1  816 138 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	
                                                                                                                                                                                                                                                                                                                                                                                                     
2 6311  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3 1537  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
4 6508  45 TRAJECTORIES OF INFLAMMATORY BIOMARKERS OVER THE EIGHTH DECADE AND THEIR ASSOCIATIONS WITH IMMUNE CELL PROFILES AND EPIGENETIC AGEING. BACKGROUND: EPIGENETIC AGE ACCELERATION (AN OLDER METHYLATION AGE COMPARED TO CHRONOLOGICAL AGE) CORRELATES STRONGLY WITH VARIOUS AGE-RELATED MORBIDITIES AND MORTALITY. CHRONIC SYSTEMIC INFLAMMATION IS THOUGHT TO BE A HALLMARK OF AGEING, BUT THE RELATIONSHIP BETWEEN AN INCREASED EPIGENETIC AGE AND THIS LIKELY KEY PHENOTYPE OF AGEING HAS NOT YET BEEN EXTENSIVELY INVESTIGATED. METHODS: WE MODELLED THE TRAJECTORIES OF THE INFLAMMATORY BIOMARKERS C-REACTIVE PROTEIN (CRP; MEASURED USING BOTH A HIGH- AND LOW-SENSITIVITY ASSAY) AND INTERLEUKIN-6 (IL-6) OVER THE EIGHTH DECADE IN THE LOTHIAN BIRTH COHORT 1936. USING LINEAR MIXED MODELS, WE INVESTIGATED THE ASSOCIATION BETWEEN CRP AND IMMUNE CELL PROFILES IMPUTED FROM THE METHYLATION DATA AND EXAMINED THE CROSS-SECTIONAL AND LONGITUDINAL ASSOCIATION BETWEEN THE INFLAMMATORY BIOMARKERS AND TWO MEASURES OF EPIGENETIC AGE ACCELERATION, DERIVED FROM THE HORVATH AND HANNUM EPIGENETIC CLOCKS. RESULTS: WE FOUND THAT LOW-SENSITIVITY CRP DECLINED, HIGH-SENSITIVITY CRP DID NOT CHANGE, AND IL-6 INCREASED OVER TIME WITHIN THE COHORT. CRP LEVELS INVERSELY ASSOCIATED WITH CD8+T CELLS AND CD4+T CELLS AND POSITIVELY ASSOCIATED WITH SENESCENT CD8+T CELLS, PLASMABLASTS AND GRANULOCYTES. CROSS-SECTIONALLY, THE HANNUM, BUT NOT THE HORVATH, MEASURE OF AGE ACCELERATION WAS POSITIVELY ASSOCIATED WITH EACH OF THE INFLAMMATORY BIOMARKERS, INCLUDING A RESTRICTED MEASURE OF CRP (</= 10 MG/L) LIKELY REFLECTING LEVELS RELEVANT TO CHRONIC INFLAMMATION. CONCLUSIONS: WE FOUND A DIVERGENT RELATIONSHIP BETWEEN INFLAMMATION AND IMMUNE SYSTEM PARAMETERS IN OLDER AGE. WE ADDITIONALLY REPORT THE HANNUM MEASURE OF EPIGENETIC AGE ACCELERATION ASSOCIATED WITH AN ELEVATED INFLAMMATORY PROFILE CROSS-SECTIONALLY, BUT NOT LONGITUDINALLY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                  
5 6083  36 THE EFFECT OF SMOKING ON DNA METHYLATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS FROM AFRICAN AMERICAN WOMEN. BACKGROUND: REGULAR SMOKING IS ASSOCIATED WITH A WIDE VARIETY OF SYNDROMES WITH PROMINENT INFLAMMATORY COMPONENTS SUCH AS CANCER, OBESITY AND TYPE 2 DIABETES. HEAVY REGULAR SMOKING IS ALSO ASSOCIATED WITH CHANGES IN THE DNA METHYLATION OF PERIPHERAL MONONUCLEAR CELLS. HOWEVER, IN YOUNGER SMOKERS, INFLAMMATORY EPIGENETIC FINDINGS ARE LARGELY ABSENT WHICH SUGGESTS THE INFLAMMATORY RESPONSE(S) TO SMOKING MAY BE DOSE DEPENDENT. TO HELP UNDERSTAND WHETHER PERIPHERAL MONONUCLEAR CELLS HAVE A ROLE IN MEDIATING THESE RESPONSES IN OLDER SMOKERS WITH HIGHER CUMULATIVE SMOKE EXPOSURE, WE EXAMINED GENOME-WIDE DNA METHYLATION IN A GROUP OF WELL CHARACTERIZED ADULT AFRICAN AMERICAN SUBJECTS INFORMATIVE FOR SMOKING, AS WELL AS SERUM C-REACTIVE PROTEIN (CRP) AND INTERLEUKIN-6 RECEPTOR (IL6R) LEVELS. IN ADDITION, COMPLEMENTARY BIOINFORMATIC ANALYSES WERE CONDUCTED TO DELINEATE POSSIBLE PATHWAYS AFFECTED BY LONG-TERM SMOKING. RESULTS: GENOME-WIDE DNA METHYLATION ANALYSIS WITH RESPECT TO SMOKING STATUS YIELDED 910 SIGNIFICANT LOCI AFTER BENJAMINI-HOCHBERG CORRECTION. IN PARTICULAR, TWO LOCI FROM THE AHRR GENE (CG05575921 AND CG23576855) AND ONE LOCUS FROM THE GPR15 GENE (CG19859270) WERE IDENTIFIED AS HIGHLY SIGNIFICANTLY DIFFERENTIALLY METHYLATED BETWEEN SMOKERS AND NON-SMOKERS. THE BIOINFORMATIC ANALYSES SHOWED THAT LONG-TERM CHRONIC SMOKING IS ASSOCIATED WITH ALTERED PROMOTER DNA METHYLATION OF GENES CODING FOR PROTEINS MAPPING TO CRITICAL SUB-NETWORKS MODERATING INFLAMMATION, IMMUNE FUNCTION, AND COAGULATION. CONCLUSIONS: WE CONCLUDE THAT CHRONIC REGULAR SMOKING IS ASSOCIATED WITH CHANGES IN PERIPHERAL MONONUCLEAR CELL METHYLATION SIGNATURE WHICH PERTURB INFLAMMATORY AND IMMUNE FUNCTION PATHWAYS AND MAY CONTRIBUTE TO INCREASED VULNERABILITY FOR COMPLEX ILLNESSES WITH INFLAMMATORY COMPONENTS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                 
6 2922  34 GENE-SPECIFIC DNA METHYLATION ASSOCIATION WITH SERUM LEVELS OF C-REACTIVE PROTEIN IN AFRICAN AMERICANS. A MORE THOROUGH UNDERSTANDING OF THE DIFFERENCES IN DNA METHYLATION (DNAM) PROFILES IN POPULATIONS MAY HOLD PROMISE FOR IDENTIFYING MOLECULAR MECHANISMS THROUGH WHICH GENETIC AND ENVIRONMENTAL FACTORS JOINTLY CONTRIBUTE TO HUMAN DISEASES. INFLAMMATION IS A KEY MOLECULAR MECHANISM UNDERLYING SEVERAL CHRONIC DISEASES INCLUDING CARDIOVASCULAR DISEASE, AND IT AFFECTS DNAM PROFILE ON BOTH GLOBAL AND LOCUS-SPECIFIC LEVELS. TO UNDERSTAND THE IMPACT OF INFLAMMATION ON THE DNAM OF THE HUMAN GENOME, WE INVESTIGATED DNAM PROFILES OF PERIPHERAL BLOOD LEUKOCYTES FROM 966 AFRICAN AMERICAN PARTICIPANTS IN THE GENETIC EPIDEMIOLOGY NETWORK OF ARTERIOPATHY (GENOA) STUDY. BY TESTING THE ASSOCIATION OF DNAM SITES ON CPG ISLANDS OF OVER 14,000 GENES WITH C-REACTIVE PROTEIN (CRP), AN INFLAMMATORY BIOMARKER OF CARDIOVASCULAR DISEASE, WE IDENTIFIED 257 DNAM SITES IN 240 GENES SIGNIFICANTLY ASSOCIATED WITH SERUM LEVELS OF CRP ADJUSTED FOR AGE, SEX, BODY MASS INDEX AND SMOKING STATUS, AND CORRECTED FOR MULTIPLE TESTING. OF THE SIGNIFICANTLY ASSOCIATED DNAM SITES, 80.5% WERE HYPOMETHYLATED WITH HIGHER CRP LEVELS. THE MOST SIGNIFICANT GENE ONTOLOGY TERMS ENRICHED IN THE GENES ASSOCIATED WITH THE CRP LEVELS WERE IMMUNE SYSTEM PROCESS, IMMUNE RESPONSE, DEFENSE RESPONSE, RESPONSE TO STIMULUS, AND RESPONSE TO STRESS, WHICH ARE ALL LINKED TO THE FUNCTIONS OF LEUKOCYTES. WHILE THE CRP-ASSOCIATED DNAM MAY BE CELL-TYPE SPECIFIC, UNDERSTANDING THE DNAM ASSOCIATION WITH CRP IN PERIPHERAL BLOOD LEUKOCYTES OF MULTI-ETHNIC POPULATIONS CAN ASSIST IN UNVEILING THE MOLECULAR MECHANISM OF HOW THE PROCESS OF INFLAMMATION AFFECTS THE RISKS OF DEVELOPING COMMON DISEASE THROUGH EPIGENETIC MODIFICATIONS.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 1345  30 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION, BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8 1519  31 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
9 3555  34 IMPACT OF AGE, ANTIRETROVIRAL THERAPY, AND CANCER ON EPIGENETIC AGING IN PEOPLE LIVING WITH HIV. BACKGROUND: PREMATURE AGING HAS BEEN IDENTIFIED AS A GLOBAL RISK FACTOR FOR CANCER. CAUSES OF PREMATURE AGING ARE MULTIFACTORIAL, INCLUDING INFLAMMATION, INFECTION, CHRONIC STRESS, AND LIFESTYLE FACTORS. METHOD: WE EVALUATED WHETHER PREMATURE AGING IN PEOPLE LIVING WITH HIV (PLWH) WAS ASSOCIATED WITH ANTIRETROVIRAL THERAPY (ART) OR THE DIAGNOSIS OF CANCER. WE USED WELL-ESTABLISHED DNA METHYLATION PATTERNS TO ASSESS PREMATURE AGING, USING HORVATH ET AL., IN INDIVIDUALS WITH HIV LOCATED IN CLEVELAND, OHIO AND COMPARED THESE TO STANDARDIZED DATASETS OF US HISTORICAL BLOOD SAMPLES. SOME OF THE PLWH DEVELOPED CANCER OVER TIME. RESULTS: WE FOUND THAT DNA METHYLATION ANALYSIS IDENTIFIED ACCELERATED AGING IN PLWH WHEREAS ART THERAPY MITIGATED THE ADVANCEMENT OF DNA METHYLATION AGE. A VARIETY OF CANCERS WERE OBSERVED IN THIS POPULATION, BUT A CANCER DIAGNOSIS WAS NOT SIGNIFICANTLY ASSOCIATED WITH MORE ADVANCED DNA METHYLATION AGE. CONCLUSION: WE FIND THAT THE AGE ACCELERATION DETECTED IN PLWH IS MITIGATED BY ART THERAPY AND IS NOT FURTHER ACCELERATED BY A DIAGNOSIS OF CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 2411  36 EPIGENETIC SCORES FOR THE CIRCULATING PROTEOME AS TOOLS FOR DISEASE PREDICTION. PROTEIN BIOMARKERS HAVE BEEN IDENTIFIED ACROSS MANY AGE-RELATED MORBIDITIES. HOWEVER, CHARACTERISING EPIGENETIC INFLUENCES COULD FURTHER INFORM DISEASE PREDICTIONS. HERE, WE LEVERAGE EPIGENOME-WIDE DATA TO STUDY LINKS BETWEEN THE DNA METHYLATION (DNAM) SIGNATURES OF THE CIRCULATING PROTEOME AND INCIDENT DISEASES. USING DATA FROM FOUR COHORTS, WE TRAINED AND TESTED EPIGENETIC SCORES (EPISCORES) FOR 953 PLASMA PROTEINS, IDENTIFYING 109 SCORES THAT EXPLAINED BETWEEN 1% AND 58% OF THE VARIANCE IN PROTEIN LEVELS AFTER ADJUSTING FOR KNOWN PROTEIN QUANTITATIVE TRAIT LOCI (PQTL) GENETIC EFFECTS. BY PROJECTING THESE EPISCORES INTO AN INDEPENDENT SAMPLE (GENERATION SCOTLAND; N = 9537) AND RELATING THEM TO INCIDENT MORBIDITIES OVER A FOLLOW-UP OF 14 YEARS, WE UNCOVERED 137 EPISCORE-DISEASE ASSOCIATIONS. THESE ASSOCIATIONS WERE LARGELY INDEPENDENT OF IMMUNE CELL PROPORTIONS, COMMON LIFESTYLE AND HEALTH FACTORS, AND BIOLOGICAL AGING. NOTABLY, WE FOUND THAT OUR DIABETES-ASSOCIATED EPISCORES HIGHLIGHTED PREVIOUS TOP BIOMARKER ASSOCIATIONS FROM PROTEOME-WIDE ASSESSMENTS OF DIABETES. THESE EPISCORES FOR PROTEIN LEVELS CAN THEREFORE BE A VALUABLE RESOURCE FOR DISEASE PREDICTION AND RISK STRATIFICATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
11 3652  34 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
12 3914  33 LIFETIME STRESS ACCELERATES EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT: RELEVANCE OF GLUCOCORTICOID SIGNALING. BACKGROUND: CHRONIC PSYCHOLOGICAL STRESS IS ASSOCIATED WITH ACCELERATED AGING AND INCREASED RISK FOR AGING-RELATED DISEASES, BUT THE UNDERLYING MOLECULAR MECHANISMS ARE UNCLEAR. RESULTS: WE EXAMINED THE EFFECT OF LIFETIME STRESSORS ON A DNA METHYLATION-BASED AGE PREDICTOR, EPIGENETIC CLOCK. AFTER CONTROLLING FOR BLOOD CELL-TYPE COMPOSITION AND LIFESTYLE PARAMETERS, CUMULATIVE LIFETIME STRESS, BUT NOT CHILDHOOD MALTREATMENT OR CURRENT STRESS ALONE, PREDICTED ACCELERATED EPIGENETIC AGING IN AN URBAN, AFRICAN AMERICAN COHORT (N = 392). THIS EFFECT WAS PRIMARILY DRIVEN BY PERSONAL LIFE STRESSORS, WAS MORE PRONOUNCED WITH ADVANCING AGE, AND WAS BLUNTED IN INDIVIDUALS WITH HIGHER CHILDHOOD ABUSE EXPOSURE. HYPOTHESIZING THAT THESE EPIGENETIC EFFECTS COULD BE MEDIATED BY GLUCOCORTICOID SIGNALING, WE FOUND THAT A HIGH NUMBER (N = 85) OF EPIGENETIC CLOCK CPG SITES WERE LOCATED WITHIN GLUCOCORTICOID RESPONSE ELEMENTS. WE FURTHER EXAMINED THE FUNCTIONAL EFFECTS OF GLUCOCORTICOIDS ON EPIGENETIC CLOCK CPGS IN AN INDEPENDENT SAMPLE WITH GENOME-WIDE DNA METHYLATION (N = 124) AND GENE EXPRESSION DATA (N = 297) BEFORE AND AFTER EXPOSURE TO THE GLUCOCORTICOID RECEPTOR AGONIST DEXAMETHASONE. DEXAMETHASONE INDUCED DYNAMIC CHANGES IN METHYLATION IN 31.2 % (110/353) OF THESE CPGS AND TRANSCRIPTION IN 81.7 % (139/170) OF GENES NEIGHBORING EPIGENETIC CLOCK CPGS. DISEASE ENRICHMENT ANALYSIS OF THESE DEXAMETHASONE-REGULATED GENES SHOWED ENRICHED ASSOCIATION FOR AGING-RELATED DISEASES, INCLUDING CORONARY ARTERY DISEASE, ARTERIOSCLEROSIS, AND LEUKEMIAS. CONCLUSIONS: CUMULATIVE LIFETIME STRESS MAY ACCELERATE EPIGENETIC AGING, AN EFFECT THAT COULD BE DRIVEN BY GLUCOCORTICOID-INDUCED EPIGENETIC CHANGES. THESE FINDINGS CONTRIBUTE TO OUR UNDERSTANDING OF MECHANISMS LINKING CHRONIC STRESS WITH ACCELERATED AGING AND HEIGHTENED DISEASE RISK.	2015	
                                                                                                                                                                                                                                                                                                                                                     
13 5638  37 SERUM METABOLOMICS REVEALS PATHWAYS AND BIOMARKERS ASSOCIATED WITH ASTHMA PATHOGENESIS. BACKGROUND: ASTHMA IS A CHRONIC INFLAMMATORY DISEASE CAUSED BY COMPLEX INTERACTIONS OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. FOR THIS REASON, NEW APPROACHES ARE REQUIRED TO CLARIFY THE PATHOGENESIS OF ASTHMA BY SYSTEMIC REVIEW. OBJECTIVE: WE APPLIED A (1)H-NMR METABOLOMICS APPROACH TO INVESTIGATE THE ALTERED METABOLIC PATTERN IN SERA FROM PATIENTS WITH ASTHMA AND SOUGHT TO IDENTIFY THE MECHANISM UNDERLYING ASTHMA AND POTENTIAL BIOMARKERS. METHOD: A GLOBAL PROFILE OF SERA FROM PATIENTS WITH ASTHMA (N = 39) AND CONTROLS (N = 26) WAS GENERATED USING (1)H-NMR SPECTROSCOPY COUPLED WITH MULTIVARIATE STATISTICAL ANALYSIS. ENDOGENOUS METABOLITES IN SERUM WERE RAPIDLY MEASURED USING THE TARGET-PROFILING PROCEDURE. RESULTS: MULTIVARIATE STATISTICAL ANALYSIS SHOWED A CLEAR DISTINCTION BETWEEN PATIENTS WITH ASTHMA AND HEALTHY SUBJECTS. SERA OF ASTHMA PATIENTS WERE CHARACTERIZED BY INCREASED LEVELS OF METHIONINE, GLUTAMINE, AND HISTIDINE AND BY DECREASED LEVELS OF FORMATE, METHANOL, ACETATE, CHOLINE, O-PHOSPHOCHOLINE, ARGININE, AND GLUCOSE. THE METABOLITES DETECTED IN THE SERA OF PATIENTS WITH ASTHMA ARE INVOLVED IN HYPERMETHYLATION, RESPONSE TO HYPOXIA, AND IMMUNE REACTION. FURTHERMORE, THE LEVELS OF SERUM METABOLITES FROM PATIENTS WITH ASTHMA CORRELATED WITH ASTHMA SEVERITY; IN PARTICULAR, LIPID METABOLISM WAS ALTERED IN PATIENTS WITH LOWER FORCED EXPIRATORY VOLUME IN 1 S PERCENTAGE (FEV(1)%) PREDICTED VALUES. IN ADDITION, POTENTIAL BIOMARKERS SHOWED STRONG PREDICTIVE POWER IN ROC ANALYSIS, AND THE PRESENCE OF ASTHMA IN EXTERNAL VALIDATION MODELS WAS PREDICTED WITH HIGH ACCURACY (90.9% FOR ASTHMA AND 100% FOR CONTROL SUBJECTS). CONCLUSION & CLINICAL RELEVANCE: THESE DATA SHOWED THAT (1)H-NMR-BASED METABOLITE PROFILING OF SERUM MAY BE USEFUL FOR THE EFFECTIVE DIAGNOSIS OF ASTHMA AND A FURTHER UNDERSTANDING OF ITS PATHOGENESIS.	2013	
                                                                                                                                                                                                                                                                                                                                                                   
14 5847  30 SUBCLINICAL ATHEROSCLEROSIS AND ACCELERATED EPIGENETIC AGE MEDIATED BY INFLAMMATION: A MULTI-OMICS STUDY. AIMS: EPIGENETIC AGE IS EMERGING AS A PERSONALIZED AND ACCURATE PREDICTOR OF BIOLOGICAL AGE. THE AIM OF THIS ARTICLE IS TO ASSESS THE ASSOCIATION OF SUBCLINICAL ATHEROSCLEROSIS WITH ACCELERATED EPIGENETIC AGE AND TO INVESTIGATE THE UNDERLYING MECHANISMS MEDIATING THIS ASSOCIATION. METHODS AND RESULTS: WHOLE BLOOD METHYLOMICS, TRANSCRIPTOMICS, AND PLASMA PROTEOMICS WERE OBTAINED FOR 391 PARTICIPANTS OF THE PROGRESSION OF EARLY SUBCLINICAL ATHEROSCLEROSIS STUDY. EPIGENETIC AGE WAS CALCULATED FROM METHYLOMICS DATA FOR EACH PARTICIPANT. ITS DIVERGENCE FROM CHRONOLOGICAL AGE IS TERMED EPIGENETIC AGE ACCELERATION. SUBCLINICAL ATHEROSCLEROSIS BURDEN WAS ESTIMATED BY MULTI-TERRITORY 2D/3D VASCULAR ULTRASOUND AND BY CORONARY ARTERY CALCIFICATION. IN HEALTHY INDIVIDUALS, THE PRESENCE, EXTENSION, AND PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS WERE ASSOCIATED WITH A SIGNIFICANT ACCELERATION OF THE GRIM EPIGENETIC AGE, A PREDICTOR OF HEALTH AND LIFESPAN, REGARDLESS OF TRADITIONAL CARDIOVASCULAR RISK FACTORS. INDIVIDUALS WITH AN ACCELERATED GRIM EPIGENETIC AGE WERE CHARACTERIZED BY AN INCREASED SYSTEMIC INFLAMMATION AND ASSOCIATED WITH A SCORE OF LOW-GRADE, CHRONIC INFLAMMATION. MEDIATION ANALYSIS USING TRANSCRIPTOMICS AND PROTEOMICS DATA REVEALED KEY PRO-INFLAMMATORY PATHWAYS (IL6, INFLAMMASOME, AND IL10) AND GENES (IL1B, OSM, TLR5, AND CD14) MEDIATING THE ASSOCIATION BETWEEN SUBCLINICAL ATHEROSCLEROSIS AND EPIGENETIC AGE ACCELERATION. CONCLUSION: THE PRESENCE, EXTENSION, AND PROGRESSION OF SUBCLINICAL ATHEROSCLEROSIS IN MIDDLE-AGED ASYMPTOMATIC INDIVIDUALS ARE ASSOCIATED WITH AN ACCELERATION IN THE GRIM EPIGENETIC AGE. MEDIATION ANALYSIS USING TRANSCRIPTOMICS AND PROTEOMICS DATA SUGGESTS A KEY ROLE OF SYSTEMIC INFLAMMATION IN THIS ASSOCIATION, REINFORCING THE RELEVANCE OF INTERVENTIONS ON INFLAMMATION TO PREVENT CARDIOVASCULAR DISEASE.	2023	
                                                                                                                                                                                                                                                                                                                                                  
15 3936  34 LIVING IN ENDEMIC AREA FOR INFECTIOUS DISEASES ACCELERATES EPIGENETIC AGE. INFLAMMAGING IS A LOW-GRADE INFLAMMATORY STATE GENERATED BY THE AGING PROCESS THAT CAN CONTRIBUTE TO FRAILTY AND AGE-RELATED DISEASES IN THE ELDERLY. HOWEVER, IT CAN HAVE DISTINCT EFFECTS IN THE ELDERLY LIVING IN ENDEMIC AREAS FOR INFECTIOUS DISEASES. AN INCREASED INFLAMMATORY RESPONSE MAY CONFER PROTECTION AGAINST INFECTIOUS AGENTS IN THESE AREAS, ALTHOUGH THIS ADVANTAGE CAN CAUSE ACCELERATING EPIGENETIC AGING. IN THIS STUDY, WE EVALUATED THE INFLAMMATORY PROFILE AND THE EPIGENETIC AGE OF INFECTED AND NONINFECTED INDIVIDUALS FROM AN ENDEMIC AREA IN BRAZIL. THE PROFILE OF CYTOKINES, CHEMOKINES AND GROWTH FACTORS ANALYZED IN THE SERA OF THE TWO GROUPS OF INDIVIDUALS SHOWED SIMILARITIES, ALTHOUGH INFECTED INDIVIDUALS HAD A HIGHER CONCENTRATION OF THESE MEDIATORS. A SIGNIFICANT INCREASE IN IL-1RA, CXCL8, CCL2, CCL3 AND CCL4 PRODUCTION WAS ASSOCIATED WITH LEPROSY INFECTION. NOTABLY, ELDERLY INDIVIDUALS DISPLAYED DISTINCT IMMUNE RESPONSES ASSOCIATED WITH THEIR INFECTION STATUS WHEN COMPARED TO ADULTS SUGGESTING AN ADAPTIVE REMODELLING OF THEIR IMMUNE RESPONSES. EPIGENETIC ANALYSIS ALSO SHOWED THAT THERE WAS NO DIFFERENCE IN EPIGENETIC AGE BETWEEN THE TWO GROUPS OF INDIVIDUALS. HOWEVER, INDIVIDUALS FROM THE ENDEMIC AREA HAD A SIGNIFICANT ACCELERATED AGING WHEN COMPARED TO INDIVIDUALS FROM SAO PAULO, A NON-ENDEMIC AREA IN BRAZIL. MOREOVER, THE LATTER COHORT WAS ALSO EPIGENETICALLY AGED IN RELATION TO AN ITALIAN COHORT. OUR DATA SHOWS THAT LIVING IN ENDEMIC AREAS FOR CHRONIC INFECTIOUS DISEASES RESULTS IN REMODELLING OF INFLAMMAGING AND ACCELERATION OF EPIGENETIC AGING IN INDIVIDUALS REGARDLESS OF THEIR INFECTIOUS STATUS. IT ALSO HIGHLIGHTS THAT GEOGRAPHICAL, GENETIC AND ENVIRONMENTAL FACTORS INFLUENCE AGING AND IMMUNOSENESCENCE IN THEIR PACE AND PROFILE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 6547  32 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	

17 1503  30 DNA METHYLATION AND GENE EXPRESSION DIFFERENCES IN CHILDREN CONCEIVED IN VITRO OR IN VIVO. EPIDEMIOLOGICAL DATA INDICATE THAT CHILDREN CONCEIVED IN VITRO HAVE A GREATER RELATIVE RISK OF LOW BIRTH-WEIGHT, MAJOR AND MINOR BIRTH DEFECTS, AND RARE DISORDERS INVOLVING IMPRINTED GENES, SUGGESTING THAT EPIGENETIC CHANGES MAY BE ASSOCIATED WITH ASSISTED REPRODUCTION. WE EXAMINED DNA METHYLATION AT MORE THAN 700 GENES (1536 CPG SITES) IN PLACENTA AND CORD BLOOD AND MEASURED GENE EXPRESSION LEVELS OF A SUBSET OF GENES THAT DIFFERED IN METHYLATION LEVELS BETWEEN CHILDREN CONCEIVED IN VITRO VERSUS IN VIVO. OUR RESULTS SUGGEST THAT IN VITRO CONCEPTION IS ASSOCIATED WITH LOWER MEAN METHYLATION AT CPG SITES IN PLACENTA AND HIGHER MEAN METHYLATION AT CPG SITES IN CORD BLOOD. WE ALSO FIND THAT IN VITRO CONCEPTION-ASSOCIATED DNA METHYLATION DIFFERENCES ARE ASSOCIATED WITH GENE EXPRESSION DIFFERENCES AT BOTH IMPRINTED AND NON-IMPRINTED GENES. THE RANGE OF INTER-INDIVIDUAL VARIATION IN GENE EXPRESSION OF THE IN VITRO AND IN VIVO GROUPS OVERLAPS SUBSTANTIALLY BUT SOME INDIVIDUALS FROM THE IN VITRO GROUP DIFFER FROM THE IN VIVO GROUP MEAN BY MORE THAN TWO STANDARD DEVIATIONS. SEVERAL OF THE GENES WHOSE EXPRESSION DIFFERS BETWEEN THE TWO GROUPS HAVE BEEN IMPLICATED IN CHRONIC METABOLIC DISORDERS, SUCH AS OBESITY AND TYPE II DIABETES. THESE FINDINGS SUGGEST THAT THERE MAY BE EPIGENETIC DIFFERENCES IN THE GAMETES OR EARLY EMBRYOS DERIVED FROM COUPLES UNDERGOING TREATMENT FOR INFERTILITY. ALTERNATIVELY, ASSISTED REPRODUCTION TECHNOLOGY MAY HAVE AN EFFECT ON GLOBAL PATTERNS OF DNA METHYLATION AND GENE EXPRESSION. IN EITHER CASE, THESE DIFFERENCES OR CHANGES MAY AFFECT LONG-TERM PATTERNS OF GENE EXPRESSION.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 6027  26 THE BLOOD DNA METHYLATION CLOCK GRIMAGE IS A ROBUST SURROGATE FOR AIRWAY EPITHELIA AGING. ONE KEY FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS THAT ITS PREVALENCE INCREASES EXPONENTIALLY WITH AGE. DNA METHYLATION CLOCKS HAVE BECOME POWERFUL BIOMARKERS TO DETECT ACCELERATED AGING IN A VARIETY OF DISEASES AND CAN HELP PROGNOSE OUTCOMES IN SEVERE COPD. THIS STUDY INVESTIGATED WHICH DNA METHYLATION CLOCK COULD BEST REFLECT AIRWAY EPIGENETIC AGE WHEN USED IN MORE ACCESSIBLE BLOOD SAMPLES. OUR ANALYSES SHOWED THAT OUT OF SIX DNA METHYLATION CLOCKS INVESTIGATED, DNAMGRIMAGE DEMONSTRATED THE STRONGEST CORRELATION AND THE SMALLEST DIFFERENCE BETWEEN THE AIRWAY EPITHELIUM AND BLOOD. OUR FINDINGS SUGGESTS THAT BLOOD DNAMGRIMAGE ACCURATELY REFLECTS AIRWAY EPIGENETIC AGE OF INDIVIDUALS AND THAT ITS ELEVATION IS HIGHLY ASSOCIATED WITH COPD.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19  175  22 ACCELERATED AGING WITH HIV BEGINS AT THE TIME OF INITIAL HIV INFECTION. LIVING WITH HIV INFECTION IS ASSOCIATED WITH EARLY ONSET OF AGING-RELATED CHRONIC CONDITIONS, SOMETIMES DESCRIBED AS ACCELERATED AGING. EPIGENETIC DNA METHYLATION PATTERNS CAN EVALUATE ACCELERATION OF BIOLOGICAL AGE RELATIVE TO CHRONOLOGICAL AGE. THE IMPACT OF INITIAL HIV INFECTION ON FIVE EPIGENETIC MEASURES OF AGING WAS EXAMINED BEFORE AND APPROXIMATELY 3 YEARS AFTER HIV INFECTION IN THE SAME INDIVIDUALS (N=102). SIGNIFICANT EPIGENETIC AGE ACCELERATION (MEDIAN 1.9-4.8 YEARS) AND ESTIMATED TELOMERE LENGTH SHORTENING (ALL P</= 0.001) WERE OBSERVED FROM PRE-TO POST-HIV INFECTION, AND REMAINED SIGNIFICANT IN THREE EPIGENETIC MEASURES AFTER CONTROLLING FOR T CELL CHANGES. NO ACCELERATION WAS SEEN IN AGE- AND TIME INTERVAL-MATCHED HIV-UNINFECTED CONTROLS. CHANGES IN GENOME-WIDE CO-METHYLATION CLUSTERS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INITIAL HIV INFECTION (P</= 2.0 X 10(-4)). THESE LONGITUDINAL OBSERVATIONS CLEARLY DEMONSTRATE AN EARLY AND SUBSTANTIAL IMPACT OF HIV INFECTION ON THE EPIGENETIC AGING PROCESS, AND SUGGEST A ROLE FOR HIV ITSELF IN THE EARLIER ONSET OF CLINICAL AGING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20 1497  32 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