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  1625  44 DNAM-BASED SIGNATURES OF ACCELERATED AGING AND MORTALITY IN BLOOD ARE ASSOCIATED WITH LOW RENAL FUNCTION. BACKGROUND: THE DIFFERENCE BETWEEN AN INDIVIDUAL'S CHRONOLOGICAL AND DNA METHYLATION PREDICTED AGE (DNAMAGE), TERMED DNAMAGE ACCELERATION (DNAMAA), CAN CAPTURE LIFE-LONG ENVIRONMENTAL EXPOSURES AND AGE-RELATED PHYSIOLOGICAL CHANGES REFLECTED IN METHYLATION STATUS. SEVERAL STUDIES HAVE LINKED DNAMAA TO MORBIDITY AND MORTALITY, YET ITS RELATIONSHIP WITH KIDNEY FUNCTION HAS NOT BEEN ASSESSED. WE EVALUATED THE ASSOCIATIONS BETWEEN SEVEN DNAM AGING AND LIFESPAN PREDICTORS (AS WELL AS GRIMAGE COMPONENTS) AND FIVE KIDNEY TRAITS (ESTIMATED GLOMERULAR FILTRATION RATE [EGFR], URINE ALBUMIN-TO-CREATININE RATIO [UACR], SERUM URATE, MICROALBUMINURIA AND CHRONIC KIDNEY DISEASE [CKD]) IN UP TO 9688 EUROPEAN, AFRICAN AMERICAN AND HISPANIC/LATINO INDIVIDUALS FROM SEVEN POPULATION-BASED STUDIES. RESULTS: WE IDENTIFIED 23 SIGNIFICANT ASSOCIATIONS IN OUR LARGE TRANS-ETHNIC META-ANALYSIS (P < 1.43E-03 AND CONSISTENT DIRECTION OF EFFECT ACROSS STUDIES). AGE ACCELERATION MEASURED BY THE EXTRINSIC AND PHENOAGE ESTIMATORS, AS WELL AS ZHANG'S 10-CPG EPIGENETIC MORTALITY RISK SCORE (MRS), WERE ASSOCIATED WITH ALL PARAMETERS OF POOR KIDNEY HEALTH (LOWER EGFR, PREVALENT CKD, HIGHER UACR, MICROALBUMINURIA AND HIGHER SERUM URATE). SIX OF THESE ASSOCIATIONS WERE INDEPENDENTLY OBSERVED IN EUROPEAN AND AFRICAN AMERICAN POPULATIONS. MRS IN PARTICULAR WAS CONSISTENTLY ASSOCIATED WITH EGFR (BETA = - 0.12, 95% CI = [- 0.16, - 0.08] CHANGE IN LOG-TRANSFORMED EGFR PER UNIT INCREASE IN MRS, P = 4.39E-08), PREVALENT CKD (ODDS RATIO (OR) = 1.78 [1.47, 2.16], P = 2.71E-09) AND HIGHER SERUM URATE LEVELS (BETA = 0.12 [0.07, 0.16], P = 2.08E-06). THE "FIRST-GENERATION" CLOCKS (HANNUM, HORVATH) AND GRIMAGE SHOWED DIFFERENT PATTERNS OF ASSOCIATION WITH THE KIDNEY TRAITS. THREE OF THE DNAM-ESTIMATED COMPONENTS OF GRIMAGE, NAMELY ADRENOMEDULLIN, PLASMINOGEN-ACTIVATION INHIBITION 1 AND PACK YEARS, WERE POSITIVELY ASSOCIATED WITH HIGHER UACR, SERUM URATE AND MICROALBUMINURIA. CONCLUSION: DNAMAGE ACCELERATION AND DNAM MORTALITY PREDICTORS ESTIMATED IN WHOLE BLOOD WERE ASSOCIATED WITH MULTIPLE KIDNEY TRAITS, INCLUDING EGFR AND CKD, IN THIS MULTI-ETHNIC STUDY. EPIGENETIC BIOMARKERS WHICH REFLECT THE SYSTEMIC EFFECTS OF AGE-RELATED MECHANISMS SUCH AS IMMUNOSENESCENCE, INFLAMMAGING AND OXIDATIVE STRESS MAY HAVE IMPORTANT MECHANISTIC OR PROGNOSTIC ROLES IN KIDNEY DISEASE. OUR STUDY HIGHLIGHTS NEW FINDINGS LINKING KIDNEY DISEASE TO BIOLOGICAL AGING, AND OPPORTUNITIES WARRANTING FUTURE INVESTIGATION INTO DNA METHYLATION BIOMARKERS FOR PROGNOSTIC OR RISK STRATIFICATION IN KIDNEY DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
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  2148  40 EPIGENETIC MARKERS OF RENAL FUNCTION IN AFRICAN AMERICANS. CHRONIC KIDNEY DISEASE (CKD) IS AN INCREASING CONCERN IN THE UNITED STATES DUE TO ITS RAPIDLY RISING PREVALENCE, PARTICULARLY AMONG AFRICAN AMERICANS. EPIGENETIC DNA METHYLATION MARKERS ARE BECOMING IMPORTANT BIOMARKERS OF CHRONIC DISEASES SUCH AS CKD. TO BETTER UNDERSTAND HOW THESE METHYLATION MARKERS PLAY A ROLE IN KIDNEY FUNCTION, WE MEASURED 26,428 DNA METHYLATION SITES IN 972 AFRICAN AMERICANS FROM THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY (GENOA) STUDY. WE THEN EVALUATED (1) WHETHER EPIGENETIC MARKERS ARE ASSOCIATED WITH ESTIMATED GLOMERULAR FILTRATION RATE (EGFR), (2) WHETHER THE SIGNIFICANTLY ASSOCIATED MARKERS ARE ALSO ASSOCIATED WITH TRADITIONAL RISK FACTORS AND/OR NOVEL BIOMARKERS FOR EGFR, AND (3) HOW MUCH ADDITIONAL VARIATION IN EGFR IS EXPLAINED BY EPIGENETIC MARKERS BEYOND ESTABLISHED RISK FACTORS AND BIOMARKERS. THE MAJORITY OF METHYLATION MARKERS MOST SIGNIFICANTLY ASSOCIATED WITH EGFR (24 OUT OF THE TOP 30) APPEARED TO FUNCTION, AT LEAST IN PART, THROUGH PATHWAYS RELATED TO AGING, INFLAMMATION, OR CHOLESTEROL. HOWEVER, SIX EPIGENETIC MARKERS WERE STILL ABLE TO SIGNIFICANTLY PREDICT EGFR AFTER ADJUSTMENT FOR OTHER RISK FACTORS. THIS WORK SHOWS THAT EPIGENETIC MARKERS MAY OFFER VALUABLE NEW INSIGHT INTO THE COMPLEX PATHOPHYSIOLOGY OF CKD IN AFRICAN AMERICANS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  3636  25 INCREASED DNA METHYLTRANSFERASE ACTIVITY AND DNA METHYLATION FOLLOWING EPIDERMAL GROWTH FACTOR STIMULATION IN OVARIAN CANCER CELLS. OVARIAN CANCER PROGRESSION IS CORRELATED WITH ACCUMULATION OF ABERRANT CPG ISLAND METHYLATION. IN OVARIAN CANCER, ASCITES FLUID CONTAINS NUMEROUS EPIDERMAL-GROWTH-FACTOR-RECEPTOR (EGFR) ACTIVATORS, WHICH COULD RESULT IN A TUMOR MICROENVIRONMENT OF CONSTANT EGFR ACTIVATION. SIGNALING PATHWAYS DOWNSTREAM OF EGFR, SUCH AS RAS, REGULATE DNA METHYLATION. WE HYPOTHESIZED THAT CHRONIC EGFR ACTIVATION COULD ALTER DNA METHYLATION. WE FOUND THAT EGFR ACTIVATION INCREASED DNA METHYLTRANSFERASE (DNMT) ACTIVITY ACUTELY, AS WELL AS AFTER LONG-TERM EGF TREATMENT OR EXPRESSION OF A MUTATIONALLY ACTIVATED EGFR. FURTHERMORE, THIS INCREASE IN DNMT ACTIVITY WAS DEPENDENT ON EGFR CATALYTIC ACTIVITY AND RESULTED IN INCREASED GLOBAL DNA METHYLATION. ADDITIONALLY, TREATMENT WITH THE DNMT INHIBITOR/HYPOMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE (AZA) INHIBITED THE EGF INDUCED INCREASE OF BOTH DNMT ACTIVITY AND GLOBAL METHYLATION. THESE DATA SUPPORT A ROLE FOR EGFR IN THE PROCESS OF ACCUMULATED DNA METHYLATION DURING OVARIAN CANCER PROGRESSION AND SUGGEST THAT EPIGENETIC THERAPY MAY BE BENEFICIAL FOR THE TREATMENT OF OVARIAN CANCER.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6  2005  42 EPIGENETIC ASSOCIATIONS WITH ESTIMATED GLOMERULAR FILTRATION RATE AMONG MEN WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION. BACKGROUND: PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (HIV) INFECTION HAVE HIGHER RISK FOR CHRONIC KIDNEY DISEASE (CKD), DEFINED BY A REDUCED ESTIMATED GLOMERULAR FILTRATION RATE (EGFR). PREVIOUS STUDIES HAVE IMPLICATED EPIGENETIC CHANGES RELATED TO CKD; HOWEVER, THE MECHANISM OF HIV-RELATED CKD HAS NOT BEEN THOROUGHLY INVESTIGATED. METHODS: WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY OF EGFR AMONG 567 HIV-POSITIVE AND 117 HIV-NEGATIVE MALE PARTICIPANTS IN THE VETERANS AGING COHORT STUDY TO IDENTIFY EPIGENETIC SIGNATURES OF KIDNEY FUNCTION. RESULTS: BY SURVEYING MORE THAN 400 000 CYTOSINE GUANINE DINUCLEOTIDE (CPG) SITES MEASURED FROM PERIPHERAL BLOOD MONONUCLEAR CELLS, WE IDENTIFIED 15 SITES THAT WERE SIGNIFICANTLY ASSOCIATED WITH EGFR (FALSE DISCOVERY RATE Q VALUE < 0.05) AMONG HIV-POSITIVE PARTICIPANTS. THE MOST SIGNIFICANT CPG SITES, LOCATED AT MAD1L1, TSNARE1/BAI1, AND LTV1, WERE ALL NEGATIVELY ASSOCIATED WITH EGFR (CG06329547, P = 5.25 X 10-9; CG23281907, P = 1.37 X 10-8; CG18368637, P = 5.17 X 10-8). WE ALSO REPLICATED PREVIOUSLY REPORTED EGFR-ASSOCIATED CPG SITES INCLUDING CG17944885 (P = 2.5 X 10-5) LOCATED BETWEEN ZNF788 AND ZNF20 ON CHROMOSOME 19 IN THE POOLED POPULATION. CONCLUSIONS: IN THIS STUDY WE UNCOVERED NOVEL EPIGENETIC ASSOCIATIONS WITH KIDNEY FUNCTION AMONG PEOPLE LIVING WITH HIV AND SUGGEST POTENTIAL EPIGENETIC MECHANISMS LINKED WITH HIV-RELATED CKD RISK.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7   173  26 ACCELERATED AGING IN BIPOLAR DISORDERS: AN EXPLORATORY STUDY OF SIX EPIGENETIC CLOCKS. BIPOLAR DISORDER (BD) IS A CHRONIC AND SEVERE PSYCHIATRIC DISORDER ASSOCIATED WITH SIGNIFICANT MEDICAL MORBIDITY AND REDUCED LIFE EXPECTANCY. IN THIS STUDY, WE ASSESSED ACCELERATED EPIGENETIC AGING IN INDIVIDUALS WITH BD USING VARIOUS DNA METHYLATION (DNAM)-BASED MARKERS. FOR THIS PURPOSE, WE USED FIVE EPIGENETIC CLOCKS (HORVATH, HANNUM, EN, PHENOAGE, AND GRIMAGE) AND A DNAM-BASED TELOMERE LENGTH CLOCK (DNAMTL). DNAM PROFILES WERE OBTAINED USING INFINIUM METHYLATIONEPIC ARRAYS FROM WHOLE-BLOOD SAMPLES OF 184 INDIVIDUALS WITH BD. WE ALSO ESTIMATED BLOOD CELL COUNTS BASED ON DNAM LEVELS FOR ADJUSTMENT. SIGNIFICANT CORRELATIONS BETWEEN CHRONOLOGICAL AGE AND EACH EPIGENETIC AGE ESTIMATED USING THE SIX DIFFERENT CLOCKS WERE OBSERVED. FOLLOWING ADJUSTMENT FOR BLOOD CELL COUNTS, WE FOUND THAT THE SIX EPIGENETIC AGEACCELS (AGE ACCELERATIONS) WERE SIGNIFICANTLY ASSOCIATED WITH THE BODY MASS INDEX. GRIMAGE AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH MALE SEX, SMOKING STATUS AND CHILDHOOD MALTREATMENT. DNAMTL AGEACCEL WAS SIGNIFICANTLY ASSOCIATED WITH SMOKING STATUS. OVERALL, THIS STUDY SHOWED THAT DISTINCT EPIGENETIC CLOCKS ARE SENSITIVE TO DIFFERENT ASPECTS OF AGING PROCESS IN BD. FURTHER INVESTIGATIONS WITH COMPREHENSIVE EPIGENETIC CLOCK ANALYSES AND LARGE SAMPLES ARE REQUIRED TO CONFIRM OUR FINDINGS OF POTENTIAL DETERMINANTS OF AN ACCELERATED EPIGENETIC AGING IN BD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  1189  36 CORRELATION BETWEEN GLOBAL METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES AND SERUM C REACTIVE PROTEIN LEVEL MODIFIED BY MTHFR POLYMORPHISM: A CROSS-SECTIONAL STUDY. BACKGROUND: CHRONIC INFLAMMATORY CONDITIONS ARE ASSOCIATED WITH HIGHER TUMOR INCIDENCE THROUGH EPIGENETIC AND GENETIC ALTERATIONS. HERE, WE FOCUSED ON AN ASSOCIATION BETWEEN AN INFLAMMATION MARKER, C-REACTIVE-PROTEIN (CRP), AND GLOBAL DNA METHYLATION LEVELS OF PERIPHERAL BLOOD LEUKOCYTES. METHODS: THE SUBJECTS WERE 384 HEALTHY JAPANESE WOMEN ENROLLED AS THE CONTROL GROUP OF A CASE-CONTROL STUDY FOR BREAST CANCER CONDUCTED FROM 2001 TO 2005. GLOBAL DNA METHYLATION WAS QUANTIFIED BY LUMINOMETRIC METHYLATION ASSAY (LUMA). RESULTS: WITH ADJUSTMENT FOR LIFESTYLE-RELATED FACTORS, INCLUDING FOLATE INTAKE, THE GLOBAL DNA METHYLATION LEVEL OF PERIPHERAL BLOOD LEUKOCYTES WAS SIGNIFICANTLY BUT WEAKLY INCREASED BY 0.43% PER QUARTILE CATEGORY FOR CRP (P FOR TREND = 0.010). ESTIMATED METHYLATION LEVELS STRATIFIED BY CRP QUARTILE WERE 70.0%, 70.8%, 71.4%, AND 71.3%, RESPECTIVELY. IN ADDITION, INTERACTION BETWEEN POLYMORPHISM OF MTHFR (RS1801133, KNOWN AS C677T) AND CRP WAS SIGNIFICANT (P FOR INTERACTION = 0.046); THE GLOBAL METHYLATION LEVEL WAS SIGNIFICANTLY INCREASED BY 0.61% PER QUARTILE CATEGORY FOR CRP IN THE CT/TT GROUP (THOSE WITH THE MINOR ALLELE T, P FOR TREND = 0.001), WHEREAS NO ASSOCIATION WAS OBSERVED IN THE CC GROUP (WILD TYPE). CONCLUSIONS: OUR STUDY SUGGESTS THAT CRP CONCENTRATION IS WEAKLY ASSOCIATED WITH GLOBAL DNA METHYLATION LEVEL. HOWEVER, THIS ASSOCIATION WAS OBSERVED MORE CLEARLY IN INDIVIDUALS WITH THE MINOR ALLELE OF THE MTHFR MISSENSE SNP RS1801133. BY ELUCIDATING THE COMPLEX MECHANISM OF THE REGULATION OF DNA METHYLATION BY BOTH ACQUIRED AND GENETIC FACTORS, OUR RESULTS MAY BE IMPORTANT FOR CANCER PREVENTION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
9  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	

10  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  1955  29 EPIGENETIC AGE ACCELERATION PREDICTS CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY IN A GERMAN CASE COHORT. BACKGROUND: PREVIOUS STUDIES HAVE DEVELOPED MODELS PREDICTING METHYLATION AGE FROM DNA METHYLATION IN BLOOD AND OTHER TISSUES (EPIGENETIC CLOCK) AND SUGGESTED THE DIFFERENCE BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGES AS A MARKER OF HEALTHY AGING. THE GOAL OF THIS STUDY WAS TO CONFIRM AND EXPAND SUCH OBSERVATIONS BY INVESTIGATING WHETHER DIFFERENT CONCEPTS OF THE EPIGENETIC CLOCKS IN A POPULATION-BASED COHORT ARE ASSOCIATED WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. RESULTS: DNA METHYLATION AGE WAS ESTIMATED IN A COHORT OF 1863 OLDER PEOPLE, AND THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE (DELTAAGE) WAS CALCULATED. A CASE-COHORT DESIGN AND WEIGHTED PROPORTIONAL COX HAZARD MODELS WERE USED TO ESTIMATE ASSOCIATIONS OF DELTAAGE WITH CANCER, CARDIOVASCULAR, AND ALL-CAUSE MORTALITY. HAZARD RATIOS FOR DELTAAGE (PER 5 YEARS) CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HORVATH WERE 1.23 (95 % CI 1.10-1.38) FOR ALL-CAUSE MORTALITY, 1.22 (95 % CI 1.03-1.45) FOR CANCER MORTALITY, AND 1.19 (95 % CI 0.98-1.43) FOR CARDIOVASCULAR MORTALITY AFTER ADJUSTMENT FOR BATCH EFFECTS, AGE, SEX, EDUCATIONAL LEVEL, HISTORY OF CHRONIC DISEASES, HYPERTENSION, SMOKING STATUS, BODY MASS INDEX, AND LEUCOCYTE DISTRIBUTION. ASSOCIATIONS WERE SIMILAR BUT WEAKER FOR DELTAAGE CALCULATED USING THE EPIGENETIC CLOCK DEVELOPED BY HANNUM. CONCLUSIONS: THESE RESULTS SHOW THAT AGE ACCELERATION IN TERMS OF THE DIFFERENCE BETWEEN AGE PREDICTED BY DNA METHYLATION AND CHRONOLOGICAL AGE IS AN INDEPENDENT PREDICTOR OF ALL-CAUSE AND CAUSE-SPECIFIC MORTALITY AND MAY BE USEFUL AS A GENERAL MARKER OF HEALTHY AGING.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12   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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13  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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  1780  29 EDUCATION AND LIFESTYLE FACTORS ARE ASSOCIATED WITH DNA METHYLATION CLOCKS IN OLDER AFRICAN AMERICANS. DNA METHYLATION (DNAM) CLOCKS ARE IMPORTANT BIOMARKERS OF CELLULAR AGING AND ARE ASSOCIATED WITH A VARIETY OF AGE-RELATED CHRONIC DISEASES AND ALL-CAUSE MORTALITY. EXAMINING THE RELATIONSHIP BETWEEN EDUCATION AND LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND MULTIPLE DNAM CLOCKS CAN INCREASE THE UNDERSTANDING OF HOW RISK FACTORS CONTRIBUTE TO AGING AT THE CELLULAR LEVEL. THIS STUDY EXPLORED THE ASSOCIATION BETWEEN EDUCATION OR LIFESTYLE RISK FACTORS FOR AGE-RELATED DISEASES AND THE ACCELERATION OF FOUR DNAM CLOCKS, INCLUDING INTRINSIC (IEAA) AND EXTRINSIC EPIGENETIC AGE ACCELERATION (EEAA), PHENOAGE ACCELERATION (PHENOAA), AND GRIMAGE ACCELERATION (GRIMAA) IN THE AFRICAN AMERICAN PARTICIPANTS OF THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY. WE PERFORMED BOTH CROSS-SECTIONAL AND LONGITUDINAL ANALYSES. IN CROSS-SECTIONAL ANALYSES, GENDER, EDUCATION, BMI, SMOKING, AND ALCOHOL CONSUMPTION WERE ALL INDEPENDENTLY ASSOCIATED WITH GRIMAA, WHEREAS ONLY SOME OF THEM WERE ASSOCIATED WITH OTHER CLOCKS. THE EFFECT OF SMOKING AND EDUCATION ON GRIMAA VARIED BY GENDER. LONGITUDINAL ANALYSES SUGGEST THAT AGE AND BMI CONTINUED TO INCREASE GRIMAA, AND THAT AGE AND CURRENT SMOKING CONTINUED TO INCREASE PHENOAA AFTER CONTROLLING DNAM CLOCKS AT BASELINE. IN CONCLUSION, EDUCATION AND COMMON LIFESTYLE RISK FACTORS WERE ASSOCIATED WITH MULTIPLE DNAM CLOCKS. HOWEVER, THE ASSOCIATION WITH EACH RISK FACTOR VARIED BY CLOCK, WHICH SUGGESTS THAT DIFFERENT CLOCKS MAY CAPTURE ADVERSE EFFECTS FROM DIFFERENT ENVIRONMENTAL STIMULI.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15  5746  27 SMOKING-RELATED DNA METHYLATION IS ASSOCIATED WITH DNA METHYLATION PHENOTYPIC AGE ACCELERATION: THE VETERANS AFFAIRS NORMATIVE AGING STUDY. DNA METHYLATION MAY PLAY A CRITICAL ROLE IN AGING AND AGE-RELATED DISEASES. DNA METHYLATION PHENOTYPIC AGE (DNAMPHENOAGE) IS A NEW AGING BIOMARKER AND PREDICTOR OF CHRONIC DISEASE RISK. WHILE SMOKING IS A STRONG RISK FACTOR FOR CHRONIC DISEASES AND INFLUENCES METHYLATION, ITS INFLUENCE ON DNAMPHENOAGE IS UNKNOWN. WE INVESTIGATED ASSOCIATIONS OF SELF-REPORTED AND EPIGENETIC SMOKING INDICATORS WITH DNAMPHENOAGE ACCELERATION IN A LONGITUDINAL AGING STUDY IN EASTERN MASSACHUSETTS. DNA METHYLATION WAS MEASURED IN WHOLE BLOOD SAMPLES FROM MULTIPLE VISITS FOR 692 MALE PARTICIPANTS IN THE VETERANS AFFAIRS NORMATIVE AGING STUDY DURING 1999-2013. ACCELERATION WAS DEFINED USING RESIDUALS FROM LINEAR REGRESSION OF THE DNAMPHENOAGE ON THE CHRONOLOGICAL AGE. CUMULATIVE SMOKING (PACK-YEARS) WAS SIGNIFICANTLY ASSOCIATED WITH DNAMPHENOAGE ACCELERATION, WHEREAS SELF-REPORTED SMOKING STATUS WAS NOT. WE OBSERVED SIGNIFICANT VALIDATED ASSOCIATIONS BETWEEN SMOKING-RELATED LOCI AND DNAMPHENOAGE ACCELERATION FOR 52 CPG SITES, WHERE 18 WERE HYPOMETHYLATED AND 34 WERE HYPERMETHYLATED, MAPPED TO 16 GENES. THE AHRR GENE HAD THE MOST LOCI (N = 8) AMONG THE 16 GENES. WE GENERATED A SMOKING AGING INDEX BASED ON THESE 52 LOCI, WHICH SHOWED POSITIVE SIGNIFICANT ASSOCIATIONS WITH DNAMPHENOAGE ACCELERATION. THESE EPIGENETIC BIOMARKERS MAY HELP TO PREDICT AGE-RELATED RISKS DRIVEN BY SMOKING.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  2150  32 EPIGENETIC MEASURES OF AGEING PREDICT THE PREVALENCE AND INCIDENCE OF LEADING CAUSES OF DEATH AND DISEASE BURDEN. BACKGROUND: INDIVIDUALS OF THE SAME CHRONOLOGICAL AGE DISPLAY DIFFERENT RATES OF BIOLOGICAL AGEING. A NUMBER OF MEASURES OF BIOLOGICAL AGE HAVE BEEN PROPOSED WHICH HARNESS AGE-RELATED CHANGES IN DNA METHYLATION PROFILES. THESE MEASURES INCLUDE FIVE 'EPIGENETIC CLOCKS' WHICH PROVIDE AN INDEX OF HOW MUCH AN INDIVIDUAL'S BIOLOGICAL AGE DIFFERS FROM THEIR CHRONOLOGICAL AGE AT THE TIME OF MEASUREMENT. THE FIVE CLOCKS ENCOMPASS METHYLATION-BASED PREDICTORS OF CHRONOLOGICAL AGE (HORVATHAGE, HANNUMAGE), ALL-CAUSE MORTALITY (DNAM PHENOAGE, DNAM GRIMAGE) AND TELOMERE LENGTH (DNAM TELOMERE LENGTH). A SIXTH EPIGENETIC MEASURE OF AGEING DIFFERS FROM THESE CLOCKS IN THAT IT ACTS AS A SPEEDOMETER PROVIDING A SINGLE TIME-POINT MEASUREMENT OF THE PACE OF AN INDIVIDUAL'S BIOLOGICAL AGEING. THIS MEASURE OF AGEING IS TERMED DUNEDINPOAM. IN THIS STUDY, WE TEST THE ASSOCIATION BETWEEN THESE SIX EPIGENETIC MEASURES OF AGEING AND THE PREVALENCE AND INCIDENCE OF THE LEADING CAUSES OF DISEASE BURDEN AND MORTALITY IN HIGH-INCOME COUNTRIES (N </= 9537, GENERATION SCOTLAND: SCOTTISH FAMILY HEALTH STUDY). RESULTS: DNAM GRIMAGE PREDICTED INCIDENCE OF CLINICALLY DIAGNOSED CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD), TYPE 2 DIABETES AND ISCHEMIC HEART DISEASE AFTER 13 YEARS OF FOLLOW-UP (HAZARD RATIOS = 2.22, 1.52 AND 1.41, RESPECTIVELY). DUNEDINPOAM PREDICTED THE INCIDENCE OF COPD AND LUNG CANCER (HAZARD RATIOS = 2.02 AND 1.45, RESPECTIVELY). DNAM PHENOAGE PREDICTED INCIDENCE OF TYPE 2 DIABETES (HAZARD RATIO = 1.54). DNAM TELOMERE LENGTH ASSOCIATED WITH THE INCIDENCE OF ISCHEMIC HEART DISEASE (HAZARD RATIO = 0.80). DNAM GRIMAGE ASSOCIATED WITH ALL-CAUSE MORTALITY, THE PREVALENCE OF COPD AND SPIROMETRY MEASURES AT THE STUDY BASELINE. THESE ASSOCIATIONS WERE PRESENT AFTER ADJUSTING FOR POSSIBLE CONFOUNDING RISK FACTORS INCLUDING ALCOHOL CONSUMPTION, BODY MASS INDEX, DEPRIVATION, EDUCATION AND TOBACCO SMOKING AND SURPASSED STRINGENT BONFERRONI-CORRECTED SIGNIFICANCE THRESHOLDS. CONCLUSIONS: OUR DATA SUGGEST THAT EPIGENETIC MEASURES OF AGEING MAY HAVE UTILITY IN CLINICAL SETTINGS TO COMPLEMENT GOLD-STANDARD METHODS FOR DISEASE ASSESSMENT AND MANAGEMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
17  2643  29 EPIGENOMIC ASSOCIATION ANALYSIS IDENTIFIES SMOKING-RELATED DNA METHYLATION SITES IN AFRICAN AMERICANS. CIGARETTE SMOKING IS AN ENVIRONMENTAL RISK FACTOR FOR MANY CHRONIC DISEASES, AND DISEASE RISK CAN OFTEN BE MANAGED BY SMOKING CONTROL. SMOKING CAN INDUCE CELLULAR AND MOLECULAR CHANGES, INCLUDING EPIGENETIC MODIFICATION, BUT THE SHORT- AND LONG-TERM EPIGENETIC MODIFICATIONS CAUSED BY CIGARETTE SMOKING AT THE GENE LEVEL HAVE NOT BEEN WELL UNDERSTOOD. RECENT STUDIES HAVE IDENTIFIED SMOKING-RELATED DNA METHYLATION (DNAM) SITES IN CAUCASIANS. TO DETERMINE WHETHER THE SAME DNAM SITES ASSOCIATE WITH SMOKING IN AFRICAN AMERICANS, AND TO IDENTIFY NOVEL SMOKING-RELATED DNAM SITES, WE CONDUCTED A METHYLOME-WIDE ASSOCIATION STUDY OF CIGARETTE SMOKING USING A DISCOVERY SAMPLE OF 972 AFRICAN AMERICANS, AND A REPLICATION SAMPLE OF 239 AFRICAN AMERICANS WITH TWO ARRAY-BASED METHODS. AMONG 15 DNAM SITES SIGNIFICANTLY ASSOCIATED WITH SMOKING AFTER CORRECTION FOR MULTIPLE TESTING IN OUR DISCOVERY SAMPLE, 5 DNAM SITES ARE REPLICATED IN AN INDEPENDENT COHORT, AND 14 SITES IN THE REPLICATION SAMPLE HAVE EFFECTS IN THE SAME DIRECTION AS IN THE DISCOVERY SAMPLE. THE TOP TWO SMOKING-RELATED DNAM SITES IN F2RL3 (FACTOR II RECEPTOR-LIKE 3) AND GPR15 (G-PROTEIN-COUPLED RECEPTOR 15) OBSERVED IN AFRICAN AMERICANS ARE CONSISTENT WITH PREVIOUS FINDINGS IN CAUCASIANS. THE ASSOCIATIONS BETWEEN THE REPLICATED DNAM SITES AND SMOKING REMAIN SIGNIFICANT AFTER ADJUSTING FOR GENETIC BACKGROUND. DESPITE THE DISTINCT GENETIC BACKGROUND BETWEEN AFRICAN AMERICANS AND CAUCASIANS, THE DNAM FROM THE TWO ETHNIC GROUPS SHARES COMMON ASSOCIATIONS WITH CIGARETTE SMOKING, WHICH SUGGESTS A COMMON MOLECULAR MECHANISM OF EPIGENETIC MODIFICATION INFLUENCED BY ENVIRONMENTAL EXPOSURE.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
18   404  34 ANALYSIS OF EPIGENETIC AGE PREDICTORS IN PAIN-RELATED CONDITIONS. CHRONIC PAIN PREVALENCE IS HIGH WORLDWIDE AND INCREASES AT OLDER AGES. SIGNS OF PREMATURE AGING HAVE BEEN ASSOCIATED WITH CHRONIC PAIN, BUT FEW STUDIES HAVE INVESTIGATED AGING BIOMARKERS IN PAIN-RELATED CONDITIONS. A SET OF DNA METHYLATION (DNAM)-BASED ESTIMATES OF AGE, CALLED "EPIGENETIC CLOCKS," HAS BEEN PROPOSED AS BIOLOGICAL MEASURES OF AGE-RELATED ADVERSE PROCESSES, MORBIDITY, AND MORTALITY. THE AIM OF THIS STUDY IS TO ASSESS IF DIFFERENT PAIN-RELATED PHENOTYPES SHOW ALTERATIONS IN DNAM AGE. IN OUR ANALYSIS, WE CONSIDERED THREE COHORTS FOR WHICH WHOLE-BLOOD DNAM DATA WERE AVAILABLE: HEAT PAIN SENSITIVITY (HPS), INCLUDING 20 MONOZYGOTIC TWIN PAIRS DISCORDANT FOR HEAT PAIN TEMPERATURE THRESHOLD; FIBROMYALGIA (FM), INCLUDING 24 CASES AND 20 CONTROLS; AND HEADACHE, INCLUDING 22 CHRONIC MIGRAINE AND MEDICATION OVERUSE HEADACHE PATIENTS (MOH), 18 EPISODIC MIGRAINEURS (EM), AND 13 HEALTHY SUBJECTS. WE USED THE HORVATH'S EPIGENETIC AGE CALCULATOR TO OBTAIN DNAM-BASED ESTIMATES OF EPIGENETIC AGE, TELOMERE LENGTH, LEVELS OF 7 PROTEINS IN PLASMA, NUMBER OF SMOKED PACKS OF CIGARETTES PER YEAR, AND BLOOD CELL COUNTS. WE DID NOT FIND DIFFERENCES IN EPIGENETIC AGE ACCELERATION, CALCULATED USING FIVE DIFFERENT EPIGENETIC CLOCKS, BETWEEN SUBJECTS DISCORDANT FOR PAIN-RELATED PHENOTYPES. TWINS WITH HIGH HPS HAD INCREASED CD8+ T CELL COUNTS (NOMINAL P = 0.028). HPS THRESHOLDS WERE NEGATIVELY ASSOCIATED WITH ESTIMATED LEVELS OF GDF15 (NOMINAL P = 0.008). FM PATIENTS SHOWED DECREASED NAIVE CD4+ T CELL COUNTS COMPARED WITH CONTROLS (NOMINAL P = 0.015). THE SEVERITY OF FM MANIFESTATIONS EXPRESSED THROUGH VARIOUS EVALUATION TESTS WAS ASSOCIATED WITH DECREASED LEVELS OF LEPTIN, SHORTER LENGTH OF TELOMERES, AND REDUCED CD8+ T AND NATURAL KILLER CELL COUNTS (NOMINAL P < 0.05), WHILE THE DURATION OF PAINFUL SYMPTOMS WAS POSITIVELY ASSOCIATED WITH TELOMERE LENGTH (NOMINAL P = 0.034). NO DIFFERENCES IN DNAM-BASED ESTIMATES WERE DETECTED FOR MOH OR EM COMPARED WITH CONTROLS. IN SUMMARY, OUR STUDY SUGGESTS THAT HPS, FM, AND MOH/EM DO NOT SHOW SIGNS OF EPIGENETIC AGE ACCELERATION IN WHOLE BLOOD, WHILE HPS AND FM ARE ASSOCIATED WITH DNAM-BASED ESTIMATES OF IMMUNOLOGICAL PARAMETERS, PLASMA PROTEINS, AND TELOMERE LENGTH. FUTURE STUDIES SHOULD EXTEND THESE OBSERVATIONS IN LARGER COHORTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19  4825  33 OCULAR FUNDUS ABNORMALITIES IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY AND OTHER CHRONIC KIDNEY DISEASES. AIM: THE AIM OF THIS STUDY WAS TO EXAMINE THE OCULAR FUNDUS PATHOLOGY IN PATIENTS WITH BALKAN ENDEMIC NEPHROPATHY (BN) AND CHRONIC KIDNEY DISEASES (CKD). METHODS: THE STUDY INCLUDED 51 PATIENTS WITH BN FROM THE SOUTH MORAVA RIVER REGION IN SERBIA, AND 102 SUBJECTS WITH DIFFERENT STAGES OF CHRONIC RENAL DISEASES, MATCHED ACCORDING TO AGE AND GENDER, OBTAINED FROM A DATABASE USED IN A RECENTLY PUBLISHED STUDY. ALL PATIENTS HAD VISITED OUTPATIENT DEPARTMENT OF THE CLINIC OF NEPHROLOGY, CLINICAL CENTER NIS. ALL PATIENTS UNDERWENT ROUTINE OPHTHALMIC EXAMINATIONS. RESULTS: THERE WERE SIGNIFICANTLY MORE (P < 0.001) PATIENTS WITH AGE-RELATED MACULAR DEGENERATION (AMD) IN THE GROUP WITH BN (31.37 %) THAN IN THOSE WITH CKD (5.88 %). MULTIVARIATE LOGISTIC REGRESSION ANALYSIS CONFIRMED THAT THE SIGNIFICANT FACTORS RELATED TO AMD IN THE GROUP WITH BN WERE ALBUMINURIA (P < 0.05) AND PROTEINURIA (P < 0.05); IN CKD PATIENTS, THE LEVEL OF HDL (P < 0.05), WHILE NEGATIVE CORRELATION WITH THE LEVEL OF TRIGLYCERIDE WAS REGISTERED (P < 0.05). THERE WAS NO ASSOCIATION BETWEEN ESTIMATED GLOMERULAR FILTRATION RATE AND AMD. THE SIGNIFICANT FACTORS RELATED TO RETINOPATHY IN THE GROUP WITH BN ARE AGE (P < 0.05) AND SERUM CREATININE VALUES (P < 0.05), IN PATIENTS WITH CKD INCREASING AGE (P < 0.001) AND DM (P < 0.05). CONCLUSION: OCULAR FUNDUS PATHOLOGY IN PATIENTS WITH BN IS SIMILAR TO THE PATHOLOGY OF OTHER CKD, BUT WITH SIGNIFICANTLY MORE AMD (ABOUT FOUR TIMES), PROBABLY RELATED TO THE GENETIC/EPIGENETIC FACTORS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20  6460  33 TIME TO RELAPSE IN CHRONIC LYMPHOCYTIC LEUKEMIA AND DNA-METHYLATION-BASED BIOLOGICAL AGE. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS A MATURE B CELL NEOPLASM WITH A PREDILECTION FOR OLDER INDIVIDUALS. WHILE PREVIOUS STUDIES HAVE IDENTIFIED EPIGENETIC SIGNATURES ASSOCIATED WITH CLL, WHETHER AGE-RELATED DNA METHYLATION CHANGES MODULATE CLL RELAPSE REMAINS ELUSIVE. IN THIS STUDY, WE EXAMINED THE ASSOCIATION BETWEEN EPIGENETIC AGE ACCELERATION AND TIME TO CLL RELAPSE IN A PUBLICLY AVAILABLE DATASET. DNA METHYLATION PROFILING OF 35 CLL PATIENTS PRIOR TO INITIATING CHEMOIMMUNOTHERAPY WAS PERFORMED USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP. FOUR EPIGENETIC AGE ACCELERATION METRICS (INTRINSIC EPIGENETIC AGE ACCELERATION [IEAA], EXTRINSIC EPIGENETIC AGE ACCELERATION [EEAA], PHENOAGE ACCELERATION [PHENOAA], AND GRIMAGE ACCELERATION [GRIMAA]) WERE ESTIMATED FROM BLOOD DNA METHYLATION LEVELS. LINEAR, QUANTILE, AND LOGISTIC REGRESSION AND RECEIVER OPERATING CHARACTERISTIC CURVE ANALYSES WERE CONDUCTED TO ASSESS THE ASSOCIATION BETWEEN EACH EPIGENETIC AGE METRIC AND TIME TO CLL RELAPSE. EEAA (P = 0.011) AND PHENOAA (P = 0.046) WERE NEGATIVELY AND GRIMAA (P = 0.040) WAS POSITIVELY ASSOCIATED WITH TIME TO CLL RELAPSE. SIMULTANEOUS ASSESSMENT OF EEAA AND GRIMAA IN MALE PATIENTS DISTINGUISHED PATIENTS WHO RELAPSED EARLY FROM PATIENTS WHO RELAPSED LATER (P = 0.039). NO ASSOCIATIONS WERE OBSERVED WITH IEAA. THESE FINDINGS SUGGEST EPIGENETIC AGE ACCELERATION PRIOR TO CHEMOIMMUNOTHERAPY INITIATION IS ASSOCIATED WITH TIME TO CLL RELAPSE. OUR RESULTS PROVIDE NOVEL INSIGHT INTO THE ASSOCIATION BETWEEN AGE-RELATED DNA METHYLATION CHANGES AND CLL RELAPSE AND MAY SERVE HAS BIOMARKERS FOR TREATMENT RELAPSE, AND POTENTIALLY, TREATMENT SELECTION.	2023