1  2643 118 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2  5005  27 PERIPHERAL BLOOD DNA METHYLATION-BASED MACHINE LEARNING MODELS FOR PREDICTION OF KNEE OSTEOARTHRITIS PROGRESSION: BIOLOGIC SPECIMENS AND DATA FROM THE OSTEOARTHRITIS INITIATIVE AND JOHNSTON COUNTY OSTEOARTHRITIS PROJECT. OBJECTIVE: THE LACK OF ACCURATE BIOMARKERS TO PREDICT KNEE OSTEOARTHRITIS (OA) PROGRESSION IS A KEY UNMET NEED IN OA CLINICAL RESEARCH. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP BASELINE PERIPHERAL BLOOD EPIGENETIC BIOMARKER MODELS TO PREDICT KNEE OA PROGRESSION. METHODS: GENOME-WIDE BUFFY COAT DNA METHYLATION PATTERNS FROM 554 INDIVIDUALS FROM THE OSTEOARTHRITIS BIOMARKERS CONSORTIUM (OABC) WERE DETERMINED USING ILLUMINA INFINIUM METHYLATIONEPIC 850K ARRAYS. DATA WERE DIVIDED INTO MODEL DEVELOPMENT AND VALIDATION SETS, AND MACHINE LEARNING MODELS WERE TRAINED TO CLASSIFY FUTURE OA PROGRESSION BY KNEE PAIN, RADIOGRAPHIC IMAGING, KNEE PAIN PLUS RADIOGRAPHIC IMAGING, AND ANY PROGRESSION (PAIN, RADIOGRAPHIC, OR BOTH). PARSIMONIOUS MODELS USING THE TOP 13 CPG SITES MOST FREQUENTLY SELECTED DURING DEVELOPMENT WERE TESTED ON INDEPENDENT SAMPLES FROM PARTICIPANTS IN THE JOHNSTON COUNTY OSTEOARTHRITIS (JOCO OA) PROJECT (N = 128) AND A PREVIOUSLY PUBLISHED OSTEOARTHRITIS INITIATIVE (OAI) DATA SET (N = 55). RESULTS: FULL MODELS ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC-ONLY PROGRESSION (MEAN +/- SEM ACCURACY 87 +/- 0.8%, AREA UNDER THE CURVE [AUC] 0.94 +/- 0.004), PAIN-ONLY PROGRESSION (ACCURACY 89 +/- 0.9%, AUC 0.97 +/- 0.004), PAIN PLUS RADIOGRAPHIC PROGRESSION (ACCURACY 72 +/- 0.7%, AUC 0.79 +/- 0.006), AND ANY PROGRESSION (ACCURACY 78 +/- 0.4%, AUC 0.86 +/- 0.004). PAIN-ONLY AND RADIOGRAPHIC-ONLY PROGRESSORS WERE NOT DISTINGUISHABLE (MEAN +/- SEM ACCURACY 58 +/- 1%, AUC 0.62 +/- 0.001). PARSIMONIOUS MODELS SHOWED SIMILAR PERFORMANCE AND ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC PROGRESSORS IN THE OABC COHORT AND IN BOTH VALIDATION COHORTS (MEAN +/- SEM ACCURACY 80 +/- 0.3%, AUC 0.88 +/- 0.003 [USING JOCO OA PROJECT DATA], ACCURACY 80 +/- 0.8%, AUC 0.89 +/- 0.002 [USING PREVIOUS OAI DATA]). CONCLUSION: OUR DATA SUGGEST THAT PAIN AND STRUCTURAL PROGRESSION SHARE SIMILAR EARLY SYSTEMIC IMMUNE EPIGENOTYPES. FURTHER STUDIES SHOULD FOCUS ON EVALUATING THE PATHOPHYSIOLOGIC CONSEQUENCES OF DIFFERENTIAL DNA METHYLATION AND PERIPHERAL BLOOD CELL EPIGENOTYPES IN INDIVIDUALS WITH KNEE OA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
3  5746  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4    93  26 A PILOT STUDY OF PERIPHERAL BLOOD DNA METHYLATION MODELS AS PREDICTORS OF KNEE OSTEOARTHRITIS RADIOGRAPHIC PROGRESSION: DATA FROM THE OSTEOARTHRITIS INITIATIVE (OAI). KNEE OSTEOARTHRITIS (OA) IS A LEADING CAUSE OF CHRONIC DISABILITY WORLDWIDE, BUT NO DIAGNOSTIC OR PROGNOSTIC BIOMARKERS ARE AVAILABLE. INCREASING EVIDENCE SUPPORTS EPIGENETIC DYSREGULATION AS A CONTRIBUTOR TO OA PATHOGENESIS. IN THIS PILOT STUDY, WE INVESTIGATED EPIGENETIC PATTERNS IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AS MODELS TO PREDICT FUTURE RADIOGRAPHIC PROGRESSION IN OA PATIENTS ENROLLED IN THE LONGITUDINAL OSTEOARTHRITIS INITIATIVE (OAI) STUDY. PBMC DNA WAS ANALYZED FROM BASELINE OAI VISITS IN 58 FUTURE RADIOGRAPHIC PROGRESSORS (JOINT SPACE NARROWING AT 24 MONTHS, SUSTAINED AT 48 MONTHS) COMPARED TO 58 NON-PROGRESSORS. DNA METHYLATION WAS QUANTIFIED VIA ILLUMINA MICROARRAYS AND BETA- AND M-VALUES WERE USED TO GENERATE LINEAR CLASSIFICATION MODELS. DATA WERE RANDOMLY SPLIT INTO A 60% DEVELOPMENT AND 40% VALIDATION SUBSETS, MODELS DEVELOPED AND TESTED, AND CROSS-VALIDATED IN A TOTAL OF 40 CYCLES. M-VALUE BASED MODELS OUTPERFORMED BETA-VALUE BASED MODELS (ROC-AUC 0.81 +/- 0.01 VS. 0.73 +/- 0.02, MEAN +/- SEM, COMPARISON P = 0.002), WITH A MEAN CLASSIFICATION ACCURACY OF 73 +/- 1% (MEAN +/- SEM) FOR M- AND 69 +/- 1% FOR BETA-BASED MODELS. ADJUSTING FOR COVARIATES DID NOT SIGNIFICANTLY ALTER MODEL PERFORMANCE. OUR FINDINGS SUGGEST THAT PBMC DNA METHYLATION-BASED MODELS MAY BE USEFUL AS BIOMARKERS OF OA PROGRESSION AND WARRANT ADDITIONAL EVALUATION IN LARGER PATIENT COHORTS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
5  3056  42 GENOME-WIDE DNA METHYLATION ANALYSIS IMPLICATES ENRICHMENT OF INTERFERON PATHWAY IN AFRICAN AMERICAN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND EUROPEAN AMERICANS WITH LUPUS NEPHRITIS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A CHRONIC, MULTISYSTEM, INFLAMMATORY AUTOIMMUNE DISEASE THAT DISPROPORTIONATELY AFFECTS WOMEN. TRENDS IN SLE PREVALENCE AND CLINICAL COURSE DIFFER BY ANCESTRY, WITH THOSE OF AFRICAN AMERICAN ANCESTRY PRESENTING WITH MORE ACTIVE, SEVERE AND RAPIDLY PROGRESSIVE DISEASE THAN EUROPEAN AMERICANS. PREVIOUS RESEARCH ESTABLISHED ALTERED EPIGENETIC SIGNATURES IN SLE PATIENTS COMPARED TO CONTROLS. HOWEVER, THE CONTRIBUTION OF ABERRANT DNA METHYLATION (DNAM) TO THE RISK OF SLE BY ANCESTRY AND DIFFERENCES AMONG PATIENTS WITH SLE-ASSOCIATED LUPUS NEPHRITIS (LN) HAS NOT BEEN WELL DESCRIBED. WE EVALUATED THE DNA METHYLOMES OF 87 INDIVIDUALS INCLUDING 41 SLE PATIENTS, WITH AND WITHOUT LN, AND 46 CONTROLS ENROLLED IN AN ANCESTRY DIVERSE, WELL-CHARACTERIZED COHORT STUDY OF ESTABLISHED SLE (41 SLE PATIENTS [20 SLE-LN+, 21 SLE-LN-] AND 46 SEX-, RACE- AND AGE-MATCHED CONTROLS; 55% AFRICAN AMERICAN, 45% EUROPEAN AMERICAN). PARTICIPANTS WERE GENOTYPED USING THE INFINIUM GLOBAL DIVERSITY ARRAY (GDA), AND GENETIC ANCESTRY WAS ESTIMATED USING PRINCIPAL COMPONENTS. GENOME-WIDE DNA METHYLATION WAS INITIALLY MEASURED USING THE ILLUMINA METHYLATIONEPIC 850K BEADCHIP ARRAY FOLLOWED BY METHYLATION-SPECIFIC QPCR TO VALIDATE THE METHYLATION STATUS AT PUTATIVE LOCI. DIFFERENTIALLY METHYLATED POSITIONS (DMP) WERE IDENTIFIED USING A CASE-CONTROL APPROACH ADJUSTED FOR ANCESTRY. WE IDENTIFIED A TOTAL OF 51 DMPS IN CPGS AMONG SLE PATIENTS COMPARED TO CONTROLS. GENES PROXIMAL TO THESE CPGS WERE HIGHLY ENRICHED FOR INVOLVEMENT IN TYPE I INTERFERON SIGNALING. DMPS AMONG EUROPEAN AMERICAN SLE PATIENTS WITH LN WERE SIMILAR TO AFRICAN AMERICAN SLE PATIENTS WITH AND WITHOUT LN. OUR FINDINGS WERE VALIDATED USING AN ORTHOGONAL, METHYL-SPECIFIC PCR FOR THREE SLE-ASSOCIATED DMPS NEAR OR PROXIMAL TO MX1, USP18, AND IFITM1. OUR STUDY CONFIRMS PREVIOUS REPORTS THAT DMPS IN CPGS ASSOCIATED WITH SLE ARE ENRICHED IN TYPE I INTERFERON GENES. HOWEVER, WE SHOW THAT EUROPEAN AMERICAN SLE PATIENTS WITH LN HAVE SIMILAR DNAM PATTERNS TO AFRICAN AMERICAN SLE PATIENTS IRRESPECTIVE OF LN, SUGGESTING THAT ABERRANT DNAM ALTERS ACTIVITY OF TYPE I INTERFERON PATHWAY LEADING TO MORE SEVERE DISEASE INDEPENDENT OF ANCESTRY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6   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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
7   173  30 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  1956  33 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	

9  3063  47 GENOME-WIDE DNA METHYLATION AND LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IN KOREAN ADULTS. BACKGROUND: AMBIENT AIR POLLUTION IS ASSOCIATED WITH NUMEROUS ADVERSE HEALTH OUTCOMES, BUT THE UNDERLYING MECHANISMS ARE NOT WELL UNDERSTOOD; EPIGENETIC EFFECTS INCLUDING ALTERED DNA METHYLATION COULD PLAY A ROLE. TO EVALUATE ASSOCIATIONS OF LONG-TERM AIR POLLUTION EXPOSURE WITH DNA METHYLATION IN BLOOD, WE CONDUCTED AN EPIGENOME-WIDE ASSOCIATION STUDY IN A KOREAN CHRONIC OBSTRUCTIVE PULMONARY DISEASE COHORT (N = 100 INCLUDING 60 CASES) USING ILLUMINA'S INFINIUM HUMANMETHYLATION450K BEADCHIP. ANNUAL AVERAGE CONCENTRATIONS OF PARTICULATE MATTER </= 10 MUM IN DIAMETER (PM(10)) AND NITROGEN DIOXIDE (NO(2)) WERE ESTIMATED AT PARTICIPANTS' RESIDENTIAL ADDRESSES USING EXPOSURE PREDICTION MODELS. WE USED ROBUST LINEAR REGRESSION TO IDENTIFY DIFFERENTIALLY METHYLATED PROBES (DMPS) AND TWO DIFFERENT APPROACHES, DMRCATE AND COMB-P, TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS). RESULTS: AFTER MULTIPLE TESTING CORRECTION (FALSE DISCOVERY RATE < 0.05), THERE WERE 12 DMPS AND 27 DMRS ASSOCIATED WITH PM(10) AND 45 DMPS AND 57 DMRS RELATED TO NO(2). DMP CG06992688 (OTUB2) AND SEVERAL DMRS WERE ASSOCIATED WITH BOTH EXPOSURES. ELEVEN DMPS IN RELATION TO NO(2) CONFIRMED PREVIOUS FINDINGS IN EUROPEANS; THE REMAINDER WERE NOVEL. METHYLATION LEVELS OF 39 DMPS WERE ASSOCIATED WITH EXPRESSION LEVELS OF NEARBY GENES IN A SEPARATE DATASET OF 3075 INDIVIDUALS. ENRICHED NETWORKS WERE RELATED TO OUTCOMES ASSOCIATED WITH AIR POLLUTION INCLUDING CARDIOVASCULAR AND RESPIRATORY DISEASES AS WELL AS INFLAMMATORY AND IMMUNE RESPONSES. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE THAT LONG-TERM AMBIENT AIR POLLUTION EXPOSURE IMPACTS DNA METHYLATION. THE DIFFERENTIAL METHYLATION SIGNALS CAN SERVE AS POTENTIAL AIR POLLUTION BIOMARKERS. THESE RESULTS MAY HELP BETTER UNDERSTAND THE INFLUENCES OF AMBIENT AIR POLLUTION ON HUMAN HEALTH.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10  1955  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
11  5395  35 REDUCED EPIGENETIC AGE IN OLDER ADULTS WITH HIGH SENSE OF PURPOSE IN LIFE. PSYCHOSOCIAL RISK FACTORS HAVE BEEN LINKED WITH ACCELERATED EPIGENETIC AGING, BUT LITTLE IS KNOWN ABOUT WHETHER PSYCHOSOCIAL RESILIENCE FACTORS (EG, SENSE OF PURPOSE IN LIFE) MIGHT REDUCE EPIGENETIC AGE ACCELERATION. IN THIS STUDY, WE TESTED IF OLDER ADULTS WHO EXPERIENCE HIGH LEVELS OF PURPOSE MIGHT SHOW REDUCED EPIGENETIC AGE ACCELERATION. WE EVALUATED THE RELATIONSHIP BETWEEN PURPOSE AND EPIGENETIC AGE ACCELERATION AS MEASURED BY 13 DNA METHYLATION (DNAM) "EPIGENETIC CLOCKS" ASSESSED IN 1 572 OLDER ADULTS FROM THE HEALTH AND RETIREMENT STUDY (MEAN AGE 70 YEARS). WE QUANTIFIED THE TOTAL ASSOCIATION BETWEEN PURPOSE AND DNAM AGE ACCELERATION AS WELL AS THE EXTENT TO WHICH THAT TOTAL ASSOCIATION MIGHT BE ATTRIBUTABLE TO DEMOGRAPHIC FACTORS, CHRONIC DISEASE, OTHER PSYCHOSOCIAL VARIABLES (EG, POSITIVE AFFECT), AND HEALTH-RELATED BEHAVIORS (HEAVY DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BODY MASS INDEX [BMI]). PURPOSE IN LIFE WAS ASSOCIATED WITH REDUCED EPIGENETIC AGE ACCELERATION ACROSS 4 "SECOND-GENERATION" DNAM CLOCKS OPTIMIZED FOR PREDICTING HEALTH AND LONGEVITY (FALSE DISCOVERY RATE [FDR] Q < 0.0001: PHENOAGE, GRIMAGE, ZHANG EPIGENETIC MORTALITY INDEX; FDR Q < 0.05: DUNEDINPOAM). THESE ASSOCIATIONS WERE INDEPENDENT OF DEMOGRAPHIC AND PSYCHOSOCIAL FACTORS, BUT SUBSTANTIALLY ATTENUATED AFTER ADJUSTING FOR HEALTH-RELATED BEHAVIORS (DRINKING, SMOKING, PHYSICAL ACTIVITY, AND BMI). PURPOSE SHOWED NO SIGNIFICANT ASSOCIATION WITH 9 "FIRST-GENERATION" DNAM EPIGENETIC CLOCKS TRAINED ON CHRONOLOGICAL AGE. OLDER ADULTS WITH GREATER PURPOSE IN LIFE SHOW "YOUNGER" DNAM EPIGENETIC AGE ACCELERATION. THESE RESULTS MAY BE DUE IN PART TO ASSOCIATED DIFFERENCES IN HEALTH-RELATED BEHAVIORS. RESULTS SUGGEST NEW OPPORTUNITIES TO REDUCE BIOLOGICAL AGE ACCELERATION BY ENHANCING PURPOSE AND ITS BEHAVIORAL SEQUELAE IN LATE ADULTHOOD.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12  6460  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13   972  39 CHRONIC OBSTRUCTIVE PULMONARY DISEASE IS ASSOCIATED WITH EPIGENOME-WIDE DIFFERENTIAL METHYLATION IN BAL LUNG CELLS. DNA METHYLATION PATTERNS IN CHRONIC PULMONARY OBSTRUCTIVE DISEASE (COPD) MIGHT OFFER NEW INSIGHTS INTO DISEASE PATHOGENESIS. TO ASSESS METHYLATION PROFILES IN THE MAIN COPD TARGET ORGAN, WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY ON BAL CELLS. BRONCHOSCOPIES WERE PERFORMED IN 18 SUBJECTS WITH COPD AND 15 CONTROL SUBJECTS (EX- AND CURRENT SMOKERS). DNA METHYLATION WAS MEASURED USING THE ILLUMINA METHYLATIONEPIC BEADCHIP KIT, COVERING MORE THAN 850,000 CPGS. DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE EXAMINED FOR 1) ENRICHMENT IN PATHWAYS AND FUNCTIONAL GENE RELATIONSHIPS USING THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES AND GENE ONTOLOGY, 2) ACCELERATED AGING USING HORVATH'S EPIGENETIC CLOCK, 3) CORRELATION WITH GENE EXPRESSION, AND 4) COLOCALIZATION WITH GENETIC VARIATION. WE FOUND 1,155 BONFERRONI-SIGNIFICANT (P < 6.74 X 10(-8)) DMPS ASSOCIATED WITH COPD, MANY WITH LARGE EFFECT SIZES. FUNCTIONAL ANALYSIS IDENTIFIED BIOLOGICALLY PLAUSIBLE PATHWAYS AND GENE RELATIONSHIPS, INCLUDING ENRICHMENT FOR TRANSCRIPTION FACTOR ACTIVITY. STRONG CORRELATION WAS FOUND BETWEEN DNA METHYLATION AND CHRONOLOGICAL AGE BUT NOT BETWEEN COPD AND ACCELERATED AGING. FOR 79 UNIQUE DMPS, DNA METHYLATION CORRELATED SIGNIFICANTLY WITH GENE EXPRESSION IN BAL CELLS. THIRTY-NINE PERCENT OF DMPS WERE COLOCALIZED WITH COPD-ASSOCIATED SNPS. TO THE BEST OF OUR KNOWLEDGE, THIS IS THE FIRST EPIGENOME-WIDE ASSOCIATION STUDY OF COPD ON BAL CELLS, AND OUR ANALYSES REVEALED MANY DIFFERENTIAL METHYLATION SITES. INTEGRATION WITH MRNA DATA SHOWED A STRONG FUNCTIONAL READOUT FOR RELEVANT GENES, IDENTIFYING SITES WHERE DNA METHYLATION MIGHT DIRECTLY AFFECT EXPRESSION. ALMOST HALF OF DMPS WERE COLOCATED WITH SNPS IDENTIFIED IN PREVIOUS GENOME-WIDE ASSOCIATION STUDIES OF COPD, SUGGESTING JOINT GENETIC AND EPIGENETIC PATHWAYS RELATED TO DISEASE.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
14  2150  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
15  3637  26 INCREASED EPIGENETIC AGE ACCELERATION IN THE HIDRADENITIS SUPPURATIVA SKIN. EPIGENETIC (OR DNA METHYLATION) AGE IS CALCULATED BASED ON METHYLATION OF CERTAIN CYTOSINE-GUANINE (CPG) REPEATS, AND IT CAN ACCURATELY ESTIMATE ONE'S CHRONOLOGIC AGE. IMPORTANTLY, EPIGENETIC AGE ACCELERATION (EAA) IS HIGHLY PREDICTIVE OF AGE-ASSOCIATED MORBIDITY AND ALL-CAUSE MORTALITY. HIDRADENITIS SUPPURATIVA (HS) IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH SIGNIFICANT SYSTEMIC DISEASE BURDEN. HERE, WE PERFORMED A PILOT STUDY TO CALCULATE EAA FROM FORMALIN-FIXED PARAFFIN-EMBEDDED SKIN SAMPLES USING ILLUMINA INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS. OUR RESULTS DEMONSTRATED NO SIGNIFICANT DIFFERENCE IN INTRINSIC EAA AMONG HS COMPARED TO CONTROLS (- 1.00 YEARS, P-VALUE = 0.52), SIGNIFICANT INCREASES IN BOTH EXTRINSIC EAA (13.72 YEARS, P-VALUE < 0.001) AND PHENOAGE ACCELERATION (7.72 YEARS, P-VALUE = 0.003), AND A SIGNIFICANT DECREASE IN GRIMAGE ACCELERATION (- 5.14 YEARS, P-VALUE < 0.001). OUR FINDINGS SUGGEST THAT THE ACCELERATION OF EPIGENETIC AGE IN THE HS SKIN MAY BE ASSOCIATED WITH EXTRINSIC IMMUNE-RELATED CHANGES AND CAN POTENTIALLY SERVE AS A BIOMARKER OF THE PRESENT AND/OR FUTURE DISEASE BURDEN IN HS PATIENTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
16  4249  37 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17  3557  45 IMPACT OF BMI AND WAIST CIRCUMFERENCE ON EPIGENOME-WIDE DNA METHYLATION AND IDENTIFICATION OF EPIGENETIC BIOMARKERS IN BLOOD: AN EWAS IN MULTI-ETHNIC ASIAN INDIVIDUALS. BACKGROUND: THE PREVALENCE OF OBESITY AND ITS RELATED CHRONIC DISEASES HAVE BEEN INCREASING ESPECIALLY IN ASIAN COUNTRIES. OBESITY-RELATED GENETIC VARIANTS HAVE BEEN IDENTIFIED, BUT THESE EXPLAIN LITTLE OF THE VARIATION IN BMI. RECENT STUDIES REPORTED ASSOCIATIONS BETWEEN DNA METHYLATION AND OBESITY, MOSTLY IN NON-ASIAN POPULATIONS. METHODS: WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY (EWAS) ON GENERAL ADIPOSITY (BODY MASS INDEX, BMI) AND ABDOMINAL ADIPOSITY (WAIST CIRCUMFERENCE, WC) IN 409 MULTI-ETHNIC ASIAN INDIVIDUALS AND REPLICATED BMI AND WAIST-ASSOCIATED DNA METHYLATION CPGS IDENTIFIED IN OTHER POPULATIONS. THE CROSS-LAGGED PANEL MODEL AND MENDELIAN RANDOMIZATION WERE USED TO ASSESS THE TEMPORAL RELATIONSHIP BETWEEN METHYLATION AND BMI. THE TEMPORAL RELATIONSHIP BETWEEN THE IDENTIFIED CPGS AND INFLAMMATION AND METABOLIC MARKERS WAS ALSO EXAMINED. RESULTS: EWAS IDENTIFIED 116 DNA METHYLATION CPGS INDEPENDENTLY ASSOCIATED WITH BMI AND EIGHT INDEPENDENTLY ASSOCIATED WITH WC AT FALSE DISCOVERY RATE P(FDR) < 0.05 IN 409 ASIAN SAMPLES. WE REPLICATED 110 BMI-ASSOCIATED CPGS PREVIOUSLY REPORTED IN EUROPEANS AND IDENTIFIED SIX NOVEL BMI-ASSOCIATED CPGS AND TWO NOVEL WC-ASSOCIATED CPGS. WE OBSERVED HIGH CONSISTENCY IN ASSOCIATION DIRECTION OF EFFECT COMPARED TO STUDIES IN OTHER POPULATIONS. CAUSAL RELATIONSHIP ANALYSES INDICATED THAT BMI WAS MORE LIKELY TO BE THE CAUSE OF DNA METHYLATION ALTERATION, RATHER THAN THE CONSEQUENCE. THE CAUSAL ANALYSES USING BMI-ASSOCIATED METHYLATION RISK SCORE ALSO SUGGESTED THAT HIGHER LEVELS OF THE INFLAMMATION MARKER IL-6 WERE LIKELY THE CONSEQUENCE OF METHYLATION CHANGE. CONCLUSION: OUR STUDY PROVIDES EVIDENCE OF AN ASSOCIATION BETWEEN OBESITY AND DNA METHYLATION IN MULTI-ETHNIC ASIANS AND SUGGESTS THAT OBESITY CAN DRIVE METHYLATION CHANGE. THE RESULTS ALSO SUGGESTED POSSIBLE CAUSAL INFLUENCE THAT OBESITY-RELATED METHYLATION CHANGES MIGHT HAVE ON INFLAMMATION AND LIPOPROTEIN LEVELS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
18  1550  33 DNA METHYLATION IS ASSOCIATED WITH AIRFLOW OBSTRUCTION IN PATIENTS LIVING WITH HIV. INTRODUCTION: PEOPLE LIVING WITH HIV (PLWH) SUFFER FROM AGE-RELATED COMORBIDITIES SUCH AS COPD. THE PROCESSES RESPONSIBLE FOR REDUCED LUNG FUNCTION IN PLWH ARE LARGELY UNKNOWN. WE PERFORMED AN EPIGENOME-WIDE ASSOCIATION STUDY TO INVESTIGATE WHETHER BLOOD DNA METHYLATION IS ASSOCIATED WITH IMPAIRED LUNG FUNCTION IN PLWH. METHODS: USING BLOOD DNA METHYLATION PROFILES FROM 161 PLWH, WE TESTED THE EFFECT OF METHYLATION ON FEV(1), FEV(1)/FVC RATIO AND FEV(1) DECLINE OVER A MEDIAN OF 5 YEARS. WE EVALUATED THE GLOBAL METHYLATION OF PLWH WITH AIRFLOW OBSTRUCTION BY TESTING THE DIFFERENTIAL METHYLATION OF TRANSPOSABLE ELEMENTS ALU AND LINE-1, A WELL-DESCRIBED MARKER OF EPIGENETIC AGEING. RESULTS: AIRFLOW OBSTRUCTION AS DEFINED BY A FEV(1)/FVC<0.70 WAS ASSOCIATED WITH 1393 DIFFERENTIALLY METHYLATED POSITIONS (DMPS), WHILE 4676 WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION BASED ON THE FEV(1)/FVC<LOWER LIMIT OF NORMAL. THESE DMPS WERE ENRICHED FOR BIOLOGICAL PATHWAYS ASSOCIATED WITH CHRONIC VIRAL INFECTIONS. THE AIRFLOW OBSTRUCTION GROUP WAS GLOBALLY HYPOMETHYLATED COMPARED WITH THOSE WITHOUT AIRFLOW OBSTRUCTION. 103 AND 7112 DMPS WERE ASSOCIATED WITH FEV(1) AND FEV(1)/FVC, RESPECTIVELY. NO POSITIONS WERE ASSOCIATED WITH FEV(1) DECLINE. CONCLUSION: A LARGE NUMBER OF DMPS WERE ASSOCIATED WITH AIRFLOW OBSTRUCTION AND LUNG FUNCTION IN A UNIQUE COHORT OF PLWH. AIRFLOW OBSTRUCTION IN EVEN RELATIVELY YOUNG PLWH IS ASSOCIATED WITH GLOBAL HYPOMETHYLATION, SUGGESTING ADVANCED EPIGENETIC AGEING COMPARED WITH THOSE WITH NORMAL LUNG FUNCTION. THE DISTURBANCE OF THE EPIGENETIC REGULATION OF KEY GENES NOT PREVIOUSLY IDENTIFIED IN NON-HIV COPD COHORTS COULD EXPLAIN THE UNIQUE RISK OF COPD IN PLWH.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19  4252  42 METHYLOME CHANGES ASSOCIATED WITH FUNCTIONAL MOVEMENT/CONVERSION DISORDER: INFLUENCE OF BIOLOGICAL SEX AND CHILDHOOD ABUSE EXPOSURE. EPIGENETIC CHANGES, SUCH AS DNA METHYLATION (DNAM), MAY REPRESENT AN IMPORTANT MECHANISM IMPLICATED IN THE ETIOPATHOGENESIS OF FUNCTIONAL MOVEMENT/CONVERSION DISORDER (FMD). HERE, WE AIMED TO IDENTIFY METHYLOMIC VARIATIONS IN A CASE-CONTROL COHORT OF FMD AND TO UNCOVER SPECIFIC EPIGENETIC SIGNATURES ASSOCIATED WITH FEMALE SEX AND CHILDHOOD ABUSE, TWO KEY RISK FACTORS FOR FMD AND OTHER FUNCTIONAL NEUROLOGICAL DISORDERS. GENOME-WIDE DNAM ANALYSIS WAS PERFORMED FROM PERIPHERAL BLOOD IN 57 PATIENTS WITH FMD AND 47 HEALTHY CONTROLS WITH AND WITHOUT CHILDHOOD ABUSE. USING PRINCIPAL COMPONENT ANALYSIS, WE EXAMINED THE ASSOCIATION OF PRINCIPAL COMPONENTS WITH FMD STATUS IN ABUSED AND NON-ABUSED INDIVIDUALS, IN THE ENTIRE STUDY SAMPLE AND IN FEMALE SUBJECTS ONLY. NEXT, WE USED ENRICHMENT PATHWAY ANALYSIS TO INVESTIGATE THE BIOLOGICAL SIGNIFICANCE OF DNAM CHANGES AND EXPLORED DIFFERENCES IN METHYLATION LEVELS OF GENES ANNOTATED TO THE TOP ENRICHED BIOLOGICAL PATHWAYS SHARED ACROSS COMPARISONS. WE FOUND THAT FMD WAS ASSOCIATED WITH DNAM VARIATION ACROSS THE GENOME AND IDENTIFIED A COMMON EPIGENETIC 'SIGNATURE' ENRICHED FOR BIOLOGICAL PATHWAYS IMPLICATED IN CHRONIC STRESS AND CHRONIC PAIN. HOWEVER, METHYLATION LEVELS OF GENES INCLUDED IN THE TOP TWO SHARED PATHWAYS HARDLY OVERLAPPED, SUGGESTING THAT TRANSCRIPTIONAL PROFILES MAY DIFFER AS A FUNCTION OF CHILDHOOD ABUSE EXPOSURE AND SEX AMONG SUBJECTS WITH FMD. THIS STUDY IS UNIQUE IN PROVIDING GENOME-WIDE EVIDENCE OF DNAM CHANGES IN FMD AND IN INDICATING A POTENTIAL MECHANISM LINKING CHILDHOOD ABUSE EXPOSURE AND FEMALE SEX TO DIFFERENCES IN FMD PATHOPHYSIOLOGY. FUTURE STUDIES ARE NEEDED TO REPLICATE OUR FINDINGS IN INDEPENDENT COHORTS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
20  4256  39 METHYLOMIC MARKERS OF PERSISTENT CHILDHOOD ASTHMA: A LONGITUDINAL STUDY OF ASTHMA-DISCORDANT MONOZYGOTIC TWINS. BACKGROUND: ASTHMA IS THE MOST COMMON CHRONIC INFLAMMATORY DISORDER IN CHILDREN. THE AETIOLOGY OF ASTHMA PATHOLOGY IS COMPLEX AND HIGHLY HETEROGENEOUS, INVOLVING THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS THAT IS HYPOTHESIZED TO INVOLVE EPIGENETIC PROCESSES. OUR AIM WAS TO EXPLORE WHETHER METHYLOMIC VARIATION IN EARLY CHILDHOOD IS ASSOCIATED WITH DISCORDANCE FOR ASTHMA SYMPTOMS WITHIN MONOZYGOTIC (MZ) TWIN PAIRS RECRUITED FROM THE ENVIRONMENTAL RISK (E-RISK) LONGITUDINAL TWIN STUDY. WE ALSO AIMED TO IDENTIFY DIFFERENCES IN DNA METHYLATION THAT ARE ASSOCIATED WITH ASTHMA THAT DEVELOPS IN CHILDHOOD AND PERSISTS INTO EARLY ADULTHOOD AS THESE MAY REPRESENT USEFUL PROGNOSTIC BIOMARKERS. RESULTS: WE EXAMINED GENOME-WIDE PATTERNS OF DNA METHYLATION IN BUCCAL CELL SAMPLES COLLECTED FROM 37 MZ TWIN PAIRS DISCORDANT FOR ASTHMA AT AGE 10. DNA METHYLATION AT INDIVIDUAL CPG SITES DEMONSTRATED SIGNIFICANT VARIABILITY WITHIN DISCORDANT MZ TWIN PAIRS WITH THE TOP-RANKED NOMINALLY SIGNIFICANT DIFFERENTIALLY METHYLATED POSITION (DMP) LOCATED IN THE HGSNAT GENE. WE STRATIFIED OUR ANALYSIS BY ASSESSING DNA METHYLATION DIFFERENCES IN A SUB-GROUP OF MZ TWIN PAIRS WHO REMAINED PERSISTENTLY DISCORDANT FOR ASTHMA AT AGE 18. THE TOP-RANKED NOMINALLY SIGNIFICANT DMP ASSOCIATED WITH PERSISTING ASTHMA IS LOCATED IN THE VICINITY OF THE HLX GENE, WHICH HAS BEEN PREVIOUSLY IMPLICATED IN CHILDHOOD ASTHMA. CONCLUSIONS: WE IDENTIFIED DNA METHYLATION DIFFERENCES ASSOCIATED WITH CHILDHOOD ASTHMA IN PERIPHERAL DNA SAMPLES FROM DISCORDANT MZ TWIN PAIRS. OUR DATA SUGGEST THAT DIFFERENCES IN DNA METHYLATION ASSOCIATED WITH CHILDHOOD ASTHMA WHICH PERSISTS INTO EARLY ADULTHOOD ARE DISTINCT FROM THOSE ASSOCIATED WITH ASTHMA WHICH REMITS.	2015