1 1785 165 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  448  52 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
4  587  36 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 3568  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  667  45 BLOOD-BASED EPIGENOME-WIDE ANALYSES OF 19 COMMON DISEASE STATES: A LONGITUDINAL, POPULATION-BASED LINKED COHORT STUDY OF 18,413 SCOTTISH INDIVIDUALS. BACKGROUND: DNA METHYLATION IS A DYNAMIC EPIGENETIC MECHANISM THAT OCCURS AT CYTOSINE-PHOSPHATE-GUANINE DINUCLEOTIDE (CPG) SITES. EPIGENOME-WIDE ASSOCIATION STUDIES (EWAS) INVESTIGATE THE STRENGTH OF ASSOCIATION BETWEEN METHYLATION AT INDIVIDUAL CPG SITES AND HEALTH OUTCOMES. ALTHOUGH BLOOD METHYLATION MAY ACT AS A PERIPHERAL MARKER OF COMMON DISEASE STATES, PREVIOUS EWAS HAVE TYPICALLY FOCUSED ONLY ON INDIVIDUAL CONDITIONS AND HAVE HAD LIMITED POWER TO DISCOVER DISEASE-ASSOCIATED LOCI. THIS STUDY EXAMINED THE ASSOCIATION OF BLOOD DNA METHYLATION WITH THE PREVALENCE OF 14 DISEASE STATES AND THE INCIDENCE OF 19 DISEASE STATES IN A SINGLE POPULATION OF OVER 18,000 SCOTTISH INDIVIDUALS. METHODS AND FINDINGS: DNA METHYLATION WAS ASSAYED AT 752,722 CPG SITES IN WHOLE-BLOOD SAMPLES FROM 18,413 VOLUNTEERS IN THE FAMILY-STRUCTURED, POPULATION-BASED COHORT STUDY GENERATION SCOTLAND (AGE RANGE 18 TO 99 YEARS). EWAS TESTED FOR CROSS-SECTIONAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 14 PREVALENT DISEASE STATES, AND FOR LONGITUDINAL ASSOCIATIONS BETWEEN BASELINE CPG METHYLATION AND 19 INCIDENT DISEASE STATES. PREVALENT CASES WERE SELF-REPORTED ON HEALTH QUESTIONNAIRES AT THE BASELINE. INCIDENT CASES WERE IDENTIFIED USING LINKAGE TO SCOTTISH PRIMARY (READ 2) AND SECONDARY (ICD-10) CARE RECORDS, AND THE CENSORING DATE WAS SET TO OCTOBER 2020. THE MEAN TIME-TO-DIAGNOSIS RANGED FROM 5.0 YEARS (FOR CHRONIC PAIN) TO 11.7 YEARS (FOR CORONAVIRUS DISEASE 2019 (COVID-19) HOSPITALISATION). THE 19 DISEASE STATES CONSIDERED IN THIS STUDY WERE SELECTED IF THEY WERE PRESENT ON THE WORLD HEALTH ORGANISATION'S 10 LEADING CAUSES OF DEATH AND DISEASE BURDEN OR INCLUDED IN BASELINE SELF-REPORT QUESTIONNAIRES. EWAS MODELS WERE ADJUSTED FOR AGE AT METHYLATION TYPING, SEX, ESTIMATED WHITE BLOOD CELL COMPOSITION, POPULATION STRUCTURE, AND 5 COMMON LIFESTYLE RISK FACTORS. A STRUCTURED LITERATURE REVIEW WAS ALSO CONDUCTED TO IDENTIFY EXISTING EWAS FOR ALL 19 DISEASE STATES TESTED. THE MEDLINE, EMBASE, WEB OF SCIENCE, AND PREPRINT SERVERS WERE SEARCHED TO RETRIEVE RELEVANT ARTICLES INDEXED AS OF MARCH 27, 2023. FIFTY-FOUR OF APPROXIMATELY 2,000 INDEXED ARTICLES MET OUR INCLUSION CRITERIA: ASSAYED BLOOD-BASED DNA METHYLATION, HAD >20 INDIVIDUALS IN EACH COMPARISON GROUP, AND EXAMINED ONE OF THE 19 CONDITIONS CONSIDERED. FIRST, WE ASSESSED WHETHER THE ASSOCIATIONS IDENTIFIED IN OUR STUDY WERE REPORTED IN PREVIOUS STUDIES. WE IDENTIFIED 69 ASSOCIATIONS BETWEEN CPGS AND THE PREVALENCE OF 4 CONDITIONS, OF WHICH 58 WERE NEWLY DESCRIBED. THE CONDITIONS WERE BREAST CANCER, CHRONIC KIDNEY DISEASE, ISCHEMIC HEART DISEASE, AND TYPE 2 DIABETES MELLITUS. WE ALSO UNCOVERED 64 CPGS THAT ASSOCIATED WITH THE INCIDENCE OF 2 DISEASE STATES (COPD AND TYPE 2 DIABETES), OF WHICH 56 WERE NOT REPORTED IN THE SURVEYED LITERATURE. SECOND, WE ASSESSED REPLICATION ACROSS EXISTING STUDIES, WHICH WAS DEFINED AS THE REPORTING OF AT LEAST 1 COMMON SITE IN >2 STUDIES THAT EXAMINED THE SAME CONDITION. ONLY 6/19 DISEASE STATES HAD EVIDENCE OF SUCH REPLICATION. THE LIMITATIONS OF THIS STUDY INCLUDE THE NONCONSIDERATION OF MEDICATION DATA AND A POTENTIAL LACK OF GENERALIZABILITY TO INDIVIDUALS THAT ARE NOT OF SCOTTISH AND EUROPEAN ANCESTRY. CONCLUSIONS: WE DISCOVERED OVER 100 ASSOCIATIONS BETWEEN BLOOD METHYLATION SITES AND COMMON DISEASE STATES, INDEPENDENTLY OF MAJOR CONFOUNDING RISK FACTORS, AND A NEED FOR GREATER STANDARDISATION AMONG EWAS ON HUMAN DISEASE.	2023	

7 3502  45 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
8 1537  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9  816  24 CHARACTERISATION OF AN INFLAMMATION-RELATED EPIGENETIC SCORE AND ITS ASSOCIATION WITH COGNITIVE ABILITY. BACKGROUND: CHRONIC SYSTEMIC INFLAMMATION HAS BEEN ASSOCIATED WITH INCIDENT DEMENTIA, BUT ITS ASSOCIATION WITH AGE-RELATED COGNITIVE DECLINE IS LESS CLEAR. THE ACUTE RESPONSES OF MANY INFLAMMATORY BIOMARKERS MEAN THEY MAY PROVIDE AN UNRELIABLE PICTURE OF THE CHRONICITY OF INFLAMMATION. RECENTLY, A LARGE-SCALE EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIED DNA METHYLATION CORRELATES OF C-REACTIVE PROTEIN (CRP)-A WIDELY USED ACUTE-PHASE INFLAMMATORY BIOMARKER. DNA METHYLATION IS THOUGHT TO BE RELATIVELY STABLE IN THE SHORT TERM, MARKING IT AS A POTENTIALLY USEFUL SIGNATURE OF EXPOSURE. METHODS: WE UTILISE A DNA METHYLATION-BASED SCORE FOR CRP AND INVESTIGATE ITS TRAJECTORIES WITH AGE, AND ASSOCIATIONS WITH COGNITIVE ABILITY IN COMPARISON WITH SERUM CRP AND A GENETIC CRP SCORE IN A LONGITUDINAL STUDY OF OLDER ADULTS (N = 889) AND A LARGE, CROSS-SECTIONAL COHORT (N = 7028). RESULTS: WE IDENTIFIED NO HOMOGENEOUS TRAJECTORIES OF SERUM CRP WITH AGE ACROSS THE COHORTS, WHEREAS THE EPIGENETIC CRP SCORE WAS CONSISTENTLY FOUND TO INCREASE WITH AGE (STANDARDISED BETA = 0.07 AND 0.01) AND TO DO SO MORE RAPIDLY IN MALES COMPARED TO FEMALES. ADDITIONALLY, THE EPIGENETIC CRP SCORE HAD HIGHER TEST-RETEST RELIABILITY COMPARED TO SERUM CRP, INDICATING ITS ENHANCED TEMPORAL STABILITY. HIGHER SERUM CRP WAS NOT FOUND TO BE ASSOCIATED WITH POORER COGNITIVE ABILITY (STANDARDISED BETA = - 0.08 AND - 0.05); HOWEVER, A CONSISTENT NEGATIVE ASSOCIATION WAS IDENTIFIED BETWEEN COGNITIVE ABILITY AND THE EPIGENETIC CRP SCORE IN BOTH COHORTS (STANDARDISED BETA = - 0.15 AND - 0.08). CONCLUSIONS: AN EPIGENETIC PROXY OF CRP MAY PROVIDE A MORE RELIABLE SIGNATURE OF CHRONIC INFLAMMATION, ALLOWING FOR MORE ACCURATE STRATIFICATION OF INDIVIDUALS, AND THUS CLEARER INFERENCE OF ASSOCIATIONS WITH INCIDENT HEALTH OUTCOMES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10  780  33 CELL-FREE DNA PROMOTER HYPERMETHYLATION IN PLASMA AS A DIAGNOSTIC MARKER FOR PANCREATIC ADENOCARCINOMA. BACKGROUND: PANCREATIC CANCER HAS A 5-YEAR SURVIVAL RATE OF ONLY 5-7%. DIFFICULTIES IN DETECTING PANCREATIC CANCER AT EARLY STAGES RESULTS IN THE HIGH MORTALITY AND SUBSTANTIATES THE NEED FOR ADDITIONAL DIAGNOSTIC TOOLS. SURGERY IS THE ONLY CURATIVE TREATMENT AND UNFORTUNATELY ONLY POSSIBLE IN LOCALIZED TUMOURS. A DIAGNOSTIC BIOMARKER FOR PANCREATIC CANCER WILL HAVE A MAJOR IMPACT ON PATIENT SURVIVAL BY FACILITATING EARLY DETECTION AND THE POSSIBILITY FOR CURATIVE TREATMENT. DNA PROMOTER HYPERMETHYLATION IS A MECHANISM OF EARLY CARCINOGENESIS, WHICH CAN CAUSE INACTIVATION OF TUMOUR SUPPRESSOR GENES. THE AIM OF THIS STUDY WAS TO EXAMINE PROMOTER HYPERMETHYLATION IN A PANEL OF SELECTED GENES FROM CELL-FREE DNA, AS A DIAGNOSTIC MARKER FOR PANCREATIC ADENOCARCINOMA. METHODS: PATIENTS WITH SUSPECTED OR BIOPSY-VERIFIED PANCREATIC CANCER WERE INCLUDED PROSPECTIVELY AND CONSECUTIVELY. PATIENTS WITH CHRONIC/ACUTE PANCREATITIS WERE INCLUDED AS ADDITIONAL BENIGN CONTROL GROUPS. BASED ON AN OPTIMIZED ACCELERATED BISULFITE TREATMENT PROTOCOL, METHYLATION-SPECIFIC PCR OF A 28 GENE PANEL WAS PERFORMED ON PLASMA SAMPLES. A DIAGNOSTIC PREDICTION MODEL WAS DEVELOPED BY MULTIVARIABLE LOGISTIC REGRESSION ANALYSIS USING BACKWARD STEPWISE ELIMINATION. RESULTS: PATIENTS WITH PANCREATIC ADENOCARCINOMA (N = 95), CHRONIC PANCREATITIS (N = 97) AND ACUTE PANCREATITIS (N = 59) AND PATIENTS SCREENED, BUT NEGATIVE FOR PANCREATIC ADENOCARCINOMA (N = 27), WERE INCLUDED. THE DIFFERENCE IN MEAN NUMBER OF METHYLATED GENES IN THE CANCER GROUP (8.41 (95% CI 7.62-9.20)) VS THE TOTAL CONTROL GROUP (4.74 (95% CI 4.40-5.08)) WAS HIGHLY SIGNIFICANT (P < 0.001). A DIAGNOSTIC PREDICTION MODEL (AGE >65, BMP3, RASSF1A, BNC1, MESTV2, TFPI2, APC, SFRP1 AND SFRP2) HAD AN AREA UNDER THE CURVE OF 0.86 (SENSITIVITY 76%, SPECIFICITY 83%). THE MODEL PERFORMANCE WAS INDEPENDENT OF CANCER STAGE. CONCLUSIONS: CELL-FREE DNA PROMOTER HYPERMETHYLATION HAS THE POTENTIAL TO BE A DIAGNOSTIC MARKER FOR PANCREATIC ADENOCARCINOMA AND DIFFERENTIATE BETWEEN MALIGNANT AND BENIGN PANCREATIC DISEASE. THIS STUDY BRINGS US CLOSER TO A CLINICAL USEFUL DIAGNOSTIC MARKER FOR PANCREATIC CANCER, WHICH IS URGENTLY NEEDED. EXTERNAL VALIDATION IS, HOWEVER, REQUIRED BEFORE THE TEST CAN BE APPLIED IN THE CLINIC. TRIAL REGISTRATION: CLINICALTRIALS.GOV, NCT02079363.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 3560  33 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 2147  29 EPIGENETIC MARKER OF TELOMERIC AGE IS ASSOCIATED WITH EXACERBATIONS AND HOSPITALIZATIONS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AN AGE-RELATED CONDITION THAT HAS BEEN ASSOCIATED WITH EARLY TELOMERE ATTRITION; THE CLINICAL IMPLICATIONS OF TELOMERE SHORTENING IN COPD ARE NOT WELL KNOWN. IN THIS STUDY WE AIMED TO DETERMINE THE RELATIONSHIP OF THE EPIGENETIC REGULATION OF TELOMERIC LENGTH IN PERIPHERAL BLOOD WITH THE RISK OF EXACERBATIONS AND HOSPITALIZATION IN PATIENTS WITH COPD. METHODS: BLOOD DNA METHYLATION PROFILES WERE OBTAINED FROM 292 PATIENTS WITH COPD ENROLLED IN THE PLACEBO ARM OF THE MACROLIDE AZITHROMYCIN TO PREVENT RAPID WORSENING OF SYMPTOMS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (MACRO) STUDY AND WHO WERE FOLLOWED FOR 1-YEAR. WE CALCULATED TELOMERE LENGTH BASED ON DNA METHYLATION MARKERS (DNAMTL) AND RELATED THIS BIOMARKER TO THE RISK OF EXACERBATION AND HOSPITALIZATION AND HEALTH STATUS (ST. GEORGE RESPIRATORY QUESTIONNAIRE [SGRQ]) SCORE OVER TIME USING A COX PROPORTIONAL HAZARDS MODEL. WE ALSO USED LINEAR MODELS TO INVESTIGATE THE ASSOCIATIONS OF DNAMTL WITH THE RATES OF EXACERBATION AND HOSPITALIZATION (ADJUSTED FOR CHRONOLOGICAL AGE, LUNG FUNCTION, RACE, SEX, SMOKING, BODY MASS INDEX AND CELL COMPOSITION). RESULTS: PARTICIPANTS WITH SHORT DNAMTL DEMONSTRATED INCREASED RISK OF EXACERBATION (P = 0.02) AND HOSPITALIZATION (P = 0.03) COMPARED TO THOSE WITH LONGER DNAMTL. DNAMTL AGE ACCELERATION WAS ASSOCIATED WITH HIGHER RATES OF EXACERBATION (P = 1.35 X 10(-04)) AND HOSPITALIZATION (P = 5.21 X 10(-03)) AND POOR HEALTH STATUS (LOWER SGRQ SCORES) INDEPENDENT OF CHRONOLOGICAL AGE (P = 0.03). CONCLUSION: TELOMERIC AGE BASED ON BLOOD DNA METHYLATION IS ASSOCIATED WITH COPD EXACERBATION AND HOSPITALIZATION AND THUS A PROMISING BIOMARKER FOR POOR OUTCOMES IN COPD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13 6311  23 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
14  274  20 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
15 1497  23 DNA METHYLATION AGE IS ACCELERATED IN ALCOHOL DEPENDENCE. ALCOHOL DEPENDENCE (ALC) IS A CHRONIC, RELAPSING DISORDER THAT INCREASES THE BURDEN OF CHRONIC DISEASE AND SIGNIFICANTLY CONTRIBUTES TO NUMEROUS PREMATURE DEATHS EACH YEAR. PREVIOUS RESEARCH SUGGESTS THAT CHRONIC, HEAVY ALCOHOL CONSUMPTION IS ASSOCIATED WITH DIFFERENTIAL DNA METHYLATION PATTERNS. IN ADDITION, DNA METHYLATION LEVELS AT CERTAIN CPG SITES HAVE BEEN CORRELATED WITH AGE. WE USED AN EPIGENETIC CLOCK TO INVESTIGATE THE POTENTIAL ROLE OF EXCESSIVE ALCOHOL CONSUMPTION IN EPIGENETIC AGING. WE EXPLORED THIS QUESTION IN FIVE INDEPENDENT COHORTS, INCLUDING DNA METHYLATION DATA DERIVED FROM DATASETS FROM BLOOD (N = 129, N = 329), LIVER (N = 92, N = 49), AND POSTMORTEM PREFRONTAL CORTEX (N = 46). ONE BLOOD DATASET AND ONE LIVER TISSUE DATASET OF INDIVIDUALS WITH ALC EXHIBITED POSITIVE AGE ACCELERATION (P < 0.0001 AND P = 0.0069, RESPECTIVELY), WHEREAS THE OTHER BLOOD AND LIVER TISSUE DATASETS BOTH EXHIBITED TRENDS OF POSITIVE AGE ACCELERATION THAT WERE NOT SIGNIFICANT (P = 0.83 AND P = 0.57, RESPECTIVELY). PREFRONTAL CORTEX TISSUE EXHIBITED A TREND OF NEGATIVE AGE ACCELERATION (P = 0.19). THESE RESULTS SUGGEST THAT EXCESSIVE ALCOHOL CONSUMPTION MAY BE ASSOCIATED WITH EPIGENETIC AGING IN A TISSUE-SPECIFIC MANNER AND WARRANTS FURTHER INVESTIGATION USING MULTIPLE TISSUE SAMPLES FROM THE SAME INDIVIDUALS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16 2960  26 GENETIC AND EPIGENETIC MARKERS IN THE EVALUATION OF PANCREATIC MASSES. BACKGROUND: METHYLATION MARKERS HAVE SHOWN PROMISE IN THE EARLY DIAGNOSIS OF PANCREATIC CARCINOMA. THE AIM OF THIS STUDY WAS TO ASSESS THE DIAGNOSTIC UTILITY OF HYPERMETHYLATION STATUS OF CANDIDATE GENES IN COMBINATION WITH KRAS MUTATION DETECTION IN THE EVALUATION OF PANCREATIC MASSES. EXPERIMENTAL DESIGN: SIXTY-ONE FINE NEEDLE ASPIRATES OF PANCREATIC MASSES (43 PANCREATIC ADENOCARCINOMAS AND 18 CHRONIC PANCREATITIS) WERE STUDIED. METHYLATION STATUS OF HRH2, EN1, SPARC, CDH13 AND APC WERE ANALYSED USING MELTING CURVE ANALYSIS AFTER DNA BISULFITE TREATMENT. KRAS MUTATIONS WERE ALSO ANALYSED. RESULTS: THE METHYLATION PANEL HAD A SENSITIVITY OF 73% (27 OF 37, CI 95% 56 TO 86%) AND A SPECIFICITY OF 100% WHENEVER TWO OR MORE PROMOTERS WERE FOUND HYPERMETHYLATED. KRAS MUTATIONS SHOWED A SENSITIVITY OF 77% (33 OF 43, CI 95% 62 TO 88%) AND A SPECIFICITY OF 100%. BOTH MOLECULAR ANALYSES ADDED USEFUL INFORMATION TO CYTOLOGY BY INCREASING THE NUMBER OF INFORMATIVE CASES. WHEN GENETIC AND EPIGENETIC ANALYSES WERE COMBINED SENSITIVITY WAS 84% (36 OF 43 CI 95% 69 TO 93%) MAINTAINING A 100% SPECIFICITY. CONCLUSIONS: ANALYSIS OF HYPERMETHYLATION STATUS OF A PANEL OF GENES AND KRAS MUTATION DETECTION OFFER A SIMILAR DIAGNOSTIC YIELD IN THE EVALUATION OF PANCREATIC MASSES. THE COMBINED MOLECULAR ANALYSIS INCREASES THE NUMBER OF INFORMATIVE CASES WITHOUT DIMINISHING SPECIFICITY.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 6547  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 6043  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
19 5186  23 PREMATURITY IN MICE LEADS TO REDUCTION IN NEPHRON NUMBER, HYPERTENSION, AND PROTEINURIA. THE NEPHRON NUMBER AT BIRTH IS A QUANTITATIVE TRAIT THAT CORRELATES INVERSELY WITH THE RISK OF HYPERTENSION AND CHRONIC KIDNEY DISEASE LATER IN LIFE. DURING KIDNEY DEVELOPMENT, THE NEPHRON NUMBER IS CONTROLLED BY MULTIPLE FACTORS INCLUDING GENETIC, EPIGENETIC, AND ENVIRONMENTAL MODIFIERS. PREMATURE BIRTH, WHICH REPRESENTS MORE THAN 12% OF ANNUAL LIVE BIRTHS IN THE UNITED STATES, HAS BEEN LINKED TO LOW NEPHRON NUMBER AND THE DEVELOPMENT OF HYPERTENSION LATER IN LIFE. IN THIS REPORT, WE DESCRIBE THE DEVELOPMENT OF A MOUSE MODEL OF PREMATURITY-INDUCED REDUCTION OF NEPHRON NUMBER. PREMATURE MICE, DELIVERED 1 AND 2 DAYS EARLY, HAVE 17.4 +/- 2.3% (N = 6) AND 23.6 +/- 2% (N = 10) FEWER NEPHRONS, RESPECTIVELY, WHEN COMPARED WITH FULL-TERM ANIMALS (12,252 +/- 571 NEPHRONS/KIDNEY, N = 10). AFTER 5 WEEKS OF AGE, THE MICE DELIVERED 2 DAYS PREMATURE SHOW LOWER REAL-TIME GLOMERULAR FILTRATION RATE (GFR, 283 +/- 13 VS 389 +/- 26 MUL/MIN). THE PREMATURE MICE ALSO DEVELOP HYPERTENSION (MEAN ARTERIAL PRESSURE [MAP], 134 +/- 18 VS 120 +/- 14 MM HG) AND ALBUMINURIA (286 +/- 83 VS 176 +/- 59 MUG ALBUMIN/MG CREATININE). THIS MOUSE MODEL PROVIDES A PROOF OF CONCEPT THAT PREMATURITY LEADS TO REDUCED NEPHRON NUMBER AND HYPERTENSION, AND THIS MODEL WILL BE USEFUL IN STUDYING THE PATHOPHYSIOLOGY OF PREMATURITY-INDUCED NEPHRON NUMBER REDUCTIONS AND HYPERTENSION.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20 1444  29 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