEOUSLY. ALKALINE PHOSPHATASE (ALP) IS A ROBUST PREDICTOR OF CVD AND ALL-CAUSE MORTALITY AND IMPLICATED IN PATHOGENIC PROCESSES ASSOCIATED WITH CVD IN CKD. RECENT FINDINGS: IN EXPERIMENTAL STUDIES, EPIGENETIC MODULATION OF ALP BY MICRORNAS OR BROMODOMAIN AND EXTRATERMINAL (BET) PROTEIN INHIBITION HAS SHOWN PROMISING RESULTS FOR THE TREATMENT OF CVD AND OTHER CHRONIC METABOLIC DISEASES. THE BET INHIBITOR APABETALONE IS CURRENTLY BEING EVALUATED FOR CARDIOVASCULAR RISK REDUCTION IN A PHASE III CLINICAL STUDY IN HIGH-RISK CVD PATIENTS, INCLUDING PATIENTS WITH CKD (CLINICALTRIALS.GOV IDENTIFIER: NCT02586155). PHASE II STUDIES DEMONSTRATE AN ALP-LOWERING POTENTIAL OF APABETALONE, WHICH WAS ASSOCIATED WITH IMPROVED CARDIOVASCULAR AND RENAL OUTCOMES. SUMMARY: ALP IS A PREDICTOR OF CVD AND MORTALITY IN CKD. EPIGENETIC MODULATION OF ALP HAS THE POTENTIAL TO AFFECT SEVERAL PATHOGENETIC PROCESSES IN CKD AND THEREBY IMPROVE CARDIOVASCULAR OUTCOME.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
7  446  40 APABETALONE DOWNREGULATES FIBROTIC, INFLAMMATORY AND CALCIFIC PROCESSES IN RENAL MESANGIAL CELLS AND PATIENTS WITH RENAL IMPAIRMENT. EPIGENETIC MECHANISMS ARE IMPLICATED IN TRANSCRIPTIONAL PROGRAMS DRIVING CHRONIC KIDNEY DISEASE (CKD). APABETALONE IS AN ORALLY AVAILABLE INHIBITOR OF BROMODOMAIN AND EXTRATERMINAL (BET) PROTEINS, WHICH ARE EPIGENETIC READERS THAT MODULATE GENE EXPRESSION. IN THE PHASE 3 BETONMACE TRIAL, APABETALONE REDUCED RISK OF MAJOR ADVERSE CARDIAC EVENTS (MACE) BY 50% IN THE CKD SUBPOPULATION, INDICATING FAVORABLE EFFECTS ALONG THE KIDNEY-HEART AXIS. ACTIVATION OF HUMAN RENAL MESANGIAL CELLS (HRMCS) TO A CONTRACTILE PHENOTYPE THAT OVERPRODUCES EXTRACELLULAR MATRIX (ECM) AND INFLAMMATORY CYTOKINES, AND PROMOTES CALCIFICATION, FREQUENTLY ACCOMPANIES CKD TO DRIVE PATHOLOGY. HERE, WE SHOW APABETALONE DOWNREGULATED HRMC ACTIVATION WITH TGF-BETA1 STIMULATION BY SUPPRESSING TGF-BETA1-INDUCED ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA) EXPRESSION, ALPHA-SMA ASSEMBLY INTO STRESS FIBERS, ENHANCED CONTRACTION, COLLAGEN OVERPRODUCTION, AND EXPRESSION OF KEY DRIVERS OF FIBROSIS, INFLAMMATION, OR CALCIFICATION INCLUDING THROMBOSPONDIN, FIBRONECTIN, PERIOSTIN, SPARC, INTERLEUKIN 6, AND ALKALINE PHOSPHATASE. LIPOPOLYSACCHARIDE-STIMULATED EXPRESSION OF INFLAMMATORY GENES IL6, IL1B, AND PTGS2 WAS ALSO SUPPRESSED. TRANSCRIPTOMICS CONFIRMED APABETALONE AFFECTED GENE SETS OF ECM REMODELING AND INTEGRINS. CLINICAL TRANSLATION OF IN VITRO RESULTS WAS INDICATED IN CKD PATIENTS WHERE A SINGLE DOSE OF APABETALONE REDUCED PLASMA LEVELS OF KEY PRO-FIBROTIC AND INFLAMMATORY MARKERS, AND INDICATED INHIBITION OF TGF-BETA1 SIGNALING. WHILE PLASMA PROTEINS CANNOT BE TRACED TO THE KIDNEY ALONE, ANTI-FIBROTIC AND ANTI-INFLAMMATORY EFFECTS OF APABETALONE IDENTIFIED IN THIS STUDY ARE CONSISTENT WITH THE OBSERVED DECREASE IN CARDIOVASCULAR RISK IN CKD PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  445  42 APABETALONE (RVX-208) REDUCES VASCULAR INFLAMMATION IN VITRO AND IN CVD PATIENTS BY A BET-DEPENDENT EPIGENETIC MECHANISM. BACKGROUND: APABETALONE (RVX-208) IS A BROMODOMAIN AND EXTRATERMINAL PROTEIN INHIBITOR (BETI) THAT IN PHASE II TRIALS REDUCED THE RELATIVE RISK (RR) OF MAJOR ADVERSE CARDIAC EVENTS (MACE) IN PATIENTS WITH CARDIOVASCULAR DISEASE (CVD) BY 44% AND IN DIABETIC CVD PATIENTS BY 57% ON TOP OF STATINS. A PHASE III TRIAL, BETONMACE, IS CURRENTLY ASSESSING APABETALONE'S ABILITY TO REDUCE MACE IN STATIN-TREATED POST-ACUTE CORONARY SYNDROME TYPE 2 DIABETIC CVD PATIENTS WITH LOW HIGH-DENSITY LIPOPROTEIN C. THE LEADING CAUSE OF MACE IS ATHEROSCLEROSIS, DRIVEN BY DYSFUNCTIONAL LIPID METABOLISM AND CHRONIC VASCULAR INFLAMMATION (VI). IN VITRO STUDIES HAVE IMPLICATED THE BET PROTEIN BRD4 AS AN EPIGENETIC DRIVER OF INFLAMMATION AND ATHEROGENESIS, SUGGESTING THAT BETI MAY BE CLINICALLY EFFECTIVE IN COMBATING VI. HERE, WE ASSESSED APABETALONE'S ABILITY TO REGULATE INFLAMMATION-DRIVEN GENE EXPRESSION AND CELL ADHESION IN VITRO AND INVESTIGATED THE MECHANISM BY WHICH APABETALONE SUPPRESSES EXPRESSION. THE CLINICAL IMPACT OF APABETALONE ON MEDIATORS OF VI WAS ASSESSED WITH PROTEOMIC ANALYSIS OF PHASE II CVD PATIENT PLASMA. RESULTS: IN VITRO, APABETALONE PREVENTED INFLAMMATORY (TNFALPHA, LPS, OR IL-1BETA) INDUCTION OF KEY FACTORS THAT DRIVE ENDOTHELIAL ACTIVATION, MONOCYTE RECRUITMENT, ADHESION, AND PLAQUE DESTABILIZATION. BRD4 ABUNDANCE ON INFLAMMATORY AND ADHESION GENE PROMOTERS AND ENHANCERS WAS REDUCED BY APABETALONE. BRD2-4 DEGRADATION BY MZ-1 ALSO PREVENTED TNFALPHA-INDUCED TRANSCRIPTION OF MONOCYTE AND ENDOTHELIAL CELL ADHESION MOLECULES AND INFLAMMATORY MEDIATORS, CONFIRMING BET-DEPENDENT REGULATION. TRANSCRIPTIONAL REGULATION BY APABETALONE TRANSLATED INTO A REDUCTION IN MONOCYTE ADHESION TO AN ENDOTHELIAL MONOLAYER. IN A PHASE II TRIAL, APABETALONE TREATMENT REDUCED THE ABUNDANCE OF MULTIPLE VI MEDIATORS IN THE PLASMA OF CVD PATIENTS (SOMASCAN(R) 1.3 K). THESE PROTEINS CORRELATE WITH CVD RISK AND INCLUDE ADHESION MOLECULES, CYTOKINES, AND METALLOPROTEINASES. INGENUITY(R) PATHWAY ANALYSIS (IPA(R)) PREDICTED THAT APABETALONE INHIBITS PRO-ATHEROGENIC REGULATORS AND PATHWAYS AND PREVENTS DISEASE STATES ARISING FROM LEUKOCYTE RECRUITMENT. CONCLUSIONS: APABETALONE SUPPRESSED GENE EXPRESSION OF VI MEDIATORS IN MONOCYTES AND ENDOTHELIAL CELLS BY INHIBITING BET-DEPENDENT TRANSCRIPTION INDUCED BY MULTIPLE INFLAMMATORY STIMULI. IN CVD PATIENTS, APABETALONE TREATMENT REDUCED CIRCULATING LEVELS OF VI MEDIATORS, AN OUTCOME CONDUCIVE WITH ATHEROSCLEROTIC PLAQUE STABILIZATION AND MACE REDUCTION. INHIBITION OF INFLAMMATORY AND ADHESION MOLECULE GENE EXPRESSION BY APABETALONE IS PREDICTED TO CONTRIBUTE TO MACE REDUCTION IN THE PHASE III BETONMACE TRIAL.	2019	
                                                                                                                                                                                                                                                                                                                          
10 6080  46 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
11  274  28 AGE-RELATED CHANGES IN DNA METHYLATION AFFECT RENAL HISTOLOGY AND POST-TRANSPLANT FIBROSIS. DURING AGEING, KIDNEY FUNCTION DECREASES DUE TO RENAL TUBULAR ATROPHY, INTERSTITIAL FIBROSIS, GLOMERULOSCLEROSIS AND ARTERIOSCLEROSIS. RECENTLY, CHANGES IN DNA METHYLATION WERE SHOWN TO CONTRIBUTE TO VARIOUS AGEING PROCESSES. HOWEVER, IT IS UNKNOWN WHETHER SUCH CHANGES ALSO CONTRIBUTE TO AGE-RELATED KIDNEY DYSFUNCTION. TO ASSESS THIS, WE PROFILED GENOME-WIDE CHANGES IN DNA METHYLATION (OVER 800 000 CPG SITES) IN 95 RENAL BIOPSIES OBTAINED PRIOR TO KIDNEY TRANSPLANTATION FROM DONORS AGED 16 TO 73 YEARS. DONOR AGE SIGNIFICANTLY ASSOCIATED WITH THE METHYLATION OF 92 778 CPGS (FALSE DISCOVERY RATE UNDER 0.05), CORRESPONDING TO 10 285 DIFFERENTIALLY METHYLATED REGIONS. THESE REGIONS WERE MOST FREQUENTLY LOCATED IN GENES INVOLVED IN THE WNT/BETA-CATENIN SIGNALING PATHWAY. USING AN INDEPENDENT COHORT OF 67 BIOPSIES, WE AUTONOMOUSLY VALIDATED THESE FINDINGS. INTERESTINGLY, THE METHYLATION STATUS OF THESE 92 778 AGE-RELATED CPGS WAS ASSOCIATED WITH GLOMERULOSCLEROSIS (34.4% OF CPGS AT A FALSE DISCOVERY RATE UNDER 0.05) AND INTERSTITIAL FIBROSIS (0.9%) AND GRAFT FUNCTION AT ONE YEAR AFTER TRANSPLANTATION, BUT NOT WITH TUBULAR ATROPHY AND ARTERIOSCLEROSIS. NO ASSOCIATION WAS OBSERVED WITH ANY OF THESE PATHOLOGIES AT THE TIME OF TRANSPLANTATION (0% AT A FALSE DISCOVERY RATE UNDER 0.05). THUS, AGE-ASSOCIATED CHANGES IN DNA METHYLATION AT THE TIME OF TRANSPLANTATION PREDICT FUTURE INJURY OF TRANSPLANTED KIDNEYS. SPECIFICALLY, OUR EPIGENOME-WIDE ASSOCIATION STUDY DEMONSTRATES THAT EPIGENETIC RENAL AGEING IS IMPLICATED IN PROGRESSIVE FIBROSIS IN BOTH THE GLOMERULUS AND THE INTERSTITIUM.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
12 3502  54 IDENTIFICATION OF POTENTIAL BIOMARKERS OF CHRONIC KIDNEY DISEASE IN INDIVIDUALS WITH DIABETES: PROTOCOL FOR A CROSS-SECTIONAL OBSERVATIONAL STUDY. BACKGROUND: THE IMPORTANCE OF IDENTIFYING PEOPLE WITH DIABETES AND PROGRESSIVE KIDNEY DYSFUNCTION RELATES TO THE EXCESS MORBIDITY AND MORTALITY OF THIS GROUP. RATES OF CARDIOVASCULAR DISEASE ARE MUCH HIGHER IN PEOPLE WITH BOTH DIABETES AND KIDNEY DYSFUNCTION THAN IN THOSE WITH ONLY ONE OF THESE CONDITIONS. BY THE TIME THESE PEOPLE ARE IDENTIFIED IN CURRENT CLINICAL PRACTICE, PROTEINURIA AND RENAL DYSFUNCTION ARE ALREADY ESTABLISHED, LIMITING THE EFFECTIVENESS OF THERAPEUTIC INTERVENTIONS. THE IDENTIFICATION OF AN EPIGENETIC OR BLOOD METABOLITE SIGNATURE OR GUT MICROBIOME PROFILE MAY IDENTIFY THOSE WITH DIABETES AT RISK OF PROGRESSIVE CHRONIC KIDNEY DISEASE, IN TURN PROVIDING TARGETED INTERVENTION TO IMPROVE PATIENT OUTCOMES. OBJECTIVE: THIS STUDY AIMS TO IDENTIFY POTENTIAL BIOMARKERS IN PEOPLE WITH DIABETES AND CHRONIC KIDNEY DISEASE (CKD) ASSOCIATED WITH PROGRESSIVE RENAL INJURY AND TO DISTINGUISH BETWEEN STAGES OF CHRONIC KIDNEY DISEASE. THREE SOURCES OF BIOMARKERS WILL BE EXPLORED, INCLUDING DNA METHYLATION PROFILES IN BLOOD LYMPHOCYTES, THE METABOLOMIC PROFILE OF BLOOD-DERIVED PLASMA AND URINE, AND THE GUT MICROBIOME. METHODS: THE CROSS-SECTIONAL STUDY RECRUITED 121 PEOPLE WITH DIABETES AND VARYING STAGES (STAGES 1-5) OF CHRONIC KIDNEY DISEASE. SINGLE-POINT DATA COLLECTION INCLUDED BLOOD, URINE, AND FECAL SAMPLES IN ADDITION TO CLINICAL DATA SUCH AS ANTHROPOMETRIC MEASUREMENTS AND BIOCHEMICAL PARAMETERS. ADDITIONAL INFORMATION OBTAINED FROM MEDICAL RECORDS INCLUDED PATIENT DEMOGRAPHICS, MEDICAL COMORBIDITIES, AND MEDICATIONS. RESULTS: DATA COLLECTION COMMENCED IN JANUARY 2018 AND WAS COMPLETED IN JUNE 2018. AT THE TIME OF SUBMISSION, 121 PATIENTS HAD BEEN RECRUITED, AND 119 SAMPLES REMAINED AFTER QUALITY CONTROL. THERE WERE 83 PARTICIPANTS IN THE EARLY DIABETES-ASSOCIATED CKD GROUP WITH A MEAN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OF 61.2 ML/MIN/1.73 M2 (EARLY CKD GROUP CONSISTING OF STAGE 1, 2, AND 3A CKD), AND 36 PARTICIPANTS IN THE LATE DIABETIC CKD GROUP WITH A MEAN EGFR OF 23.9 ML/MIN/1.73 M2 (LATE CKD GROUP, CONSISTING OF STAGE 3B, 4, AND 5), P<.001. WE HAVE SUCCESSFULLY OBTAINED DNA FOR METHYLATION AND MICROBIOME ANALYSES USING THE BIOSPECIMENS COLLECTED VIA THIS PROTOCOL AND ARE CURRENTLY ANALYZING THESE RESULTS TOGETHER WITH THE METABOLOME OF THIS COHORT OF INDIVIDUALS WITH DIABETIC CKD. CONCLUSIONS: RECENT ADVANCES HAVE IMPROVED OUR UNDERSTANDING OF THE EPIGENOME, METABOLOMICS, AND THE INFLUENCE OF THE GUT MICROBIOME ON THE INCIDENCE OF DISEASES SUCH AS CANCERS, PARTICULARLY THOSE RELATED TO ENVIRONMENTAL EXPOSURES. HOWEVER, THERE IS A PAUCITY OF LITERATURE SURROUNDING THESE INFLUENCERS IN RENAL DISEASE. THIS STUDY WILL PROVIDE INSIGHT INTO THE FUNDAMENTAL UNDERSTANDING OF THE PATHOPHYSIOLOGY OF CKD IN INDIVIDUALS WITH DIABETES, ESPECIALLY IN NOVEL AREAS SUCH AS EPIGENETICS, METABOLOMICS, AND THE KIDNEY-GUT AXIS. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16277.	2020	

13 6547  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 1271  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
15 3442  32 HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH DIABETIC COMPLICATIONS AND BIOCHEMICAL INDICATORS. BACKGROUND: DNA METHYLATION IS AN EPIGENETIC MECHANISM FOR REGULATING THE TRANSCRIPTION OF MANY GENES AND HAS BEEN LINKED TO THE DEVELOPMENT OF VARIOUS DISEASES. A PROMISING GENE TO INVESTIGATE IS METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR), SINCE THE ENZYME METHYLENETETRAHYDROFOLATE REDUCTASE (MTHFR) PROMOTES METHYL RADICAL SYNTHESIS IN THE HOMOCYSTEINE CYCLE AND CAN PROVIDE METHYL GROUPS FOR DNA METHYLATION. IN ADDITION, SEVERAL STUDIES HAVE CORRELATED GENE POLYMORPHISMS OF THIS ENZYME WITH A GREATER RISK OF DIABETES, BUT LITTLE IS KNOWN REGARDING THE RELATIONSHIP BETWEEN EPIGENETIC CHANGES IN THIS GENE AND DIABETES AND ITS COMPLICATIONS. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE RELATIONSHIP BETWEEN METHYLATION PROFILE IN THE MTHFR GENE PROMOTER AND BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS MARKERS IN INDIVIDUALS WITH TYPE 2 DIABETES (T2DM) WHO HAVE BEEN DIAGNOSED FOR 5-10 YEARS WITH OR WITHOUT DIABETIC RETINOPATHY (DR) AND NEPHROPATHY (DN). METHODS: SPECIFIC PCR FOR METHYLATION (MSP) WAS USED TO ANALYZE MTHFR METHYLATION PROFILE IN LEUCOCYTES DNA. BIOCHEMICAL MARKERS (GLYCEMIA, GLYCATED HEMOGLOBIN, TOTAL CHOLESTEROL, LDL, HDL, TRIGLYCERIDES, SERUM CREATININE), INFLAMMATORY MARKERS (C-REACTIVE PROTEIN AND ALPHA-1 ACID GLYCOPROTEIN) AND OXIDATIVE STRESS (TOTAL ANTIOXIDANT AND MALONALDEHYDE) WERE DETERMINED IN PERIPHERIC BLOOD SAMPLES AND MICROALBUMINURIA IN 24 H URINE SAMPLES. THE X(2) AND MANN-WHITNEY STATISTICAL TESTS WERE PERFORMED AND P < 0.05 WERE CONSIDERED SIGNIFICANT. RESULTS: THE HYPERMETHYLATED PROFILE WAS MOST FREQUENTLY OBSERVED IN INDIVIDUALS WITH RETINOPATHY (P < 0.01) AND WAS ASSOCIATED WITH HIGHER TOTAL CHOLESTEROL AND LDL LEVELS (P = 0.0046, 0.0267, RESPECTIVELY). INDIVIDUALS WITH DN AND HYPERMETHYLATED PROFILES HAD HIGHER LEVELS OF ALPHA-1 ACID GLYCOPROTEIN (P = 0.0080) AND TOTAL ANTIOXIDANT CAPACITY (P = 0.0169) COMPARED TO SUBJECTS WITHOUT COMPLICATIONS. CONCLUSIONS: HYPERMETHYLATION IN THE PROMOTER OF THE MTHFR GENE IS ASSOCIATED WITH THE OCCURRENCE OF DR AND WITH BIOCHEMICAL, INFLAMMATORY AND OXIDATIVE STRESS PARAMETERS IN THE CONTEXT OF CHRONIC COMPLICATIONS.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16 6311  31 THE RELATION BETWEEN DNA METHYLATION PATTERNS AND SERUM CYTOKINE LEVELS IN COMMUNITY-DWELLING ADULTS: A PRELIMINARY STUDY. BACKGROUND: THE LEVELS OF CIRCULATING CYTOKINES FLUCTUATE WITH AGE, ACUTE ILLNESS, AND CHRONIC DISEASE, AND ARE PREDICTIVE OF MORTALITY; THIS IS ALSO TRUE FOR PATTERNS OF DNA (CPG) METHYLATION. GIVEN THAT IMMUNE CELLS ARE PARTICULARLY SENSITIVE TO CHANGES IN THE CONCENTRATION OF CYTOKINES IN THEIR MICROENVIRONMENT, WE HYPOTHESIZED THAT SERUM LEVELS OF TNF, IL-6, IL-8 AND IL-10 WOULD CORRELATE WITH GENOME-WIDE ALTERATIONS IN THE DNA METHYLATION LEVELS OF BLOOD LEUKOCYTES. TO TEST THIS, WE EVALUATED COMMUNITY-DWELLING ADULTS (N = 14; 48-78 YEARS OLD) RECRUITED TO A PILOT STUDY FOR THE CANADIAN LONGITUDINAL STUDY ON AGING (CLSA), EXAMINING DNA METHYLATION PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS USING THE ILLUMINA HUMANMETHYLATION 450 K BEADCHIP. RESULTS: WE SHOW THAT, APART FROM AGE, SERUM IL-10 LEVELS EXHIBITED THE MOST SUBSTANTIAL ASSOCIATION TO DNA METHYLATION PATTERNS, FOLLOWED BY TNF, IL-6 AND IL-8. FURTHERMORE, WHILE THE LEVELS OF THESE CYTOKINES WERE HIGHER IN ELDERLY ADULTS, NO ASSOCIATIONS WITH EPIGENETIC ACCELERATED AGING, DERIVED USING THE EPIGENETIC CLOCK, WERE OBSERVED. CONCLUSIONS: AS A PRELIMINARY STUDY WITH A SMALL SAMPLE SIZE, THE CONCLUSIONS DRAWN FROM THIS WORK MUST BE VIEWED WITH CAUTION; HOWEVER, OUR OBSERVATIONS ARE ENCOURAGING AND CERTAINLY WARRANT MORE SUITABLY POWERED STUDIES OF THIS RELATIONSHIP.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
17 1444  34 DIFFERENTIALLY HYPOMETHYLATED CELL-FREE DNA AND CORONARY COLLATERAL CIRCULATION. BACKGROUND: THE FACTORS AFFECTING CARDIOPROTECTIVE COLLATERAL CIRCULATION ARE STILL INCOMPLETELY UNDERSTOOD. RECENTLY, CHARACTERISTICS, SUCH AS CPG METHYLATION OF CELL-FREE DNA (CFDNA), HAVE BEEN REPORTED AS MARKERS WITH CLINICAL UTILITY. THE AIM OF THIS STUDY WAS TO EVALUATE WHETHER CFDNA METHYLATION PATTERNS ARE ASSOCIATED WITH THE GRADE OF CORONARY COLLATERAL CIRCULATION (CCC). RESULT: IN THIS CASE-CONTROL STUDY, CLINICAL AND ANGIOGRAPHIC DATA WERE OBTAINED FROM 143 PATIENTS (MEAN AGE, 58 YEARS, MALE 71%) WITH CHRONIC TOTAL CORONARY OCCLUSION. ENZYMATIC METHYL-SEQUENCING (EM-SEQ) LIBRARIES WERE PREPARED USING THE CFDNA EXTRACTED FROM THE PLASMA. DATA WERE PROCESSED TO OBTAIN THE AVERAGE METHYLATION FRACTION (AMF) TABLES OF GENOMIC REGIONS FROM WHICH BLACKLISTED REGIONS WERE REMOVED. UNSUPERVISED ANALYSIS OF THE OBTAINED AMF VALUES SHOWED THAT SOME OF THE CHANGES IN METHYLATION WERE DUE TO CCC. THROUGH RANDOM FOREST PREPARATION PROCESS, 256 DIFFERENTIALLY METHYLATED REGION (DMR) CANDIDATES SHOWING STRONG ASSOCIATION WITH CCC WERE SELECTED. A RANDOM FOREST CLASSIFIER WAS THEN CONSTRUCTED, AND THE AREA UNDER THE CURVE OF THE RECEIVER OPERATING CHARACTERISTIC CURVE INDICATED AN APPROPRIATE PREDICTIVE FUNCTION FOR CCC. FINALLY, 20 DMRS WERE IDENTIFIED TO HAVE SIGNIFICANTLY DIFFERENT AMF VALUES BETWEEN THE GOOD AND POOR CCC GROUPS. PARTICULARLY, THE GOOD CCC GROUP EXHIBITED HYPOMETHYLATED DMRS. PATHWAY ANALYSIS REVEALED FIVE PATHWAYS, INCLUDING TGF-BETA SIGNALING, TO BE ASSOCIATED WITH GOOD CCC. CONCLUSION: THESE DATA HAVE DEMONSTRATED THAT DIFFERENTIAL HYPOMETHYLATION WAS IDENTIFIED IN DOZENS OF CFDNA REGIONS IN PATIENTS WITH GOOD CCC. OUR RESULTS SUPPORT THE CLINICAL UTILITY OF NONINVASIVELY OBTAINED EPIGENETIC SIGNATURES FOR PREDICTING COLLATERAL CIRCULATION IN PATIENTS WITH VASCULAR DISEASES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18  177  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
19 5638  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20 1537  29 DNA METHYLATION IN ADOLESCENTS WITH ANXIETY DISORDER: A LONGITUDINAL STUDY. ANXIETY DISORDERS (AD) TYPICALLY MANIFEST IN CHILDREN AND ADOLESCENTS AND MIGHT PERSIST INTO ADULTHOOD. HOWEVER, THERE ARE STILL FEW DATA CONCERNING EPIGENETIC MECHANISMS ASSOCIATED WITH ONSET, PERSISTENCE OR REMISSION OF AD OVER TIME. WE INVESTIGATED A COHORT OF ADOLESCENTS AND YOUNG ADULTS AT BASELINE (AGE; 13.19 +/- 2.38) AND AFTER 5 YEARS AND CLASSIFIED THEM ACCORDING TO THE AD DIAGNOSIS AND THEIR LONGITUDINAL TRAJECTORIES INTO 4 GROUPS: (1) TYPICALLY DEVELOPING COMPARISONS (TDC; CONTROL GROUP, N = 14); (2) INCIDENT (AD IN THE SECOND EVALUATION ONLY, N = 11); (3) PERSISTENT (AD IN BOTH EVALUATIONS, N = 14) AND (4) REMITTENT (AD IN THE FIRST EVALUATION ONLY, N = 8). DNA METHYLATION WAS EVALUATED WITH THE INFINIUM HUMANMETHYLATION450 BEADCHIP FROM SALIVA SAMPLES COLLECTED AT BOTH EVALUATIONS. GENE SET ENRICHMENT ANALYSIS WAS APPLIED TO CONSIDER BIOLOGICAL PATHWAYS. WE FOUND DECREASED DNA METHYLATION IN TDC GROUP WHILE THE CHRONIC CASES OF AD PRESENTED HYPERMETHYLATION IN CENTRAL NERVOUS SYSTEM DEVELOPMENT PATHWAYS. MOREOVER, WE SHOWED THAT THIS PERSISTENT GROUP ALSO PRESENTED HYPERMETHYLATION WHILE THE OTHER THREE GROUPS WERE ASSOCIATED WITH HYPOMETHYLATION IN NERVOUS SYSTEM DEVELOPMENT PATHWAY. INCIDENCE AND REMISSION GROUPS WERE ASSOCIATED WITH INCREASED AND DECREASED METHYLATION IN NEURON DEVELOPMENT PATHWAYS, RESPECTIVELY. LARGER STUDIES ARE LIKELY TO DETECT SPECIFIC GENES RELEVANT TO AD.	2018